Medical Microbiology and Immunology for DentistryLibrary of Congress Cataloging-in-Publication Data Düzgüneş, Nejat, author. Medical microbiology and immunology for dentistry

Medical Microbiology and Immunology for Dentistry

Professor of Biomedical Sciences

Arthur A. Dugoni School of DentistryUniversity of the Pacific

San Francisco, California

Medical Microbiology and Immunology for

DentistryNejat DüzgüneŞ, phd

Quintessence Publishing Co, IncChicago, Berlin, Tokyo, London, Paris, Milan, Barcelona, Istanbul, Moscow, New Delhi, Prague, São Paulo, Seoul, and Warsaw

Library of Congress Cataloging-in-Publication Data

Düzgüneş, Nejat, author. Medical microbiology and immunology for dentistry / Nejat Düzgüneş. p. ; cm. Includes bibliographical references and index. ISBN 978-0-86715-647-8 I. Title. [DNLM: 1. Stomatognathic Diseases--immunology. 2. StomatognathicDiseases--microbiology. 3. Dentistry--methods. WU 140] QR47 617.5’22--dc23 2015031156

© 2016 Quintessence Publishing Co, Inc

Quintessence Publishing Co, Inc4350 Chandler DriveHanover Park, IL 60133www.quintpub.com

5 4 3 2 1

All rights reserved. This book or any part thereof may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise, without prior written permission of the publisher.

Editor: Leah HuffmanEditorial Intern: Cassidy OlsonDesign: Ted PeredaProduction: Angelina Sanchez

Printed in the USA

Dedication vii Preface ix Chapter Opener Image Credits x

Immunity 1 The Immune System 1 2 Antibodies and Complement 8 3 Cellular Immunity 15 4 The Immune Response to Pathogens

and Immunopathogenesis 23 5 Vaccines 36

Bacteria 6 Bacterial Structure, Metabolism, and Genetics 39 7 Bacterial Pathogenesis 55 8 Antibacterial Chemotherapy 60 9 Sterilization, Disinfection, and Antisepsis 7010 Microbial Identification and Molecular Diagnostics 7511 Staphylococcus 8112 Streptococcus 8513 Miscellaneous Gram-Positive Bacilli 9114 Clostridium 9815 Bordetella, Legionella, and Miscellaneous

Gram-Negative Bacilli 10316 Neisseria and Neisseriaceae 11117 Spirochetes 11518 Enterobacteria, Campylobacter, and Helicobacter 12019 Mycoplasma and Ureaplasma 13120 Mycobacteria 134

Contents

21 Chlamydia, Rickettsia, and Related Bacteria 14022 Vibrio, Pseudomonas, and Related Bacteria 14623 Oral Microflora and Caries 15124 Periodontal and Endodontic Infections 160

Fungi25 Fungal Structure, Replication, and Pathogenesis 16826 Fungal Diseases 17327 Antifungal Chemotherapy 183

Viruses28 Virus Structure, Replication, and Pathogenesis 18629 Antiviral Chemotherapy 19530 Naked Capsid DNA Viruses 20131 Human Immunodeficiency Virus and Other Retroviruses 20832 Hepatitis Viruses 21733 Herpesviruses 22634 Orthomyxoviruses: Influenza Virus 23435 Paramyxoviruses: Measles, Mumps, and Respiratory

Syncytial Viruses 23936 Picornaviruses 24437 Arboviruses 24938 Rhabdoviruses, Poxviruses, and Coronaviruses 25439 Rubella Virus, Filoviruses, Reoviruses, and Noroviruses 259

Prions and Parasites40 Prions 26341 Pathogenic Parasites 267

Appendix: Cases in Medical Microbiology 273 Index 279

vii

To Maxine, Avery, and Dianafor all the wonderful experiences you have brought into my life, for your love,

and for asking many, many questionsand

to the memories of my cousin Professor Ferruh Ertürk and my aunt Sevim Uygurer, who were always there for me

Dedication

ix

This book is the outcome of my teaching the Microbiolo-gy course at the University of the Pacific Arthur A. Dugo-ni School of Dentistry in San Francisco. In my 25 years of teaching this course, I have relied on medical microbiology texts that cover all areas quite extensively, are written by numerous experts, and are excellent reference books; how-ever, all of them are too detailed for instructional purposes. Therefore, I decided to write this textbook and tailor the information specifically for dental students. Practicing den-tists and other dental professionals, as well as students in other health professions, may also benefit from the didac-tic, succinct, yet thorough coverage of the field.

Dentists are “physicians of the mouth” and thus need to have a basic understanding of medical microbiology and immunology. Most of the conditions treated by general dentists and specialists are the result of bacterial infec-tion, including caries, periodontal disease, and endodontic infections. The response of the immune system to these infections may also contribute to their pathology. Caries and periodontal disease are initiated by changes in the oral bacterial ecosystem, and understanding the microbiology of these diseases is essential for their treatment.

Dentists need to be able to diagnose oral infections, such as denture stomatitis caused by Candida species, as well as obvious systemic medical conditions whose medical implications may be lost on patients. They should also un-derstand the nature and complications of any infectious dis-ease their patients may have, including HIV/AIDS, hepatitis, tuberculosis, and emerging diseases such as SARS and MERS. Members of the dental care team as well as other patients must be protected from these infectious diseases, and dentists should be able to answer questions, address patient concerns, and allay their fears about cross infection. Finally, dentists are health care providers who can influence decisions on public health issues such as the importance of vaccinations, fluoridation of water sources, and funding for biomedical research by the National Institutes of Health. Therefore, understanding microbiology and immunology and their roles in the initiation, progression, and treatment of disease is pertinent for any practicing dentist.

The book starts with chapters on immunology and pro-ceeds with chapters on bacterial structure, genetics, and

diseases, with intervening chapters on microbial identifica-tion and control as well as antimicrobial chemotherapy. Oral microbiology is covered in two major chapters, and these are followed by a discussion of fungal structure, pathogen-esis and diseases, and antifungal chemotherapy. The book continues with chapters on virus structure, antiviral che-motherapy, and viral diseases, including HIV, hepatitis, and influenza as well as viruses that are much less prevalent. Prions and parasitic diseases conclude the didactic part of the book. The appendix includes cases in medical microbi-ology that allow readers the opportunity to integrate their knowledge of the field to diagnose cases.

The chapters also highlight some of the exciting discov-eries in microbiology, immunology, and molecular biology and pose research questions to stimulate the reader to further inquiry and thinking. Each chapter concludes with take-home messages that will be useful for reviewing the material for an examination. The reader is encouraged to consult some of the references in the bibliography for more detailed information on a given subject. Microbiology af-fects every aspect of dental practice, so it is paramount that today’s students understand the processes at work in the mouth as well as in the rest of the body.

Acknowledgments

I have benefited greatly from the contributions to the Mi-crobiology course by past and present colleagues Dr Ken Snowdowne, Dr Krystyna Konopka, Dr Taka Chino, Dr Matt Milnes, and Dr Ove Peters.

I am grateful to the staff at Quintessence, particularly Lisa Bywaters for enthusiastically supporting the project and moving it along and Leah Huffman for being a very helpful and competent editor. Jeanne Robertson also did a superb job with the illustrations.

I am fortunate to have a supportive and loving family who are all interested in science and who made sure I was work-ing on the book when I had other obligations.

Preface

#

x

Chapter Opener Image Credits

1 SEM of a neutrophil engulfing Bacillus anthracis. (Courtesy of PLoS Pathogens and Volker Brinkman.)

2

SEM of HeLa cells stained with anti- nuclear pore complex antibody and chicken anti-vimentin. (Courtesy of antibodies-online.com.)

3 SEM of a cytotoxic T cell and a somatic cell. (Courtesy of G. Wanner.)

4 Artist rendering of the immune system from “The Body on Fire.” (Courtesy of J. Flaherty.)

5 Photograph of a scientist filling a syringe with a rabies vaccine. (PHIL image 8326, courtesy of the CDC.)

6SEM of rod-shaped Mycobacterium tubercu-losis. (PHIL image 18138, courtesy of the NIAID.)

7 SEM of spherical MRSA interacting with a white blood cell. (PHIL image 18168, courtesy of the NIAID.)

8 Penicillin inhibiting growth of Staphy-lococcus aureus. (Courtesy of Christine Case, Skyline College.)

9 Chemical structure of chlorhexidine.

10

Petri dish with Streptococcus pyo-genes–inoculated trypticase soy agar. (PHIL image 8170, courtesy of Dr Richard Facklam.)

11

SEM of spheroid-shaped MRSA en-meshed within the pseudopodia of a hu-man white blood cell. (PHIL image 18125, courtesy of the NIAID.)

12 Streptococcus. (Courtesy of Tina Carval-ho, University of Hawaii at Manoa.)

13SEM of spores from the Sterne strain of Bacillus anthracis. (PHIL image 10122, courtesy of Janice Haney Carr.)

14 Illustration of Clostridium difficile. (PHIL image 16786, courtesy of Melissa Brower.)

15 SEM of Legionella pneumophila. (PHIL im-age 11147, courtesy of Janice Haney Carr.)

16 TEM of a diplococcal pair of Neisseria gonorrhoeae. (PHIL image 14493, courte-sy of Dr Wiesner at the CDC.)

17Photomicrograph of Treponema pallidum. (PHIL image 14969, courtesy of Susan Lindsley.)

18 SEM of a human white blood cell inter-acting with Klebsiella pneumoniae. (PHIL image 18170, courtesy of the NIAID.)

19 SEM of Mycoplasma pneumoniae on the surface of a cell. (Courtesy of Dr David M. Phillips.)

20 SEM of Mycobacterium chelonae. (PHIL image 227, courtesy of Janice Haney Carr.)

21

SEM of Coxiella burnetii undergoing rap-id replication in an opened vacuole of a dry-fractured Vero cell. (PHIL image 18164, courtesy of the NIAID.)

22 SEM of Pseudomonas aeruginosa. (PHIL image 10043, courtesy of Janice Haney Carr.)

23Photomicrograph of Streptococcus mu-tans with Gram stain. (PHIL image 1070, courtesy of Dr Richard Facklam.)

24Porphyromonas gingivalis. (Courtesy of Tsute Chen, PhD.)

xi

Chapter Opener Image Credits

25 SEM close-up of an asexual Aspergillus species fungal fruiting body. (PHIL image 13367, courtesy of Janice Haney Carr.)

26Spherule of a Coccidioides fungal organism. (PHIL image 14499, courtesy of the CDC.)

27Susceptibility testing to the antifungal amphotericin B. (PHIL image 15147, courtesy of James Gathany.)

28TEM of spherical MERS coronavirus virions. (PHIL image 18113, courtesy of the NIAID.)

29 An HIV-1 protease inhibitor interacting with a mutant protease. (Courtesy of Nature.com and the Protein Data Bank.)

30A simplified 3D-generated structure of adenovirus. (Courtesy of Thomas Splettstoesser.)

31Electron micrograph of monocytic THP-1 cells infected with HIV-1 cells. (Reprinted with permission from Konopka et al.*)

32 TEM showing numerous hepatitis virions of an unknown strain. (PHIL image 8153, courtesy of E. H. Cook, Jr.)

33TEM depicting cytomegalovirus virions. (PHIL image 14429, courtesy of the CDC.)

34

TEM depicting a strain of swine flu (A/New Jersey/76 [Hsw1N1]) virus in a chick-en egg. (PHIL image 1246, courtesy of Dr E. Palmer and R. E. Bates.)

35 TEM of parainfluenza virus. (PHIL image 236, courtesy of Dr Erskine Palmer.)

36 TEM of poliovirus. (Courtesy of Graham Beards.)

37 Deceased mosquitos about to undergo laboratory testing. (PHIL image 14887, courtesy of James Stewart.)

38

TEM highlighting the particle envelope of a single MERS coronavirus virion through the process of immunolabeling the envelope proteins. (PHIL image 18108, courtesy of the NIAID.)

