Pathology of Inhalational Anthrax Animal Models

Special Focus: Research Challenges and Animal Models in Biological Defense Pathology of Inhalational Anthrax Animal Models N. A. Twenhafel 1 Abstract Anthrax is a lethal disease caused by the bacterium Bacillus anthracis. There are three principal forms of the disease in humans— cutaneous, gastrointestinal, and inhalational—depending on the route of exposure. Of these, inhalational anthrax is the most dangerous; it is rapidly fatal; and it has been used as a deadly biological warfare agent in the last decade. Suitable animal models of inhalational anthrax have been utilized to study pathogenesis of disease, investigate bacterial characteristics such as virulence, and test effectiveness of vaccines and therapeutics. To date, mice, guinea pigs, rabbits, and nonhuman primates are the principal animal species used to study inhalational anthrax. Mice are valuable in studying early pathogenesis and bacterial characteristics. Few pathologic changes occur in the mouse models but may include marked bacteremia and lymphocyte destruction in the spleen and mediastinal lymph nodes. Rabbits and guinea pigs rapidly develop fulminate systemic disease, and pathologic findings often include necrotizing lymphadenitis; splenitis; pneumonia; vasculitis; and hemorrhage, congestion, and edema in multiple tissues. Nonhuman primates consistently develop the full range of classic lesions of human inhalational anthrax, including meningitis; lymphadenitis; splenitis; mediastinitis; pneumonia; vasculitis; and hemorrhage, congestion, and edema in multiple tissues. This review focuses on basic characteristics of the bacterium and its products, key aspects of pathogenesis, and the pathologic changes commonly observed in each animal model species. Keywords animal models, anthrax, Bacillus anthracis, biological warfare agent, inhalational anthrax Anthrax is a dangerous bacterial infection of livestock and humans caused by the gram-positive spore-forming bacterium Bacillus anthracis. The spores may remain dormant yet viable in the environment for decades. It is also of great concern as a biological weapon and is categorized by the Centers for Disease Control as a category A biological threat agent. Human anthrax is often classified as cutaneous, inhalational, or gastrointestinal, according to the route of bacterial infection. All forms may be lethal in humans and animals. Inhalational anthrax is of particular concern because mortality rates of untreated human cases may approach 100%, compared with 10 to 20% for the cutaneous form. Human cases studied to date have involved natural infections, such as occupational exposure (woolsorter’s disease) 2,3,11 as well as cases arising from either accidental or intentional release of B anthracis. 5,24,25 In the United States in 2001 there was intentional release of this agent in a series of bioterrorism attacks, and in 1979 in Sverdlovsk (of the former Soviet Union) there was accidental release of an aerosolized infective cloud of B anthracis. Information gathered from dozens of patients and victims from these events has led to a greater understanding of the human disease and appropriate medical treatment for improved patient survival. 1,10,36 Currently, two Food and Drug Administration– approved anthrax vaccines are available and used for at-risk individuals. Ongoing studies are aimed at (1) developing improved vaccines that provide increased immune protec- tion 26,49,52,57 and (2) testing the effectiveness of combination therapies, such as vaccination with postexposure antibiotics. 62 Approved antibiotics are also available to treat human anthrax; however, their success in treating the disease is partially based on early diagnosis and immediate initiation of treatment fol- lowing exposure, drug choice and dose, and duration of therapy. Inhalational anthrax has a rapid disease course, and death may occur in humans and animals within a few days of exposure, if left untreated. 17 Inhaled spores enter the respiratory sys- tem, including the upper respiratory tract, lungs, terminal airways, and alveoli, and may be taken up by phagocytic cells (alveolar macrophages and dendritic cells) 12,13 in which they have been shown to germinate. 14,37,55,65 Infected phagocytic cells move into the lymphatic vessels and are taken to the 1 US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland Corresponding Author: Nancy A. Twenhafel, DVM, Diplomate ACVP, Pathology Division, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702 Email: [email protected] Veterinary Pathology 47(5) 819-830 ª The American College of Veterinary Pathologists 2010 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0300985810378112 http://vet.sagepub.com 819

Pathology of Inhalational Anthrax Animal Models

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