Failures of Host Defense Mechanisms

Failures of Host DefenseMechanisms

Dr. Sheeba Murad Mall

• In the normal course of an infection, the infectious agent first triggers an innate immune response

• The foreign antigens of the infectious agent, enhanced by signals from innate immune cells, then induce an adaptive immune response that clears the infection and establishes a state of protective immunity

• This does not always happen• There are possibilities in which there are failures of host defense

against pathogens:– the avoidance or subversion of a normal immune response by the pathogen– inherited failures of immune defenses because of gene defects– acquired immune deficiency syndrome (AIDS), a generalized susceptibility to

infection that is itself due to the failure of the host to control and eliminate the human immunodeficiency virus (HIV)

The most successful pathogens persist either because they do not elicit an immune response or because they evade the response once it has occurred

Over millions of years of co-evolution with their hosts, pathogens have adapted various strategies for avoiding destruction by the immune system

Evasion and subversion of immune defenses

• Just as vertebrates have developed many different defenses against pathogens, so pathogens have evolved numerous ways of overcoming them

• some pathogens have adapted mechanisms to keep one step ahead of the adaptive immune response like:– resisting phagocytosis – avoiding recognition by the adaptive immune system– actively suppressing immune responses

Antigenic variation allows pathogens (bacteria) to escape from immunity

• antigenic variation (extracellular pathogens- generally eliminated by antibodies against their surface structures):– Streptococcus pneumoniae (bacterial

pneumonia)- 84 types/ serotypes differ in their structure of polysaccharide capsules

– Different serotypes result in to a situation that essentially the same pathogen can cause disease many times in the same individual

Fig. 13.1 Host defense againstStreptococcus pneumoniae is typespecific. The different strains ofS. pneumoniae have antigenically distinctcapsular polysaccharides. The capsuleprevents effective phagocytosis untilthe bacterium is opsonized by specificantibody and complement, allowingphagocytes to destroy it. Antibodyagainst one type of S. pneumoniaedoes not cross-react with the othertypes, so an individual immune to onetype has no protective immunity to asubsequent infection with a differenttype. An individual must generate a newadaptive immune response each time heor she is infected with a different type ofS. pneumoniae.

Antigenic variation allows pathogens (viruses) to escape from immunity

• Two important mechanisms adapted by viruses include:– Antigenic drift is mechanism of immune evasion by viruses especially in

case of influenza virus• point mutations in the genes encoding hemagglutinin and a second surface protein,

neuraminidase• Every 2-3 years a variant flu virus arises with mutations that allow it to evade neutralization by

the antibodies present in the population• Other mutations affect epitopes in the proteins that are recognized by T cells particular CD8 cytotoxic T cells• An epidemic resulting from antigenic drift is usually relatively mild

– Antigenic shift and is due to major changes in the hemagglutinin of the virus• Antigenic shift is due to reassortment of the segmented RNA genome of the human virus and

animal influenza viruses in an animal host, in which the hemagglutinin gene from the animal virus replaces the hemagglutinin gene in the human virus

• Antigenic shifts cause global pandemics of severe disease, often with substantial mortality, because the new hemagglutinin is recognized poorly, if at all, by antibodies and T cells directed against the previous variant

Fig. Two types of variation allow repeated infection with type A influenza virus. Neutralizing antibody that mediates protective immunity is directed at the viral surface protein hemagglutinin (H), which is responsible for viral binding to and entry into cells. Antigenic drift (left panels) involves the emergence of point mutants with altered binding sites for protective antibodies on the hemagglutinin. The new virus can grow in a host that is immune to the previous strain of virus, but as T cells and some antibodies can still recognize epitopes that have not been altered, the new variants cause only mild disease in previously infected individuals. Antigenic shift (right panels) is a rare event involving the reassortment of the segmented RNA viral genomes of two different influenza viruses, probably in a bird or a pig. These antigen-shifted viruses have large changes in their hemagglutinin, and therefore T cells and antibodies produced in earlier infections are not protective. These shifted strains cause severe infection that spreads widely, causing the influenza pandemics that occur every 1 0-50 years. There are eight RNA molecules in each viral genome, but for simplicity only three are shown.