39

SEM of numerous Ebola virus particles budding from a chronically infected Vero E6 cell. (PHIL image 17768, courtesy of the NIAID.)

40

Photomicrograph of a neural tissue specimen harvested from a scrapie-affected mouse showing the presence of prion protein. (PHIL image 18131, courtesy of the NIAID.)

41 SEM of an in vitro Giardia lamblia culture. (PHIL image 11636, courtesy of Dr Stan Erlandsen.)

CDC, Centers for Disease Control and Prevention; MERS, Middle East respiratory syndrome; MRSA, methicillin-resistant Staphylococcus aureus; NIAID, National Institute of Allergy and Infectious Diseases; PHIL, Public Health Image Library (of the CDC); SEM, scanning electron micrograph; TEM, transmission electron micrograph.

* Konopka K, Pretzer E, Plowman B, Düzgüneş N. Long-term noncytopathic productive infection of the human monocytic leukemia cell line THP-1 by human immunodeficiency virus type 1 (HIV-1IIIB). Virology 1993;193:877–887.

1

1

The ImmuneSystem

The protective responses of the immune system against invading microorganisms consist of natural barriers (eg, skin, mucosa, tears); nonspecific, innate immunity (eg, response of neutrophils and interferons); and antigen-specific immunity (eg, antibodies and cell-mediated immunity). The soluble mediators of the immune re-sponse include cytokines, interferons, and chemokines. All of these components of the immune system work together in harmony, much like a symphony orchestra does.

Organs and Tissues of the Immune SystemThe immune system functions within all the organs and tissues of the body to protect it from invading microorganisms. The main avenues of the immune system, however, are in the lymphatic system, which consists of the primary and secondary lymphoid organs. The primary lymphoid organs are the bone marrow and the thy-mus, where B cells and T cells mature, respectively. Cellular and humoral immune responses take place in the secondary lymphoid organs and tissues (Box 1-1). These include bronchus-associated and urogenital lymphoid tissues, bone marrow, the spleen, mesenteric and other lymph nodes, Peyer’s patches, and Waldeyer’s ring (including tonsils and adenoids).

1 The Immune System

2

Lymph node

Thoracic duct

Left subclavian vein

Postcapillary venule

Distant gut mucosa

Peyer’s patch

Lymphoid follicle

Efferentlymphatic vessel

Afferentlymphatic vessel

B cells

B cells

T cells

T cellsCD4 cells

Antigen-presenting cell

Intestinalepithelial cell

Folliculardendritic cell

M cells

Antigen

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Peyer’s patches are differentiated lymphoid tissues along the intestines that are involved in antigen internal-ization and that facilitate the encounter of the antigen with lymphocytes, macrophages, and dendritic cells (Fig 1-1). The M cells along the intestinal lumen transcytose antigens from the apical to the basolateral side of the cells. B and T lymphocytes that encounter the antigens migrate to the local lymphoid follicle. Follicular dendritic cells in the lym-phoid follicle facilitate the activation of the lymphocytes. Some of the activated lymphocytes enter an afferent lym-phatic vessel and a local lymph node. Antigen-presenting cells (APCs) —such as macrophages, dendritic cells, and B cells—and T cells in the lymph node further activate the lymphocytes. These lymphocytes enter the efferent lym-phatic vessel, the thoracic duct, and peripheral blood. The lymphocytes can then enter distal sites at postcapillary ve-nules.

In the oral cavity, the lymphoid tissues include lingual tonsils, palatine tonsils, and pharyngeal tonsils (also called adenoids).

Lymph nodes consist of the cortex (the outer layer), the paracortex, and the medulla (the inner layer) (Fig 1-2). In the cortex, B cells and macrophages are arranged in clusters called follicles. In the paracortex, dendritic cells present antigens to T cells to initiate the specific immune response. The medulla contains T cells and B cells and antibody- producing plasma cells. Following activation of lymphocytes by microbial antigens, they alter the expression of their re-ceptors for chemokines (chemoattractant cytokines). This results in the migration of T cells and B cells to meet at the edge of the follicles, with helper T (Th) cells interacting with B cells to induce the differentiation of the B cells into antibody- producing cells (plasma cells).

Lymphocytes enter the node from the circulation through postcapillary venules called high endothelial venules. Lym-phocytes and antigens from adjacent tissues or lymph nodes enter the node via the afferent lymphatic vessel. Ac-tivated lymphocytes leave the lymph node via the efferent lymphatic vessels and may enter the circulation and travel to the sites of infection.

Box 1-1Primary and secondary lymphoid organs

B cells and T cells mature in the bone marrow and thymus, respectively. Cellular and humoral immune responses occur in the secondary lymphoid organs.

Primary lymphoid organs• Bone marrow• Thymus

Secondary lymphoid organs and tissues• Waldeyer’s ring (tonsils, adenoids, and lymph nodes)• Bronchus-associated lymphoid tissue• Mesenteric lymph nodes• Other lymph nodes• Peyer’s patches • Bone marrow• Spleen

Fig 1-1 Trafficking of B cells and T cells following activation at the Pey-er’s patch.

What facilitates the localization of B cells in follicles and T cells in the paracortex?

? RESEARCH

Cells of the Immune System

The different types of cells that constitute the immune sys-tem are generated by the differentiation of hematopoietic cells. Self-renewing stem cells differentiate into pluripotent stem cells, which can in turn differentiate into either my-eloid progenitors or lymphoid progenitors (Fig 1-3). The myeloid progenitors then differentiate to produce erythroid colony-forming units (CFUs), megakaryocytes, basophil CFUs, eosinophil CFUs, and granulocyte-monocyte CFUs.

3

Cells of the Immune System

Fig 1-2 Schematic cross section of a lymph node. Note the cortex (which includes the germinal center and follicle), para-cortex, medulla, and the germinal centers. Afferent lymphatic vessel

Engulfed antigenAntigen-presenting cell

Efferent lymphatic vessel

Artery

Vein

Trabecula

Medulla

Follicle(B-cell zone)

Germinal center

Paracortex(T-cell zone)

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Fig 1-3 Differentiation of self-renewing stem cells into the cells of the immune system. CFU, colony-forming unit (to be distinguished from the CFU of bacteria grown on nutrient agar). Myeloid progenitors can also differentiate into megakaryocytes and erthyroid CFUs (not shown). NC, natural cytotoxic (also known as natural killer).

Pluripotentstem cell

Myeloid progenitor

Basophil

Basophil CFUGranulocyte-

monocyte CFU

Dendritic cellNeutrophil Monocyte

Macrophage

Eosinophil

Eosinophil CFU

B lymphocytes T lymphocytes NC cells

Lymphoid progenitor

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1 The Immune System

4

(FcR), respectively. The bacteria are internalized in phago-somes, and the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is activated to produce super-oxide anion, resulting in the consumption of excess oxygen by the cells, a process called the respiratory burst. The superoxide anion can damage bacterial cell membranes.

Macrophages can also bind bacteria via their lipopolysac-charide (LPS) receptors, mannose receptors, and glycan re-ceptors. Macrophages can be activated by receptors on their surface for the cytokines tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ) as well as for pathogen- associated molecular patterns. The receptors for the latter—including lipoarabinomannan (from mycobacte-ria), flagellin (from bacterial flagella), LPS, heat shock pro-tein (Hsp60), CpG DNA (characteristic of bacterial DNA), lipoteichoic acid, and peptidoglycan—are called pattern- recognition receptors or Toll-like receptors (called as such because of their homology to Toll receptors involved in Drosophila development) (Fig 1-5).

Another major role for macrophages is to be a central part of the specific immune responses. Macrophages present antigens on their surface to helper T lymphocytes to help the immune system select the most appropriate T lymphocytes to be stimulated to proliferate in response to a specific antigen. The antigen is presented to the out-side world after it is associated with a major histocom-patibility complex class II (MHC II) molecule embedded in the plasma membrane. Other membrane proteins such as B7 act as co-stimulatory molecules, and leukocyte func-tion antigen-3 (LFA-3) and intercellular adhesion molecule-1 (ICAM-1) facilitate adhesion between the macrophage and the Th cell.

Fig 1-4 Resident macrophages in various tissues.

Capillaryendothelial cell

Circulatingblood monocyte

Sinusoidal spaceepithelial cells

Hepatocytes

Kupffer cellsin the liver

Alveolar macrophagesin the lungs

Type I pneumocyte

Type II pneumocyte

Ependyma

Brain microglial cell

Capillary

Nerve cell

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The erythroid CFUs form erythrocytes, megakaryocytes form platelets, basophil CFUs form basophils, and eosin-ophil CFUs form eosinophils. The granulocyte-monocyte CFUs can differentiate into neutrophils, monocytes, and dendritic cells. Monocytes, in turn, can differentiate into macrophages as well as dendritic cells.

The lymphoid progenitors can differentiate into B lym-phocytes, T lymphocytes, and natural killer cells (the author prefers the term natural cytotoxic cells).

RESEARCH?What makes a myeloid progenitor cell differentiate into a granulocyte-monocyte CFU and not into an erythroid CFU?

Macrophages are phagocytotic cells that are derived via the differentiation of circulating monocytes that have en-tered tissues. They become Kupffer cells in the liver, histio-cytes in connective tissue, dendritic cells in various tissues, microglial cells in neural tissue, alveolar macrophages in the lung, osteoclasts in bone, and sinusoidal lining cells in the spleen (Fig 1-4). Macrophages engulf bacteria, fungi, and viruses in endocytotic vesicles called phagosomes and destroy them following the fusion of the phagosomes with lysosomes. Lysosomes contain numerous enzymes (acid hydrolases) that degrade proteins, nucleic acids, polysac-charides, and lipids at acidic pH. Attachment of bacteria to the macrophage membrane is facilitated by the binding of the complement component C3b or specific antibodies to the bacterial membrane. The macrophage, in turn, binds these molecules via its C3b receptor (CR1) and Fc receptor

5

Cells of the Immune System

Fig 1-5 Pattern-recognition receptors (Toll-like receptors [TLRs]).

LPS (P gingivalis)PeptidoglycanLipoproteinLipoteichoic acid

Hsp60LipopolysaccharideFungal mannansViral envelope proteins Bacterial flagellin

Plasmamembrane

TLR-1 TLR-2

TLR-3TLR-7TLR-8TLR-9

TLR-6 TLR-4 TLR-5

Endosomemembrane

Single-stranded RNAUnmethylated CpG

Adapter proteins are recruited

Protein kinases are activated

Transcription factors are activated

Inflammatory antiviral cytokinesand chemokines are expressed

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Granulocytes consist of neutrophils, basophils, and eo-sinophils. Between 50% and 70% of white blood cells (leu-kocytes) are neutrophils, 1% to 3% are eosinophils, and less than 1% are basophils. During infection, the number of circulating neutrophils increases, a condition termed leukocytosis. Neutrophils are the initial phagocytotic de-fense against bacterial infection. Their primary (azurophilic) granules contain myeloperoxidase, elastase, and cathepsin G. The secondary (specific) granules contain lysozyme and lactoferrin. Neutrophils can migrate from the circulation into tissues by squeezing in between vascular endothelial cells in a process termed diapedesis. They recognize endothelial cells that have been activated by TNF-α and histamine pro-duced as a result of the infection of the tissue. Activation of the endothelial cells involves the expression of ICAM-1 and E-selectin molecules on the cell surface. In response to TNF-α and histamine, neutrophils express integrins, L-selectin, and LFA-1 on their cell membrane. The initial binding of the neutrophil to the endothelial cell is facilitated by its mucin-like cell adhesion molecule (CAM), or selectin ligand, to the E-selectin on the endothelial cell. The chemo-kine/chemoattractant receptor on the neutrophil responds to chemokines like interleukin-8 (IL-8; also termed CXCL8 because it acts as a chemokine) secreted by the endothe-lial cell. This results in the conformational change of the integrin on the neutrophil to a high-affinity state, facilitat-ing strong binding to the integrin ligand on the endothelial cells. This is followed by migration through the endothelium (Fig 1-6).

Eosinophils are involved in defense against parasitic in-fections. Basophils are not phagocytotic but release phar-macologically active molecules.

T lymphocytes are generated from T-cell progenitors that can differentiate into CD4+ Thcells, CD8+ cytotoxic T cells, and CD8 suppressor T cells (CD8+ Treg cells). The CD4+ cells can differentiate further into Th1, Th2, Th3, Th17, and regulato-ry Treg cells. The designation CD refers to cluster of differ-entiation and is used to identify specific molecules on the surface of immune cells that are characteristic of the state of differentiation of the cells. For example, T cells have the CD3 molecule as part of the T-cell receptor complex, the set of molecules that recognize foreign antigens.

T-cell differentiation takes place in the thymus. If a devel-oping T cell reacts with a protein made by its host before it matures, it will die via apoptosis (programmed cell death), thereby eliminating many T cells that have the potential to attack the body.

? RESEARCHHow is the T cell programmed so it “knows” that it should undergo apoptosis when it encounters a “self” antigen while undergoing differentiation?

1 The Immune System

6

Fig 1-6 Leukocyte recruitment to and migration through the endothelium. (Adapted from Abbas et al.)

? RESEARCHHow were Th17 and Treg cells discovered?

Neutrophil

Low-affinityintegrin

High-affinityintegrin

Chemokine receptor

Selectinligand

Integrin ligandSelectin

Chemokines releasedby macrophages

Extravasation(diapedesis)

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In the early 1970s, Ralph Steinman and Zanvil Cohn were studying spleen cells to understand the induc-tion of immune responses in the mouse at Rockefeller University. They knew from previous research that the development of immunity by the spleen required lym-phocytes as well as other cells of uncertain function called accessory cells. Although these cells were ini-tially thought to be macrophages, Steinman and Cohn focused on cells with unusual treelike or “dendritic” shapes and processes. Steinman therefore named them dendritic cells. These cells had little resemblance to the macrophages, lacked a membrane enzyme that was typical of macrophages, detached from culture surfaces, had poor viability, and had a rapid turnover in the spleen. In contrast to macrophages, dendritic cells had few digestive bodies or lysosomes, lacked Fc receptors for particles opsonized with antibodies, and were not highly phagocytotic in vivo and in vitro. The previous experience of Steinman and Cohn with the cell biology of macrophages enabled them to readily identify dendritic cells as a new type of cell with dis-tinct functions in the immune system.

! DISCOVERY

Th1 cells promote local initial defenses and delayed-type hypersensitivity responses (as in the tuberculin skin test for tuberculosis). Th2 cells promote antibody production, whereas Th3 cells facilitate immunoglobulin A (IgA) produc-tion. Th17 cells are involved in inflammation. They produce IL-17, which induces chemokine and cytokine production in other cells, resulting in the recruitment of neutrophils. Their numbers increase in multiple sclerosis, inflammatory bow-el disease, and rheumatoid arthritis. Treg (T-regulator) cells control the immune response.

Lymphocytes differentiate into B cells in the bone mar-row and gut-associated lymphoid tissue. In the antigen- independent phase, progenitor B cells (with the CD45R surface marker) undergo Ig gene rearrangement and se-lection and become mature (but still naïve) B cells with IgM and IgD on their surface. They express MHC II mol-ecules on their surface and thus are also APCs. Following exposure to a particular antigen and to Th cells that have been presented to the antigen by APCs, the naïve B cells become activated to differentiate into plasma cells that secrete antibodies that recognize the antigen (in the pe-ripheral lymphoid tissues) (Fig 1-7). If the naïve B cells do not encounter antigen and Th cells, they undergo apoptosis. Antibody class switching also occurs at this stage, where the plasma cells switch from producing IgM antibodies (the type of antibodies that are produced initially) to producing IgG antibodies. A subset of the B cells differentiate into memory cells that facilitate the anamnestic response (the rapid response upon re-exposure to the antigen).

antibody-dependent cellular cytotoxicity cells by means of the Fc receptors that bind the Fc regions of antibodies that recognize antigens on foreign cells.

The common myeloid progenitor cells can differentiate into Langerhans cells and interstitial dendritic cells. The progenitor cells can also differentiate into monocytes, which in turn differentiate into myeloid dendritic cells. The common lymphoid progenitor can also be transformed into lymphoid dendritic cells. Long ignored, dendritic cells are now recognized as the most potent APC. They are found in very small numbers in blood (less than 0.1% of leuko-cytes). Dendritic cells are also called veiled cells because of their ruffled membrane. Langerhans cells are the dendritic cells in the skin. In draining lymph nodes, dendritic cells become interdigitating cells, carrying antigen to the T-cell regions of the node.

Lymphocyte progenitors can also differentiate into large granular lymphocytes, known as natural killer (NK) cells. Because of the anthropomorphic connotation of violence of the term killer, this monograph introduces the designation natural cytotoxic (NC) cells. These cells can also act as

7

Antigen-independent phase Antigen-dependent phase

Selection

Mature B cell

Antigen

Th cellCD45R

ProgenitorB cell

Bone marrow

No antigen

Apoptosis

Activated B cell

Class switching

Plasma cell

Secretedantibody

Peripherallymphoid tissue

MemoryB cell

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Bibliography

Fig 1-7 Differentiation of B cells. CD, cluster of differentiation; Ag, antigen; Ab, antibody.

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Coico R, Sunshine G. Immunology: A Short Course, ed 6. Hoboken, NJ: John Wiley & Sons, 2009.

Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Immunology, ed 5. New York: WH Freeman and Company, 2003.

• The primary lymphoid organs are the bone marrow and the thymus, where B cells and T cells mature, respectively.• Cellular and humoral immune responses take place in the secondary lymphoid organs and tissues. • T cells and B cells meet in the lymph nodes, where Th cells interact with B cells to induce their differentiation into

antibody-producing plasma cells.• Self-renewing stem cells differentiate into pluripotent stem cells, which can in turn differentiate into either my-

eloid progenitors or lymphoid progenitors.• Macrophages engulf bacteria, fungi, and viruses in endocytotic vesicles called phagosomes and destroy them

following the fusion of the phagosomes with lysosomes. • Macrophages, dendritic cells, and B cells present antigens on their surface to helper T lymphocytes that can rec-

ognize the antigen and proliferate in response to a specific antigen.• Neutrophils are the initial phagocytotic defense against bacterial infection; they can migrate from the circulation

into tissues through endothelial cells via diapedesis. • T-cell progenitors generate T lymphocytes that can differentiate into CD4+ helper cells, CD8+ cytotoxic cells, and

CD8+ suppressor cells. The CD4+ cells can differentiate further into Th1, Th2, Th3, Th17, and regulatory Treg cells. • Progenitor B cells undergo Ig gene rearrangement and selection and become mature (but still naïve) B cells with

specific IgM and IgD on their surface.• Lymphocyte progenitors can also differentiate into large granular lymphocytes, known as natural killer (NK) or

natural cytotoxic (NC) cells.

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, ed 6. Phil-adelphia: Mosby/Elsevier, 2009.

Pier GB, Lyczak JB, Wetzler LM. Immunology, Infection and Immunity. Washington: ASM Press, 2004.

Rockefeller University/International Society for Dendritic Cell and Vaccine Science. Introduction to Dendritic Cells. lab.rockefeller.edu/stein-man/dendritic_intro/discovery. Accessed 14 April 2015.

Roitt I, Brostoff J, Male D. Immunology, ed 5. London: Mosby, 2008.

Take-Home Messages

279

IndexPage numbers followed by “f” indicate

figures; those followed by “t” indicate tables; those followed by “b” indicate boxes

AAbortive poliomyelitis, 246Abscess, 108, 162, 164, 166Accessory cells, 6Accessory gene products, 210Acellular pertussis vaccine, 104Acidogenic, 157Aciduric, 157Acinetobacter, 149f, 149–150Acquired immunodeficiency syndrome. See

also Human immunodeficiency virus.description of, 34, 208epidemiology of, 211–213opportunistic infections associated with,

211bpathogenesis of, 211–213

Acquired pellicle, 29Actinobacillus, 109Actinomyces spp

A gerensceriae, 153A israelii, 153, 166A naeslundii, 153, 156A radicidentis, 153description of, 95–96, 153

Actinomycosis, 95, 166Acute erythematous candidiasis, 178Acute febrile pharyngitis, 202Acute hemorrhagic cystitis, 202Acute infection, 55Acute (localized) inflammation, 23–24Acute respiratory disease, 202Acute-phase response, 24–26, 25fAcyclovir, 97f, 196, 229Adaptive immunity

description of, 26to intracellular bacteria, 28fto viruses, 29, 29f

Adenoids, 2Adenosine triphosphate, 47Adenoviruses

cell entry mechanisms, 189definition of, 187description of, 201–202, 202f–203fstructure of, 186

Adenylate cyclase toxin, 104Adhesins, 57, 156Adhesion molecules, 17Adult inclusion conjunctivitis, 141–142Adult T-cell leukemia/lymphoma, 215Aerial hyphae, 169Aerobactin, 122Aerobic conditions, for fermentation, 47Aeromonas, 147–148Aerotolerant anaerobes, 48African trypanosomiasis, 271Agglutinins, 108Aggregatibacter actinomycetemcomitans,

57, 77, 109, 154, 160–161Aggressive periodontitis, 161AIDS-associated retrovirus, 208Alanine transaminase, 218–219Alcohols, as germicides, 73, 73f

Alkylating agents, 72, 73fAllergic contact dermatitis, 33Allotypes, 9Alpha toxin, 83, 99Alphaviruses, 249–251, 250fAlternative complement pathway, 12, 13f,

27, 89Alveolar macrophages, 136Amantadine, 195, 198–199, 238American trypanosomiasis, 271Ames test, 49Amikacin, 65, 67Aminoglycoside antibiotics, 61–62, 65, 105Ammonia, 170Amoebae, 268, 268fAmoebic dysentery, 124Amphotericin B

chemical structure of, 184fdescription of, 183–184formulations of, 184

Ampicillin, 63f, 113α-amylase, 152Anaerobic conditions, for fermentation, 47Anamnestic response, 12Anaphylactic hypersensitivity, 31f, 31–32Anaphylactic shock, 32Anergy, 17, 212Anogenital warts, 204–205Anthrax, 92, 92f. See also Bacillus anthracis.Antibacterial spectrum, 61, 61fAntibiotics

aminoglycoside, 61–62, 65, 105antagonism of, 61antibacterial spectrum of, 61, 61fantimicrobial activity of, 61bacterial resistance to, 66–68, 67f, 67tbactericidal activity of, 61, 62fbacteriostatic, 61, 62fbroad-spectrum, 61, 61fcarbapenem, 64cephalosporins, 64, 64fcombinations of, 61enzymatic inactivation of, 68glycopeptides, 64–65macrolides, 65, 104, 107mechanism of action

antimetabolite activity, 62, 66cell membrane alteration, 62, 65cell wall synthesis inhibition, 62–64nucleic acid synthesis inhibition, 62, 66protein synthesis inhibition, 62, 65–66

minimum inhibitory concentration of, 61, 61fmolecular targets of, 67–68monobactams, 64narrow-spectrum, 61, 61fpenicillin. See Penicillin(s).synergism of, 61, 62f