Antigenic variation allows pathogens (parasite) to escape from immunity

• antigenic variation in pathogens involves programmed gene rearrangements major health problem in Africa is the sleeping sickness

• Malaria is another serious and widespread disease caused by a protozoan parasite that varies its antigens to avoid elimination by the immune system

• African trypanosomes are insect-borne protozoan parasites that replicate in the extracellular spaces of tissues and cause the disease known as trypanosomiasis or sleeping sickness

• In African trypanosomes changes in the major surface antigen occur repeatedly within the same infected host

• The trypanosome is coated with a single type of glycoprotein, the variant-specific glycoprotein (VSG), which elicits a potent protective antibody response that rapidly clears most of the parasites

• The trypanosome genome, however, contains about 1000 VSG genes, each encoding a protein with distinct antigenic properties

• A VSG gene is expressed by being placed into the active expression site in the parasite genome• Only one VSG is expressed at a time, and it can be changed by a gene rearrangement that places a

new VSG gene into the expression site• T he few trypanosomes with changed surface glycoproteins are not affected by the antibodies

previously made by the host, and these variants multiply and cause a recurrence of disease• Antibodies are then made against the new VSG, and the whole cycle is repeated

• The chronic cycles of antigen clearance lead to immune-complex damage and inflammation, and eventually to neurological damage, resulting finally in the coma that gives sleeping sickness its name

Antigenic variation by DNA rearrangement in bacteria

• Salmonella enterica serotype Typhimurium, a common cause of salmonella food poisoning

• Salmonella Typhimurium regularly alternates two versions of its surface flagellin protein

• Inversion of a segment of DNA containing the promoter for one flagellin gene turns off expression of the gene and allows the expression of a second flagellin gene that encodes an antigenically distinct protein

• Neisseria gonorrhoeae, which causes gonorrhea, a major sexually transmitted disease and an increasing public-health problem in the United States

• N. gonorrhoeae has several variable antigens, the most important of which is the pilin protein, which is responsible for adherence of the bacterium to a mucosal surface

• Like the VSGs of the African trypanosome, there is more than one pilin gene variant, only one of which is active at any given time

• From time to time, a different pilin gene replaces the active gene under the control of the pilin promoter

Some viruses persist in vivo by ceasing to replicate

• To replicate, a virus must make viral proteins, and rapidly replicating viruses that produce acute illnesses are readily detected by T cells, which normally control them

• Some viruses, however, can enter a state known as latency, in which the virus is not being replicated

• In the latent state, the virus does not cause disease; however, because there are no viral peptides to signal its presence it cannot be eliminated

• Latent infections can be reactivated, and this results in recurrent illness

• herpesviruses, which are characterized by their ability to establish lifelong infections

• An example is herpes simplex virus (HSV), the cause of cold sores, which infects epithelial cells and spreads to sensory neurons serving the infected area

• local epithelial infection is resolved by an effective immune response

• However the virus persists in a latent state in the sensory neurons

• Factors such as sunlight, bacterial infection, or hormonal changes reactivate the virus, which then travels down the axons of the sensory neuron and re-infects the epithelial tissues

• This cycle can be repeated many times

Persistence and reactivation of herpes simplex virus infection. The initial infection in the skin is cleared by an effective immune response, but residual infection persists in sensory neurons such as those of the trigeminal ganglion, whose axons innervate the lips. When the virus is reactivated, usually by some environmental stress and/or alteration in immune status, the skin in the area served by the nerve is reinfected from virus in the ganglion and a new cold sore results. This process can be repeated many times

why the sensory neuron remains infected?

• first, the virus is quiescent and generates few virus-derived peptides to present on MHC class I molecules

• second, neurons carry very low levels of MHC class I molecules, which makes it harder for CD8 cytotoxic T cells to recognize infected neurons and attack them

Why low MHC I expression on neurons?

Why low MHC I expression on neurons?

• The low level of MHC class I expression might be beneficial for neuronal survival, in order to avoid the inappropriate attack of cytotoxic T cells on neurons

• however, the low MHC I expression make neurons vulnerable to persistent infections

• Brain is an immunocompromised organ due to the Low MHC I expression-

herpes zoster usually reactivates only once in a lifetime in an immunocompetent host

• Herpes zoster (varicella zoster), which causes chickenpox remains latent in one or a few dorsal root ganglia after the acute illness is over, and can be reactivated by stress or immunosuppression

• It then spreads down the nerve and reinfects the skin to cause the disease shingles, which is marked by the reappearance of the classic varicella rash in the area of skin served by the infected dorsal root

Shingles- marked by the reappearance of the classic varicella rash