Antibodies. See also Immunoglobulin(s).chimeric, 12diversity of, 10–11heavy chains of, 9, 10flight chains of, 10f, 10–11monoclonal, 12opsonizing, 172plasma cell production of, 11structure of, 9–10variable region of, 9

Antibody classdescription of, 9switching of, 6, 12

Antibody titer, 12Antibody-dependent cellular cytotoxicity, 11Antibody-mediated hypersensitivity, 32, 32fAntifungal agents, 183–185. See also

specific agent.Antigen(s)

definition of, 9endogenous, 17helper T cell recognition of, 15immunofluorescence detection of, 78, 79fspike proteins’ effect on, 187

Antigen presentationdendritic cells, 16description of, 15–18by major histocompatibility complex class

I molecules, 17–18, 17f–18fby major histocompatibility complex class

II molecules, 18, 19fAntigen-antibody binding, 11Antigenic drifts, 235Antigenic variation, 58, 118Antigenicity, 10Antigen-presenting cells

dendritic cells. See Dendritic cells.description of, 2, 8, 15major histocompatibility complex class II

molecules on, 15T cells, 17

Anti-inflammatory cytokine, 21Antimicrobial chemotherapy, 60Antisense oligonucleotides, 199Antisepsis, 71t, 71–72Antiseptic agents, 71t, 71–72Antiviral agents. See also specific agent.

antisense oligonucleotides, 199applications of, 199thuman immunodeficiency virus treated

with, 198, 213–215, 214binfluenza virus inhibitors, 198–199interferon-α, 199mechanism of action, 199tnon-nucleoside analog DNA polymerase

inhibitors, 198, 214bnucleoside analogs, 196–198, 197f, 214bprotease inhibitors, 198, 198f, 213, 214bresistance to, 199–200targets for, 195–196

Antiviral state, 26, 27fAP-1, 19Apical extension, 169Apolactoferrin, 30, 30tApoptosis, 212, 237

definition of, 5, 8, 22T cell, 17

Arabinose-galactose–mycolic acid, 135Arber, Werner, 52Arboviruses, 187

alphaviruses, 249–251, 250fbunyaviruses, 252flaviviruses, 251f, 251–252

ArthritisBorrelia-related, 117rheumatoid, 34suppurative, 112

Aseptic meningitis, 247

280

A Index

Aspergillosis, 179fAspergillus, 179Aspiration pneumonia, 82ATP. See Adenosine triphosphate.Attenuated Mycobacterium bovis vaccine, 37Attenuated Salmonella typhi strain vaccine, 37Attenuated vaccines, 37Atypical measles, 240Auramine-rhodamine fluorescent stain, 76Autoclaving, 70Autoimmune diseases, 20Autoimmunity, 34Autophagy, 18, 264Auxiliary proteins, 210Auxotrophic mutants, 49Avery, Oswald T., 48Azidothymidine (AZT), 197, 213Azithromycin, 87, 142, 147Azoles, 184, 184f

BB cells

differentiation of, 6, 7f, 20lymphocyte differentiation into, 6memory, 8Peyer’s patches and, 2f

B virus, 233Bacillary dysentery, 124Bacille Calmette-Guérin vaccine, 37, 137Bacillus anthracis

anthrax caused by, 92, 92fdiagnosis of, 92epidemiology of, 92pathogenesis of, 92structure of, 91, 92ftreatment of, 92vaccination for, 92

Bacillus cereus, 57, 93, 147Bacillus stearothermophilus, 70, 93Bacillus subtilis, 93Bacitracin, 65Bacteremia

Staphylococcus aureus as cause of, 82transfusion-related, 125

Bacteria. See also Microorganisms; specific bacteria.

antibiotic resistance by, 66–68, 67f, 67tattachment by, 57binary fission of, 45biofilms, 57f, 57–58capsule of, 44–45, 45fclassification of, 47–48coaggregation of, 153f, 155cocci, 39cytoskeletal elements in, 46, 46fexternal structure of, 44–45, 45fflagella of, 45general secretory pathway in, 43–44, 44fgenetics of, 48–49glucose metabolism by, 47Gram-negative. See Gram-negative

bacteria.Gram-positive. See Gram-positive

bacteria.growth of, 46, 46fhost immune system interference by, 58inflammation caused by, 58intracellular, 27–28invasion by, 57light microscopy of, 40, 40fmetabolism by, 46–48optimal growth temperature of, 48pathogenic, 57peptidoglycan layer of, 41polysaccharides, 27

rod-shaped, 39shapes of, 39slime layer of, 45spherical, 39structure of, 39–46subgingival, 151supragingival, 151toxin production by, 57–58virulence factors expressed by, 58

Bacterial chromosome, 48Bacterial infection, 55–56Bactericidal activity, of antibiotics, 61, 62fBacteriocins, 50, 155Bacteriophages, 52Bacteriostatic antibiotics, 61, 62fBacteroides, 107–108Baltimore classification of viruses, 187, 189,

189fBarré-Sinoussi, Françoise, 208Basophils, 4–5b-lactamase, 68Beta toxin, 83, 99Bifidobacterium dentium, 153Bile solubility test, 88Binary fission, 45Biofilms, 57f, 57–58, 149, 156, 158, 164BK virus, 205–206Blastomyces dermatitidis, 170–171, 175Blastospores, 169Blood protozoa, 269–272, 270f–271fBloodstream infections, 177–178Body temperature, 26Bordetella pertussis, 103–104Bornholm disease. See Pleurodynia.Borrelia, 117–118Botulinum toxin, 58Botulism, 58, 100Bovine spongiform encephalopathy, 264–265Boyer, Herbert, 52Bright-field microscopy, 40, 40f, 75Brill-Zinsser disease, 143Broad-spectrum antibiotics, 61, 61fBronchiolitis, 242Bronchitis, 114Bronchopneumonia, 150Bronchopulmonary infections, 96Brotzu, Giuseppe, 64Brucella, 105Buffered charcoal yeast extract agar, 76, 106Bulbar poliomyelitis, 245Bullous impetigo, 81Bundle-forming pili, 121Bunyaviruses, 252Burkholderia cepacia, 149Burkholderia pseudomallei, 149Burkitt lymphoma, 230–231Burn wounds, 148, 149fBurnet, Frank Macfarlane, 8–9Butyric acid, 108

CC2b, 12C3 convertase, 12C3a, 12, 24, 31C3b, 4, 12, 26C3b receptor, 4, 18C4b, 12C5 convertase, 12C5a, 12, 24, 31Calcium/calmodulin-dependent calcineurin, 19Calculus, 156Caliciviridae, 262Calprotectin, 30tCampylobacter, 127, 128f, 154Candida spp

C albicans. See Candida albicans.denture stomatitis associated with, 178description of, 155, 177–178epidemiology of, 178pathogenesis of, 178prevention of, 178treatment of, 178

Candida albicansadhesion of, 170, 171fantibodies against, 172cell wall of, 169fas opportunistic pathogen, 177–178oral candidiasis caused by, 177f, 177–178pathogenicity mechanisms of, 171fyeast-to-hyphal transformation of, 170,

178Candidiasis, 177f, 177–178, 184, 211CandiSelect 4 agar, 76Capnocytophaga, 108, 154, 160Capnophilic, 85Capsular polysaccharides, as vaccines, 38Capsule, of bacteria, 44–45, 45fCarbapenems, 64, 149Carbuncles, 82Cardiolipin, 116Caries

definition of, 157ecological plaque hypothesis of, 157f,

157–158, 164, 165fextended caries ecological hypothesis of, 158prevention of, 158Streptococcus mutans in, 157

Carrier state, 56Case studies, 273–278Caseous necrosis, 136Caspofungin, 184f, 185Catalase, 73, 83, 163Catalase-peroxidase, 137Cathelicidin, 29, 30tCathepsins, 18Cationic antimicrobial peptides, 29CD4, 189CD4+ helper T cells, 18, 20–21CD4+ T cells, 5, 8, 28, 28f, 211–212CD8+ T cells

activation of, 21–22cytotoxic, 5, 18, 172, 212suppressor, 5

CD45R surface antigen, 6CD46, 241CD55, 244Cell-mediated hypersensitivity, 33Cell-mediated immunity, 174, 176, 193, 219Cellular immunity, 15Cellulitis, 98Cellulose, 169Cephalosporins, 64, 64f, 99Cerebral malaria, 270Cervicofacial actinomycosis, 95, 95f, 166Cervicovaginal squamous epithelial cells,

205fCFUs. See Colony-forming units.Chagas disease, 271Chagoma, 272Chaperone proteins, 56Chemoautotrophs, 47Chemoheterotrophs, 47Chemokines, 2, 23, 165, 212Chemotaxis, 12Chemotaxis inhibitory protein of

Staphylococcus aureus, 83Childbed fever, 74Chimeric antibodies, 12Chitin, 169Chitinase, 30tChitosan, 169

Index

281

E

Chlamydia infection, 55Chlamydia trachomatis, 140–142, 141fChlamydophila pneumoniae, 142Chlamydophila psittaci, 142Chlorhexidine, 72, 72f, 158, 166Chlorine, 73Chloroquine, 270Chocolate agar, 76Cholera, 39, 147Cholesterol, 169, 169fCHROMagar, 76Chromosomes, 10, 48Chronic bronchitis, 114Chronic granulomatous disease, 34Chronic hepatitis, 220Chronic hyperplastic candidiasis, 178Chronic infection, 55Chronic inflammation, 24Chronic mucocutaneous candidiasis, 178Chronic periodontitis, 160–161Chronic progressive histoplasmosis, 174, 174fCidofovir, 197, 197f, 202, 206Ciprofloxacin, 66, 92Cirrhosis, 220Citrobacter, 126–127Class II–associated invariant chain peptide, 18Class switching, of antibodies, 12Classical complement pathway, 12, 13f, 27, 89Clavulanate, 63Clavulanic acid, 68Climax community, 156Clindamycin, 65–66Clonal deletion, 8Clonal selection theory, 8Cloning vector, 52, 53fClostridium botulinum, 58, 100Clostridium difficile, 100–101, 101fClostridium perfringens, 98–99Clostridium septicum, 101Clostridium tetani, 56, 99–100Clotrimazole, 184Clumping factor, 82Cluster of differentiation, 5, 7fCoagulase, 57, 81, 84Cocci

definition of, 39Gram-positive, 85

Coccidia, 269Coccidioides immitis, 168, 170, 175–176,

175f–176fCoccidioidomycosis, 175–176, 176fCoccobacilli, 39Codons, 48Cohen, Stanley, 52Cohn, Zanvil, 6, 17Cold hemagglutinins, 132Colicins, 50Collagenase, 57, 99, 163Colony-forming units, 3f, 4Commensals, 168Common cold, 193, 247, 258Community acquired respiratory distress

syndrome, 132Community-acquired methicillin-resistant

Staphylococcus aureus, 82–83Competence factor, 50Complement

description of, 30t, 31hereditary deficiencies of, 34

Complement fixation, 131Complement system, 12, 13fComplementary DNA, 209Composite transposons, 49Concatemers, 227Condylomata acuminata, 204Congenital syphilis, 116

Conidia, 169Conjugate vaccines, 38Conjugation, 50–51Conjugation complex, 50Conjunctivitis, 141–142Constant region, 9Contact dermatitis, 33Contractile proteins, 46Cord factor, 135f, 135–136Core polysaccharide, 44Coronaviruses, 257–258Corynebacteria spp, 39

C diphtheriae, 56, 93–94C jeikeium, 93C ulcerans, 93–94

Co-stimulatory signals, 17Coxiella burnetii, 106, 142, 144–145Coxsackievirus, 155, 246–247Coxsackievirus adenovirus receptor, 189,

201, 244C-reactive protein, 24, 26Creutzfeldt-Jakob disease, 264f, 264–265Crick, Francis, 52Croup. See Laryngotracheal bronchitis.Cryptitopes, 156Cryptococcal meningitis, 179Cryptococcus neoformans

description of, 169, 178–179humoral immune responses to, 172mycoses caused by, 173, 178–179

Cryptosporidiosis, 269Cryptosporidium parvum, 269, 269fCulture, 76Cutaneous anthrax, 92Cutaneous diphtheria, 93Cutaneous infections, 82Cutaneous mycoses, 168, 173, 180–181Cutaneous warts, 204Cyclooxygenase-2, 24Cystatins, 30, 30tCystic fibrosis, 148Cytochrome oxidase, 47, 148Cytochrome reductase, 47Cytokine(s)

dendritic cell release of, 16inflammation-related release of, 247macrophage release of, 24proinflammatory, 89

Cytokine storm, 33–34Cytomegalovirus, 231–232, 232fCytomegalovirus retinitis, 196–198, 200Cytotoxic CD8+ T cells, 5, 18, 172, 212Cytotoxic necrotizing factor, 122Cytotoxic T cells, 15–16, 21, 29Cytotoxic T lymphocyte–mediated lysis of

target cells, 21fCytotoxin-associated gene, 129Cytotoxins, 83, 101, 104

Dda Rocha-Lima, Henrique, 143D-alanine, 42Dane particle, 218Dapsone, 138Daptomycin, 65, 83Dark-field microscopy, 40, 40f, 75Darunavir, 213, 214fDavaine, Casimir, 91Decay accelerating factor, 244Decline phase, of bacteria growth, 46, 46fDefective interfering particles, 192Defensins, 21, 29Del-1, 163Delayed-type hypersensitivity, 33Delta agent, 217

Demyelination, 206Dendritic cells

antigen presentation by, 16cross-presentation of, 18cytokine release by, 16description of, 209, 212discovery of, 6follicular, 16interstitial, 6isolation of, 17lymphoid, 6plasmacytoid-type, 28toll-like receptor expression by, 16

Dengue hemorrhagic syndrome, 251–252Dengue shock syndrome, 251Dengue virus, 193, 251Dental plaque, 156Dental pulp infections, 165Dentinal tubules, 165Dentoalveolar abscesses, 162, 165Dentoalveolar infections, 164–166Denture stomatitis, 155, 178Dermatophytes, 168, 181Diabetes mellitus, type 1, 34Diacylglycerol, 19Diapedesis, 5, 23Diarrhea, 121, 146–147Dideoxycytidine, 197, 197fDideoxyinosine, 197, 197fDideoxynucleotide, 52Differential stains, 76Dimorphic fungi, 170Diphtheria

Corynebacterium diphtheriae as cause of, 56, 93–94

cutaneous, 93incidence of, 36vaccine for, 37, 104, 113–114

Diphtheria booster, 100Diphtheria toxin, 58Direct fluorescent antibody, 76, 106, 229Direct immunofluorescence, 78, 79fDisinfectants, 71tDisinfection, 71, 71tDisseminated intravascular coagulation, 113DNA

antifungal agents that affect synthesis of, 184

complementary, 209double-helix structure of, 52recombinant, 52, 53f

DNA gyrase, 66DNA microarray analysis, 78, 78fDNA probe analysis, 77–78DNA sequencing, 52, 53f, 78DNA viruses

description of, 187, 188t, 190naked capsid. See Naked capsid DNA

viruses.Dot blot, 78Downey cells, 231Doxycycline, 92, 105, 144–145Dry heat sterilization, 70DTaP vaccine, 38Duodenal ulcers, 128Dysentery, 124Dysplasias, 204

EE1A transactivator protein, 202E6 protein, 205E7 protein, 205Early-onset neonatal disease, 87Eastern equine encephalitis virus, 249–250, 250fEbola virus, 260

Index

282

E

Echinocandins, 185Echoviruses, 247Ecological plaque hypothesis, 157f, 157–158,

164, 165fED50. See Effective dose 50.Edelman, Gerard, 10Edema factor, 92Effective dose 50, 55Ehrlich, Paul, 9–10, 60Ehrlichia, 142, 144, 145fEikenella corrodens, 108, 114, 154Elastases, 148Electron transport chain, 47Elementary body, 140ELISAs. See Enzyme-linked immunosorbent

assays.Elk, 19Embden-Meyerhof-Parnas pathway, 47Encephalitis, 240, 249–250, 250fEndarteritis, 115Endocarditis, 114

Q fever, 145Staphylococcus aureus as cause of, 82, 84

Endocytotic vesicles, 18Endodontic infections, 164–166Endogenous antigens, 17Endogenous pyrogens, 26Endoplasmic reticulum, 18Endothelium, 6fEndotoxins, 56, 58, 163Entamoeba gingivalis, 155Entamoeba histolytica, 268, 268fEntecavir, 197, 221, 221fEnteric fever, 123Enterobacter, 126Enterobacteriaceae

Citrobacter, 126–127description of, 120Escherichia coli. See Escherichia coli.Klebsiella, 126Proteus, 126Salmonella, 123f, 123–124Shigella, 124–125Yersinia, 125–126

Enterococcus faecalis, 152, 165–166Enterotoxin, 99, 101Enteroviruses, 187, 247env, 209Enveloped viruses, 186–187, 187f, 190Enzyme, restriction, 52Enzyme immunoassays, 79, 79fEnzyme induction, 50Enzyme-linked immunosorbent assays, 12,

78, 79f, 145Eosinophils, 4–5Epidemic typhus, 143–144Epiglottitis, 109Epithelioid cells, 24Epitopes, 9Epsilon toxin, 99Epstein-Barr virus, 230–231, 231f, 231tErgosterol, 169, 169fErythema infectiosum, 206, 206fErythema migrans, 117, 117fErythromycin, 65, 87, 132Escherichia coli

adhesins used by, 57antigenic structure of, 122fclinical syndromes associated with,

121–122colicin E1 produced by, 155diagnosis of, 121–122enteroaggregative, 122enterohemorrhagic, 121–122enteroinvasive, 121enteropathogenic, 121

enterotoxigenic, 121epidemiology of, 122illustration of, 121fO157:H7, 122pathogenesis of, 122prevention of, 122–123strains of, 50treatment of, 122–123verocytotoxigenic, 121

E-selectin, 5Ethambutol, 65Ethanol, 73, 73fEthyl alcohol, 71Ethylene oxide, 72Eubacteria, 153Exanthem subitum, 232Exfoliative toxin, 83Exoenzyme S, 148Exogenous infections, 56Exogenous pyrogen, 26, 56Exosomes, 230Exotoxins, 56, 83, 86, 148Exponential growth, 46Exponential phase, of bacterial growth, 45,

46fExported repetitive protein, 137Extended caries ecological hypothesis, 158Extended-spectrum ß-lactamases, 68Extracellular adherence protein, 83Extracellular bacteria, 26–27Extravasation of leukocytes, 23Extrinsic allergic alveolitis, 32Eye infections, 148

FF+ plasmid, 51Facultative aerobes, 48FADH2. See Flavin adenine dinucleotide.Famciclovir, 196, 229Fas, 22Fas ligand, 22Fatal familial insomnia, 265Fc, 9Fc receptors, 4, 6, 9f, 11, 18, 31Fcγ receptors, 26Fermentation, 47Fertility factor, 50–51Fibrinolysin, 83, 163Fibroblasts, 24Fibronectin, 57, 86, 116, 156Fifth disease. See Erythema infectiosum.50S ribosomal subunit, 65Filoviruses, 260–261Fimbriae, 107First-generation cephalosporins, 64Flagella, 45Flagellates, 268–269, 269fFlagellin, 45Flavin adenine dinucleotide, 47Flaviviruses, 221, 224, 251f, 251–252Flow cytometry, 79Fluconazole, 176, 178, 184, 184fFlucytosine, 184fFluorescence microscopy, 40, 40f, 76Fluoride ions, 1585-fluorocytosine, 184Fluorophore, 40Fluoroquinolones, 665-fluorouracil, 184, 197, 205Follicles, 2Follicular dendritic cells, 2, 16, 212Follicular Th cells, 21Folliculitis, 82, 148Food poisoning

Bacillus cereus as cause of, 93

Clostridium perfringens as cause of, 98description of, 58Staphylococcus aureus as cause of, 82

Food-borne pathogens, 68Formaldehyde, 72Formalin, 72Fos, 19Fourth-generation cephalosporins, 64Frameshift mutations, 49Francis, Thomas Jr, 26Francisella tularensis, 58, 104–105Fungal cells, 169Fungal diseases. See also Mycoses.

antifungal agents for, 183–185Blastomyces dermatitidis, 170–171, 175Coccidioides immitis, 168, 170, 175–176,

175f–176fCryptococcus neoformans, 173, 178–179Histoplasma capsulatum, 168, 170, 174–

175, 174f–175fHortaea werneckii, 180Malassezia furfur, 168, 173, 180opportunistic, 177f, 177–180, 179f–180foverview of, 168–169pathogenesis of, 170–172Piedraia hortae, 180Pneumocystis jirovecii, 180Sporothrix schenckii, 181Trichosporon, 180

Fungal meningitis, 179Fungi

adhesion of, 170definition of, 168description of, 29, 155dimorphic, 170heat shock protein expression in, 171hormonal factors that affect, 171immune response to, 171–172immune system evasion by, 171intracellular survival, 170–171invasion by, 170replication of, 169–170structure of, 169–170

Furuncles, 82Fusobacterium, 108, 154, 160Fusospirochetal complex, 108, 162

Ggag, 209ß-galactosidase, 49, 51fGametocytes, 269Ganciclovir, 196–197, 232Gangliosides, 147Gardasil, 205Gas gangrene. See Myonecrosis.Gastric cancer, 128Gastric ulcers, 128Gastroenteritis, acute, 262Gel electrophoresis, 79Gene exchange, 50–52Gene expression, 49–50General secretory pathway, 43–44, 44fGeneralized tetanus, 99Generalized transduction, 52Generation time, 46Genetic code, 52t, 52–53Genetic mutation, 49Genital herpes, 228Genomic RNA, 236Gentamicin, 65German measles, 259Germicides

alcohols, 73, 73falkylating agents, 72, 73foxidizing agents, 73

Index

283

H

phenolics, 72, 72fphenols, 72, 72fsurfactants, 73

Gerstmann-Sträussler-Scheinker disease, 264–265

Giardia lamblia, 268, 269fGimenez stain, 106Gingipains, 30–31Gingival crevicular fluid, 155Gingivitis, 160–162, 163fGingivostomatitis, 228, 229fGlial cells, 206Globotriaosylceramide, 122Glomerulonephritis, 32α-(1,3)-glucan, 171α-glucan, 169ß-(1,3)-glucan, 185ß-glucan, 169Glucans, 156Glucose, 47Glutaraldehyde, 70, 72Glycolipids, 156Glycolysis, 47Glycopeptides, 64–65Glycoprotein S, 258Glycoproteins, 187Glycosaminoglycans, 23, 24fGlycosylated surface protein, 209Gonococcal conjunctivitis, 112fGoodpasture syndrome, 32gp120, 209Gram, Christian, 41Gram stain, 76, 82Gram-negative bacilli, 154Gram-negative bacteremia, 33Gram-negative bacteria. See also specific

bacteria.antibiotic resistance by, 67description of, 41, 41f–42f, 44fsecretion systems used by, 56, 56f

Gram-negative cocci, 153, 154f, 161. See also specific bacteria.

Gram-positive bacilli, 153Gram-positive bacteria. See also specific

bacteria.in dentinal tubules, 165description of, 41f–42f, 41–43, 46f, 50secretion systems used by, 56, 56ftypes of, 161

Gram-positive cocci, 85, 152. See also specific bacteria.

Granulation tissue, 24Granulocyte-monocytes, 4Granulocytes, 5Granulomas, 105Granulomatous inflammation, 24, 58Granzymes, 22, 29Graves disease, 32Griffith, Frederick, 48, 49fGriseofulvin, 185Guanosine-5’-triphosphate, 47Guillain-Barré syndrome, 127

HH antigen, 120HAART. See Highly active antiretroviral

therapy.Haemophilus influenzae, 109Haemophilus parainfluenzae, 154Hairy leukoplakia, 211, 231Hand-foot-and-mouth disease, 247Hansen disease. See Leprosy.Hantaan virus, 252Hantavirus pulmonary syndrome, 252Hantaviruses, 252

Haptens, 10Hausen, Harald zur, 205Heat shock proteins, 171Heat-stable enterotoxin, 93Heavy chain gene, 11Heavy chains, 9, 10fHelicobacter pylori, 128–129Helper T cells

antigen recognition by, 15CD4+, 18, 20–21description of, 2, 171macrophages and, 4Th1 cells, 6Th2 cells, 6Th3 cells, 6

Hemagglutination, 237Hemagglutinin, 187, 234–236, 236f, 241Hemagglutinin-protease, 147Hemin, 162Hemolysins, 122α-hemolysis, 85b-hemolysis, 85Hemolytic disease of the newborn, 32Hemolytic uremic syndrome, 58, 121Hemorrhagic colitis, 121Hemorrhagic lymphadenitis, 125Hendra virus, 239, 243Henipavirus, 242Hepacivirus, 221Hepadnaviruses, 218Heparan sulfate, 23, 228Hepatitis. See also specific subtype.

chronic, 220definition of, 217

Hepatitis A viruscharacteristics of, 218tclinical syndromes associated with,

217–218epidemiology of, 218pathogenesis of, 218prevention of, 218structure of, 218ftreatment of, 218vaccine for, 37–38

Hepatitis B envelope antigen, 218–219Hepatitis B surface antigen, 38, 218, 220Hepatitis B virus

carrier of, 220characteristics of, 218tchronic infection, 218clinical syndromes associated with,

218–220description of, 32, 218diagnosis of, 218–220epidemiology of, 220–221hepatocellular carcinoma associated with,

220pathogenesis of, 220–221replication of, 218fserum hepatitis caused by, 217serum markers in, 220fstructure of, 218, 219ftransmission of, 221treatment of, 221vaccine for, 37–38, 221vertical transmission of, 221

Hepatitis C viruscell entry mechanism of, 221characteristics of, 218tclassification of, 221clinical syndromes associated with, 222diagnosis of, 222discovery of, 222epidemiology of, 222–223hepatocellular carcinoma caused by, 222interferon-α for, 199

pathogenesis of, 222–223prevalence of, 221prevention of, 223protease inhibitors for, 198replication of, in hepatocytes, 222transmission of, 223treatment of, 223

Hepatitis D virus, 217, 218t, 223f, 223–224Hepatitis E virus, 217, 218t, 224Hepatitis G virus, 217, 218t, 224Hepatocellular carcinoma, 220, 222Hepatocytes, 220, 222Herpangina, 246Herpes encephalitis, 228Herpes simplex virus, 155, 227f, 228–229Herpes zoster, 229, 230fHerpesviridae, 226Herpesvirus simiae, 233Herpesviruses

B virus, 233cytomegalovirus, 231–232, 232fEpstein-Barr virus, 230–231, 231f, 231thuman herpesvirus 6, 232human herpesvirus 7, 232human herpesvirus 8, 193, 211, 232–233infection strategies for, 227Kaposi sarcoma–associated, 233replication of, 226–227, 227fstructure of, 187, 226–227types of, 227tvaricella zoster virus, 229–230, 230f

Herpetic keratitis, 228Herpetic stomatitis, 228Herpetic whitlow, 228Heterophile antibody test, 231High-frequency recombination, 51High-level disinfection, 71Highly active antiretroviral therapy, 198, 211,

213, 214bHistamine, 24Histatins, 29, 30tHistidine, 49Histidine auxotrophs, 49Histone deacetylase, 214Histoplasma capsulatum, 168, 170, 174–175Histoplasmosis, chronic progressive, 174,

174fHIV. See Human immunodeficiency virus.Hodgkin disease, 231Hooke, Robert, 40Horizontal gene transfer, 50Hortaea werneckii, 180Hospital-acquired infections, 68, 83, 178Host-range mutants, 37Houghton, Michael, 222Human diploid cell vaccine, 256Human herpesvirus 6, 232Human herpesvirus 7, 232Human herpesvirus 8, 193, 211, 232–233Human immunodeficiency virus. See also

Acquired immunodeficiency syndrome.antiviral agents for, 198, 213–215, 214bblood transmission of, 213CD4+ T cells, 211–212clinical syndromes associated with,

210–211description of, 34, 195diagnosis of, 210–211genome of, 209hepatitis G virus and, 224highly active antiretroviral therapy for, 213,

214bneedlestick injuries and, 213plasma half-life of, 212prevention of, 215replication of, 209f, 209–210

Index

284

H

sexual transmission of, 213structure of, 209f, 209–210transmission of, 213treatment of, 213–215vertical transmission of, 213viremia, 212, 212f

Human monocytic ehrlichiosis, 144Human papillomavirus, 193

clinical syndromes caused by, 204, 205fdiagnosis of, 204epidemiology of, 205in oral lesions, 155pathogenesis of, 205prevention of, 205treatment of, 205vaccine for, 38, 205

Human parvovirus B19, 206Human T-cell lymphotropic virus, 193, 215Hutchinson incisors, 116Hyaluronidase, 83, 87, 99, 116, 163Hybridization, 77–78, 78fHydrogen peroxide, 70, 73, 152Hydrogen sulfide, 154Hydrophobins, 170Hydroxyapatite, 157Hypersensitivity responses, 31f, 31–33Hyphae, 169Hypnozoites, 269Hypothalamus, 26

IIdiotypes, 9IgA/IgG proteases, 163Immersion oil, 75Immune complex–mediated hypersensitivity,

32, 33fImmune responses

to fungi, 171–172inefficiency of, 220macrophages in, 4primary, 11f, 11–12secondary, 11f, 11–12

Immune system, 1–2, 163–164Immune tolerance phase, 219Immunity

adaptive, 26, 28fcell-mediated, 174, 176, 193, 219to extracellular bacteria, 26–27to fungi, 29innate, 26, 28fto intracellular bacteria, 27–28in oral cavity, 29–31to viruses, 28–29, 29f

Immunization schedule, 38Immunodeficiencies, 34Immunofluorescence, 78, 79fImmunogenicity, 10Immunogens, 10Immunoglobulin(s). See also Antibodies.

D, 11E, 11G, 9f, 11, 32, 82, 86isotypes of, 11M, 11, 32, 86tetanus, 100

Immunoglobulin Adescription of, 6, 11, 58secretory. See Secretory immunoglobulin A.

Immunoglobulin A protease, 112Immunologic tolerance, 9Immunological synapse, 20Immunoreceptor tyrosine-based activating

motifs, 19Immunosuppressive factor, 161, 163Impetigo, 58, 81

Inactivated vaccines, 37–38Incidence, 157Inclusion bodies, 193Indirect immunofluorescence, 79Induced phagocytosis, 142Infant botulism, 100Infection

acute, 55bacterial, 55–56bronchopulmonary, 96carrier state from, 56chronic, 55dentoalveolar, 164–166endodontic, 164–166exogenous, 56eye, 148hospital-acquired, 68, 83intra-abdominal, 107latent, 56, 193lymphocutaneous, 96lytic, 192mixed, 56opportunistic. See Opportunistic

infections.polymicrobial, 56primary, 55pyogenic, 56, 82root canal, 166bsecondary, 55subclinical, 55transmission of, 56viral, 192–193. See also Viruses.

Infectious mononucleosis, 231Inflammasome, 24Inflammation

acute (localized), 23–24acute-phase response, 24–26, 25fbacteria as cause of, 58chronic, 24cytokine release secondary to, 247definition of, 23fever, 26granulomatous, 24, 58interferons, 26manifestations of, 23pyogenic, 58

Influenza virusantiviral inhibitors of, 198–199clinical syndromes associated with,

236–237diagnosis of, 236–237epidemiology of, 237pandemics of, 234pathogenesis of, 237replication of, 234–236, 236fstructure of, 234–236subtypes of, 237, 237fvaccine for

inactivated, 37–38live attenuated, 37, 238production of, 238

Inhalation anthrax, 92Innate immunity

to extracellular bacteria, 26time course of, 28fto viruses, 28, 29f

Inositol triphosphate, 19Insertion sequence elements, 49Integrase inhibitors, 214bIntegrins, 23Intercellular adhesion molecule, 17Intercellular adhesion molecule-1, 4–5, 189,

244Interdigitating cells, 6Interferon-α, 26, 196, 199

pegylated, 221

Interferon-ß, 26Interferon-γ, 20, 22, 24, 25f, 27, 171Interferons, 26Interleukin-1, 23–24Interleukin-2, 17, 21Interleukin-2 receptor, 17, 21Interleukin-4, 12Interleukin-5, 12Interleukin-6, 24Interleukin-6 trans-signaling, 26Interleukin-8, 5Interleukin-10, 21Interleukin-12, 27Interleukin-17, 163Interleukin-22, 21Interstitial dendritic cells, 6Interstitial pneumonia, 229Intestinal protozoa, 268–269, 268f–269fIntra-abdominal infections, 107Intracellular bacteria, 27–28Intracellular infections, 20Intraepithelial cervical neoplasia, 204Invariant chain, 18Invasin, 125Invasive fasciitis, 86Iodine, 73Iodophor, 73Ionizing radiation, 70Isoniazid, 65, 137Isopropanol, 73, 73fIsopropyl alcohol, 71Isotypes, 9Itraconazole, 175–176, 184

JJacob, François, 50Japanese encephalitis virus, 252Jarisch-Herxheimer reaction, 116JC virus, 205–206Jerne, Niels, 9Jun, 19Junctional diversity, 11

KKanagawa hemolysin, 147Kaposi sarcoma, 211, 232–233Kaposi sarcoma–associated herpesvirus, 233κ light chain, 10–11Keratin, 181Ketoconazole, 184, 184fKhorana, Gobind, 52Kinin system, 24Kinyoun stain, 76Klebsiella, 126Koch, Robert, 59, 91Koch’s postulates, 59, 128Köhler, Georges, 12Koplik spots, 240, 240fKrebs cycle, 47Kunkel, Henry, 10Kupffer cells, 4, 218Kuru, 265

LLa Crosse encephalitis virus, 252b-lactamase, 68Lactic acid, 47Lactobacilli, 153Lactobacillus, 157Lactoferrin, 5, 30, 30tLactoferrin-binding protein, 112Lactose operon, 50, 51f

Index

285

M

Lag phase, of bacterial growth, 46, 46f light chain, 10–11Lamivudine, 197, 197f, 221Lancefield, Rebecca, 85Landsteiner, Karl, 245Langerhans cells, 6, 16, 136Laryngeal papillomas, 204Laryngotracheal bronchitis, 241Latency-associated transcript, 228Latent infection, 56, 193Late-onset neonatal disease, 87Latex allergy, 33Laveran, Charles, 270Lbp, 112LD50. See Lethal dose 50.Lectin complement pathway, 12, 13f, 27Lectins, 57Lederberg, Joshua, 50–51, 151Leeuwenhoek, Antonie van, 40, 40f, 165Legionella pneumophila

diagnosis of, 106discovery of, 105epidemiology of, 106–107illustration of, 105flife cycle of, 106fpathogenesis of, 106–107prevention of, 107treatment of, 107

Legionnaires disease, 106Leishmania spp, 271, 271fLeishmaniasis, 271Lentivirinae, 215Lentiviruses, 198Lepromatous leprosy, 138Leprosy, 138–139Leptospira interrogans, 118–119Lethal dose 50, 55Leukocidin, 57Leukocyte(s), 23Leukocyte function antigen-1, 5, 163Leukocyte function antigen-3, 4Leukocytosis, 5Leukotoxin, 161LFA-1. See Leukocyte function antigen-1.Light chain gene, 11Light chains, 10f, 10–11Light microscopy, 40, 40fLinezolid, 66, 83Lipases, 83Lipid A, 44Lipidic carrier, 43Lipoarabinomannan, 45-lipooxygenase, 24Lipopolysaccharide, 10, 26, 44, 45f, 56, 58,

107, 112, 163Lipopolysaccharide receptors, 4Liposomes, 38Lipoteichoic acids, 42–43, 57Lister, Joseph, 72Listeria monocytogenes

clinical syndromes caused by, 94description of, 17, 27, 94diagnosis of, 94epidemiology of, 94optimal growth temperature for, 48pathogenesis of, 94replication of, 58treatment of, 94

Listeriolysin O, 94Listeriosis, 94Live attenuated polio vaccine, 37Localized tetanus, 99Long terminal repeat, 209Louse-borne typhus, 143Löwenstein-Jensen medium, 76Low-level disinfection, 71

Low-temperature mutants, 37L-selectin, 26Ludwig’s angina, 166Lyme disease, 117f, 117–118Lymph nodes, 2, 3fLymphadenopathy, 174Lymphadenopathy associated virus, 208Lymphocutaneous infections, 96Lymphocutaneous sporotrichosis, 181Lymphocytes, 2, 6. See also B cells; T cells.Lymphocytosis, 104Lymphogranuloma venereum, 141Lymphoid dendritic cells, 6Lymphoid organs, 1, 2bLymphoid progenitors, 2Lysogenic conversion, 52Lysogeny, 52Lysosomes, 4Lysozyme, 30, 82Lytic infections, 192

MM cells, 2, 123, 125M protein, 57–58, 86M1 protein, 234M2 protein, 198, 234, 236MacConkey agar, 76MacLeod, Colin, 48 Macrolides, 65, 104, 107Macrophage(s)

alveolar, 136chemotaxis by, 12cytokine release by, 24definition of, 4description of, 4fin granulomatous inflammation, 58helper T cells and, 4in immune response, 4

Macrophage-activating factor, 26Mad cow disease. See Bovine spongiform

encephalopathy.Major histocompatibility complex

antigen presentation by, 17–18, 17f–18fclass I molecules, 17–18, 17f–18fclass II molecules, 4, 6, 8, 15, 18, 19f

Malaria, 269–270Malassezia furfur, 168, 173, 180Mannan, 169Mannan-binding protein, 12Mannose-binding lectin, 13f, 24, 26Marburg hemorrhagic fever, 261Marburg virus, 260–261Marshall, Barry, 128MBP. See Mannan-binding protein.McCarty, Maclyn, 48McClintock, Barbara, 49Measles, mumps, and rubella vaccine, 37–38,

240–241Measles virus, 36, 193, 239–241, 240fMechnikov, Ilya Ilyich, 60Medawar, Peter, 9Mefloquine, 270Membrane attack complex, 12Memory cells, 6, 8, 212Meningitis, 88, 109, 114, 175, 179, 247Meningococcal disease, 113Meningococcemia, 113, 113fMercaptans, 163Merkel cell polyomavirus, 205Mesophiles, 48Messenger RNA, 48Metabolic end products, 155Metagenomics, 158Metatranscriptomics, 158Metazoa, 267

Methicillin, 63fMethicillin-resistant Staphylococcus aureus,

68, 82–83Methisazone, 195Methyl mercaptan, 154Metronidazole, 66, 100–101, 108, 268–269Microbial community, 155Microbial pathogenicity, 56Microbiome, 151Microorganisms. See also Bacteria; specific

microorganism.antibiotic resistance by, 66–68, 67f, 67tin biofilms, 57definition of, 56habitat of, 155identification methods for

biochemistry, 76culture, 76microscopy, 75–76staining, 76

in oral cavity, 155–156in periodontitis, 160, 161ftransmission of, 56

Microscopyof bacteria, 40, 40fbright-field, 40, 40f, 75dark-field, 40, 40f, 75fluorescence, 40, 40f, 76microbial identification using, 75–76phase-contrast, 76

Microsporum, 181Microvesicles, 179Middle East respiratory syndrome

coronavirus, 257, 257fMiddlebrook agar, 76Miliary tuberculosis, 136–137Milstein, César, 12Minimum bactericidal concentration, 61, 61fMinimum fungicidal concentration, 183Minimum inhibitory concentration, 61, 61f,

88, 183Mixed infections, 56MMR vaccine. See Measles, mumps, and

rubella vaccine.Molds, 169Molecular diagnostics

description of, 77DNA microarray analysis, 78, 78fDNA probe analysis, 77–78DNA sequencing, 78dot blot, 78enzyme immunoassays, 79, 79fflow cytometry, 79hybridization techniques, 77–78, 78fimmune detection, 78–79real-time polymerase chain reaction, 77reverse transcription polymerase chain

reaction, 77types of, 78fWestern blotting, 79whole genomic checkerboard DNA-DNA

hybridization, 78Molluscum contagiosum virus, 257Monobactams, 64Monoclonal antibodies, 12Monocytes, 4Monod, Jacques, 50Montagnier, Luc, 208Moraxella catarrhalis, 114, 150, 153MreB, 46Mucin glycoproteins 1 and 2, 29Mucins, 29, 30tMucormycosis, rhinocerebral, 180, 180fMueller-Hinton agar, 76Mullis, Kary, 77Multidrug efflux systems, 149

Index

286

M

Multifocal papillomavirus epithelial hyperplasia, 204, 205f

Multinucleated giant cells, 24Multinucleated syncytia, 210Multiple sclerosis, 34Mumps virus, 239, 241–242Murein hydrolases, 63Murine typhus, 143Myasthenia gravis, 32Mycobacteria

atypical, 139cell wall of, 135, 135fcharacteristics of, 134staining of, 134, 135f

Mycobacterium avium-intracellulare complex, 134, 138

Mycobacterium chelonae, 139Mycobacterium fortuitum, 139Mycobacterium kansasii, 139Mycobacterium leprae, 55, 138–139Mycobacterium marinum, 139Mycobacterium scrofulaceum, 139Mycobacterium tuberculosis. See also

Tuberculosis.clinical syndromes caused by, 135–136description of, 56disseminated disease caused by, 134global incidence of, 134growth of, 45multidrug-resistant strains of, 137oral manifestations of, 137osteomyelitis of the jaw and, 166prevention of, 137rifampin for, 66staining of, 41, 41f, 136treatment of, 137

Mycobacterium ulcerans, 139Mycolic acids, 93, 135Mycoplasma pneumoniae, 57, 131–132,

132f, 154Mycoses. See also Fungal diseases.

antifungal agents for, 183–185Aspergillus, 179Blastomyces dermatitidis, 170–171, 175Coccidioides immitis, 168, 170, 175–176,

175f–176fCryptococcus neoformans, 173, 178–179cutaneous, 168, 173, 180–181Epidermophyton, 181Histoplasma capsulatum, 168, 170f, 174–

175, 174f–175fHortaea werneckii, 180Malassezia furfur, 168, 173, 180Microsporum, 181opportunistic, 168, 177f, 177–180,

179f–180fParacoccidioides brasiliensis, 176Pneumocystis jirovecii, 180Sporothrix schenckii, 181subcutaneous, 168, 173, 180–181superficial, 168, 173, 180systemic, 168, 173–176, 174f–176fTrichophyton, 181Trichosporon, 180

Myeloid progenitors, 2, 3f

Myeloma cells, 12Myonecrosis, 98

NN-acetylglucosamine, 41N-acetylmuramic acid, 41NADH. See Nicotinamide adenine

dinucleotide.Naked capsid DNA viruses

adenoviruses, 201–202, 202f–203fhuman papillomaviruses. See Human

papillomavirus.parvoviruses, 206polyomaviruses, 205–206

Naked capsid viruses, 186–187, 187fNarrow-spectrum antibiotics, 61, 61fNasopharynx

carcinoma of, 231Staphylococcus aureus in, 82–83

Natural cytotoxic cells. See Natural killer cells.

Natural killer cells, 4, 6, 11, 16, 24, 27, 218, 237

Necrotizing bronchopneumonia, 148Necrotizing enteritis, 98Necrotizing fasciitis, 107, 107fNecrotizing pneumonia, 82Necrotizing tonsillitis, 108Necrotizing ulcerative gingivitis, 162, 163fNeedlestick injuries, 213Nef, 210Negative staining, 76Neisser, Albert Ludwig, 111Neisseria, 111, 153Neisseria gonorrhoeae

adhesins used by, 57antigenic variation by, 58clinical syndromes caused by, 112description of, 45diagnosis of, 112epidemiology of, 112gonococcal conjunctivitis caused by, 112fillustration of, 112fpathogenesis of, 112postgonococcal urethritis caused by, 141transmission of, 56treatment of, 112–113

Neisseria meningitidis, 38, 58, 113–114Nematodes, 267Neomycin, 65Neonatal conjunctivitis, 141Neonatal tetanus, 99Neuraminidase, 187, 196, 199, 234Neutrophils, 5, 30Niche, 155Nicotinamide adenine dinucleotide, 47, 142Nipah virus, 239, 242Nirenberg, Marshall, 52Nocardia, 96Nongonococcal urethritis, 141Non-Hodgkin lymphoma, 231Non-nucleoside analog DNA polymerase

inhibitors, 198, 214bNon-nucleoside analog reverse transcriptase

inhibitors, 198, 214bNonparalytic poliomyelitis, 246Noroviruses, 262, 262fNorthern blot, 78Nuclear factor kappa B, 19, 26Nuclear pore complex, 190Nucleases, 163Nucleic acids, 10Nucleoid, 39Nucleoproteins, 186Nucleoside analogs, 196–198, 197f, 214bNucleotide-binding oligomerization domain

1, 129Null mutations, 49Numerical aperture, 75Nystatin, 62, 184

OO antigen, 44, 58, 120Obligate aerobes, 48

Obligate anaerobes, 48Occludin, 222Oculoglandular tularemia, 104Odontogenic abscess, 165Ogston, Alexander, 82Oligonucleotide probes, 77Oncogenic viruses, 193Onychomycosis, 181Oophoritis, 241Operons, 49–50, 51fOpportunistic infections

in acquired immunodeficiency syndrome, 211b

Aspergillus, 179Candida albicans, 177–178Cryptococcus neoformans, 173, 178–179description of, 55–56, 95, 148fungal, 177f, 177–180, 179f–180fPneumocystis jirovecii, 180Zygomycetes, 179–180

Opsonins, 26Opsonizing antibodies, 172Optimal growth temperature, for bacteria, 48Oral candidiasis, 177f, 177–178, 184, 211Oral cavity

ecosystem of, 155–156habitats of, 155–156immunity in, 29–31microorganisms in, 155–156

Oral microfloracolonization of, 156diseases caused by, 151fungi, 155Gram-negative bacilli, 154Gram-negative cocci, 153, 154fGram-positive bacilli, 153Gram-positive cocci, 85, 152Mycoplasma, 154protozoa, 155Streptococcus, 152. See also Streptococci;

specific Streptococcus.viruses, 155

Orbivirus, 261Orchitis, 241Oropharyngeal cancer, 205Oropharyngeal candidiasis, 184Oropharyngeal tularemia, 104Oropharyngeal ulcers, 174, 174fOrthomyxoviruses

definition of, 234description of, 190influenza virus. See Influenza virus.

Orthoreoviruses, 261Oseltamivir, 187, 199, 238Osteomyelitis

description of, 82, 166tuberculosis-related, 137

Osteoprotegerin, 31Otitis externa, 148Otitis media, 114, 150Outer membrane proteins, 116Owl’s eye inclusion bodies, 232, 232fOxidation-reduction potential, 156Oxidizing agents, 73Oxygen tension, 156

Pp53, 202PAMPs. See Pathogen-associated molecular

patterns.Pandemics, 234Panton-Valentine leukocidin, 83Papanicolaou-stained cervical smears, 204,

205fPara-aminobenzoic acid, 62

Index

287

P

Parachlorometaxylenol, 72Paracoccidioides brasiliensis, 170–171, 176Paracoccidioidomycosis, 176Paracresol, 72, 72fParainfluenza viruses, 239, 241Paralytic poliomyelitis, 245Paramyxoviruses

cell entry mechanisms of, 192fdiseases caused by, 239Hendra virus, 239, 243measles virus, 36, 193, 239–241, 240fmumps virus, 239, 241–242Nipah virus, 239, 242parainfluenza viruses, 239, 241replication of, 239, 240frespiratory syncytial virus, 197, 239, 242structure of, 187, 239, 240f

Parasites, pathogenicdescription of, 168, 267infections caused by, 267, 268tprotozoa. See Protozoa.

Parvimonas micra, 152Parvoviruses, 206Pasteur, Louis, 255Pasteurella, 109Pasteurellaceae, 109Pathogen recognition receptors, 24Pathogen-associated molecular patterns, 4, 24Pathogenesis, bacterial, 55–56Pathogenic bacteria, 57Pathogenicity island, 129Pattern-recognition receptors, 4, 5fPaucibacillary Hansen disease, 138PBPs. See Penicillin-binding proteins.PCR. See Polymerase chain reaction.Pegylated interferon-α, 221Pelvic inflammatory disease, 112, 131Penciclovir, 196Penicillin(s)

allergies to, 10clavulanate and, 63description of, 61development of, 63fenhanced spectrum, 63G, 63f, 112, 116Jarisch-Herxheimer reaction to, 116ß-lactam structure of, 63Neisseria meningitidis treated with, 113penicillinase-resistant, 63structure of, 63, 63fsyphilis treated with, 116V, 63f

Penicillinase, 63Penicillin-binding proteins, 62–63, 67Penicillium griseofulvin, 185Pentameric C-reactive protein, 26Pentose phosphate pathway, 47Peptidoglycan, 39, 41, 43, 43f, 82, 89Peptostreptococcus micros, 161Peptostreptococcus stomatis, 152Peracetic acid, for sterilization, 70Perforin, 22, 29Perfringolysin O, 99, 99fPeriarteritis, 115Periodontal abscess, 166Periodontal disease

bacterial products in, 163, 163tecological plaque hypothesis of, 164, 165fgingivitis, 160–162, 163fperiodontitis. See Periodontitis.

Periodontitisaggressive, 161chronic, 160–161definition of, 160host immune system in, 163–164microorganisms in, 160, 161f

Periodontium, 160, 161fPeritrichous flagella, 45Permethrin, 252Pertussis, 103–104Pertussis toxin, 104Peyer’s patches, 2, 26Phage DNA, 52Phagocytosis, 12, 26–27, 142Phagosomes, 4Pharyngitis, 86, 202Pharyngoconjunctival fever, 202Phase-contrast microscopy, 76Phenolics, 72, 72fPhenols, 72, 72fPhenol-soluble modulins, 83Phenotypic switching, 177Phosphatidylserine, 22Phosphoenolpyruvate, 47Phospholipase A, 163Phospholipase C, 99, 149Phosphonoacetic acid, 198Phosphonoformate, 196Phosphonoformic acid, 198Phosphorylation, substrate-level, 47Photoautotrophs, 47Photochromogens, 135Photoheterotrophs, 47Picornaviruses

cellular protein synthesis and, 245Coxsackieviruses, 155, 246–247description of, 186echoviruses, 247enteroviruses, 187, 247poliovirus, 245–246, 246freplication of, 244–245, 245frhinoviruses, 247–248structure of, 244–245, 245ftypes of, 244

Pili, 45, 112Pinocytosis, 267Pioneer organisms, 156Pirquet, Clemens von, 33Pityriasis versicolor, 168, 173, 180Plague, 125–126Planktonic organisms, 57Plasma cells, 2, 11Plasmacytoid-type dendritic cells, 28Plasmids, 50, 68Plasmin system, 24Plasmodium spp, 269–270, 270fPlatyhelminthes, 267Pleurodynia, 247Pneumococcal conjugate vaccine, 89Pneumocystis jirovecii, 180, 211Pneumolysin, 88Pneumonia

aspiration, 82Chlamydophila pneumoniae as cause of,

142Moraxella catarrhalis as cause of, 114Mycoplasma pneumoniae as cause of, 131necrotizing, 82Pneumocystis jirovecii, 211primary atypical, 131Streptococcus pneumoniae as cause of, 88

Pneumonic plague, 125Pneumovirus, 242pol, 209Polar flagella, 146, 147fPoliovirus

description of, 193, 193f, 245–246, 246fvaccine for, 37, 246, 246f

Poliovirus receptor, 244Polyarthritis, 206Polymerase chain reaction, 77, 87Polymicrobial infections, 56

Polymyxins, 62, 65Polyomaviruses, 205–206Polyribitol phosphate, 109Polysaccharides, 10, 27Pontiac fever, 106PorB, 112Porin proteins, 149Porins, 44Porphyromonas endodontalis, 107, 154Porphyromonas gingivalis, 30–31, 107, 154,

158, 160–162, 164Porter, Rodney, 10Posadas, Alejandro, 176Post-exposure prophylaxis, 37Postgonococcal urethritis, 141Postherpetic neuralgia, 229Poxviruses, 256f, 256–257Precursor Th cells, 20Preintegration complex, 209, 210fPrevotella intermedia, 154, 160–162Primary atypical pneumonia, 131Primary immune response, 11f, 11–12Primary infection, 55Primary lymphoid organs, 1, 2bPrimers, 77Prion protein, 263Prions, 263–265, 264fprM protein, 251Programmed cell death. See Apoptosis.Progressive multifocal leukoencephalopathy,

206Proinflammatory cytokines, 89Proline-rich proteins, 29Prophage, 52Propionibacterium acnes, 153Propionibacterium propionicus, 153Prostaglandins, 24Protease inhibitors, 30, 198, 198f, 213, 214bProteases, 163Protein A, 58, 82Protein kinase C, 19Protein secretion, 56, 56fProteus, 126Proton gradient, 47Protons, 47Protozoa, 155

blood, 269–272, 270f–271fCryptosporidium parvum, 269, 269fdescription of, 267Entamoeba histolytica, 268, 268fGiardia lamblia, 268, 269fintestinal, 268–269, 268f–269fLeishmania spp, 271, 271fmotility of, 267Plasmodium spp, 269–270, 270ftissue, 269–272, 270f–271fToxoplasma gondii, 271Trichomonas vaginalis, 268–269, 269fTrypanosoma spp, 271f, 271–272urogenital, 268–269, 268f–269f

Provirus, 209Prowazek, Stanislaus von Lanov, 143PrPSc, 263–264PRRs. See Pathogen recognition receptors.Prusiner, Stanley, 264Pseudohyphae, 169, 177Pseudomembranous candidiasis, 177, 177fPseudomembranous enterocolitis, 100Pseudomonas aeruginosa, 148–149,

148f–149fPseudopods, 267Psychrophiles, 48Puerperal endometritis, 74Purified protein derivative, 33, 136–137Pustular impetigo, 58Puumala virus, 252

Index

288

P

Pyocyanin, 148–149Pyoderma, 86Pyogenic infections, 56, 82Pyogenic inflammation, 58Pyoverdin, 148Pyrimethamine, 271Pyrogenic exotoxins, 86Pyrogens, 26, 56Pyroptosis, 24Pyruvate, 47

QQ fever, 106, 142, 144–145Quaternary ammonium salts, 73, 73fQuellung reaction, 88Quinine, 270Quinolones, 62, 66, 68

RR factors, 49R plasmids, 50, 68R5 virus, 211Rabies virus

description of, 190, 254–256, 255fvaccine for, 37, 256

Ras pathway, 19Ras-GTP, 19Real-time polymerase chain reaction, 77Receptor activator of nuclear factor-κB

ligand, 31Receptor-mediated endocytosis, 189–190,

191fRecombinant DNA, 52, 53fRecombinant soluble CD4, 195Recombination, 50–51Recurrent respiratory papillomatosis, 204Redox potential, 156Regulatory T cells, 6, 21f, 22Relapsing fever, 117–118Reoviruses, 261Repressible genes, 49Resolving power, of microscope, 75Respiratory anaphylaxis, 32Respiratory burst, 4Respiratory syncytial virus, 197, 239, 242Restriction enzymes, 52Reticulate body, 140Retinoblastoma gene product, 202Retroviruses

definition of, 208endogenous, 215human immunodeficiency virus. See

Human immunodeficiency virus.human T-cell lymphotropic virus, 215replication of, 208

Rev, 210Reverse transcriptase, 208Reverse transcription polymerase chain

reaction, 77Reverse transcription, 209Reverse transcription quantitative

polymerase chain reaction, 262Rev-responsive element, 210Reye syndrome, 237Rhabdoviruses, 190, 254–256Rheumatic fever, 34Rheumatoid arthritis, 34Rhinocerebral mucormycosis, 180, 180fRhinoviruses, 247–248Ribavirin, 196, 197, 197f, 223, 224Ribonucleic acid. See RNA.Ribosomal RNA, 48Ribozyme, 223Rice-water stools, 146

Ricketts, Howard Taylor, 143Rickettsia akari, 144Rickettsia prowazekii, 143Rickettsia rickettsii, 143Rickettsia typhi, 143Rickettsiae, 142–144Rifabutin, 66, 138Rifampin, 62, 66, 138Rimantadine, 195, 198–199, 238Ringworm, 168, 173, 181Ritonavir, 198, 213Ritter disease. See Staphylococcal scalded

skin syndrome.Rituximab, 206RNA

antiviral agent targeting of, 196description of, 184genomic, 236messenger, 48ribosomal, 48transfer, 48

RNA polymerase, 222RNA polymerase II, 209, 223RNA viruses, 187, 188t–189t, 189–190Roberts, Richard J., 203Rocky Mountain spotted fever, 142–143Rod-shaped bacteria, 39Rolling circle replication, 50Root canal infections, 166bRoseola infantum. See Exanthem subitum.Ross, Ronald, 270Rotaviruses, 261, 261fRowe, Wallace, 202RT-PCR. See Reverse transcription

polymerase chain reaction.Rubella virus

description of, 259–260, 260fvaccine for, 37–38, 240–241

Rubeola virus, 240

SSabin polio vaccine, 37, 246, 246fSabouraud dextrose agar, 76Saliva, 155Salk, Jonas, 37, 246Salk polio vaccine, 37, 246, 246fSalmonella, 123f, 123–124Salmonella pathogenicity island 1, 123Salpingitis, 112Sanger, Fred, 52–53, 53fSaprobes, 168SARS. See Severe acute respiratory

syndrome.Scardovia, 153Scarlet fever, 86, 87fSchatz, Albert, 61Scrapie-associated fibrils, 263Scrapie-like prion protein, 263Secondary immune response, 11f, 11–12Secondary infection, 55Secondary lymphoid organs, 1, 2bSecond-generation cephalosporins, 64Secretory immunoglobulin A

antibodies, 29description of, 11, 30t, 112

Secretory immunoglobulin A protease, 88Secretory leukocyte protease inhibitor, 30Selective toxicity, 60Self-antigens, 8Self-renewing stem cells, 2, 3fSem