L11 - Immunity against Infection: evasion of host defences & immunopathology in infection Flashcards
Evasion mechanisms that pathogens have evolved
- Concealment of antigens
- Antigenic variation
- Immunosuppression
- Interference with effector mechanisms
Concealment of antigens
Pathogens evade attack by immune system by living inside cells (cloak effect)
• e.g. Schistosomes (bilharzia) – takes on the host cells so not recognised by the immune system
Or live beyond the reach of antibodies (privileged sites)
• e.g. latency of Herpes zoster virus in CNS (chicken pox -> shingles)
Cold sores
Caused by Herpes Simplex virus
Likes to live in the trigeminal nerves
Can be reactivated during periods of stress
What is antigenic variation?
Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response
Types of antigenic variation
Large number of antigenic types
Mutation (antigenic drift)
Recombination (antigenic shift)
Gene switching
ANTIGENIC VARIATION
Large number of antigenic types
Example
Streptococcus pneumoniae
- Causes otitis media, sinusitis, bronchitis and pneumonia; also bacteremia and meningitis
- Gram positive; surrounded by a thick polysaccharide capsule which protects it from phagocytosis
- Antibodies to the capsule opsonise the bacteria and protect
- Large number of different capsular types (91)
Streptococcus pneumoniae vaccines
Streptococcus pneumoniae – 23 major disease causing polysaccharide capsules (strains)
Vaccines:
• Pneumovax
• Prevnar 13
Pneumovax vaccine against Streptococcus pneumoniae
Polysaccharide vaccine (contains antigens to all 23 capsules)
Not effective in children under two or those with poor immune function (eg. HIV) – low level response – just B cell IgM response
Prevnar 13 vaccine against Streptococcus pneumoniae
Conjugate vaccine
Only 13 capsule antigens but bound to the diphtheria toxoid which is highly immunogenic but non-toxic
T cell and B cell (all Ig) response
Converts TI-2 polysaccharide antigen to a TD form
Better for children: young children cannot produce an immune response to polysaccharides
Why can young children not produce an immune response to polysaccharides?
Thought to be due to immunologic immaturity
ANTIGENIC VARIATION
Antigenic drift and shift
Example
Influenza virus
- An RNA virus with a negative sense segmented genome
- Can infect humans, birds and other animals
- Causes epidemics and pandemics
- Major surface antigens are haemagglutinin and neuraminidase
- Can undergo antigenic drift (epidemics) and antigenic shift (pandemics)
What causes epidemics?
Antigenic drift
What causes pandemics?
Antigenic shift
ANTIGENIC VARIATION
Gene switching
Example
Trypanosoma brucei
- Protozoal parasite that causes African sleeping sickness
- Spread by the tsetse fly – warm climates
- Patients undergo bouts of parasitemia
- Correlates with changes in the major surface antigen of the trypanosome, brought about by genetic rearrangement
- Variant-specific glycoprotein (VSG) – antibodies don’t recognise the epitope
IMMUNOSUPPRESION
What are the 2 types?
Infection of immune cells
Induction of regulatory T cells
IMMUNOSUPPRESION
Infection of immune cells
Example
HIV
- Depletion of CD4+ cells
- Opportunistic infections in the symptomatic phase
IMMUNOSUPPRESION
Induction of regulatory T cells
Example
Helicobacter pylori
- Gram negative bacterium that causes gastric and duodenal ulcers (also gastric adenocarcinomas)
- Regulatory T cells may be involved in allowing it to establish a persistent infection
What do regulatory T cells do?
- Type of CD4+ cell
- Regulate the immune system – suppress differentiation and proliferation of TH1 and TH2 cells
- Immunosuppressive eg IL10
- Maintain tolerance to self-antigens
- Help prevent autoimmune disease
Induction of regulatory T cells in Leishmania
Immunosuppression
- Parasite – genus of trypanosomes
- Vector – sand fly
- Can hide and survive in macrophages
- Can increase expression of Treg cells
- Decrease immune response
Measles virus
An RNA virus; disease is associated with a rash commonly accompanied by profound malaise and respiratory symptoms
Complications include secondary bacterial respiratory infections
Causes immunosuppression which can lead to secondary infections
Shown to infect dendritic cells
Infection of dendritic cells by measles virus causes what effects?
Increased apoptosis
Decreased stimulation of T cells
Decreased IL-12 production (NK cells and TH1 affected – response dampened down)
EVASION OF THE IMMUNE DEFENCES
How do pathogens interfere with effector mechanisms?
Molecules interfering with antibody function
Molecules interfering with complement
Molecules binding cytokines
Subvert responses by producing molecules with cytokine activity
Inhibition of phagocytic killing
EVASION OF THE IMMUNE DEFENCES
Molecules interfering with antibody function
e.g IgA proteases chop up IgA (Streptococcus pneumoniae, Neisseria spp.)
Fc-binding molecules – bind to FcR on immune cells to activate them (Staphylococcal protein A; Herpes simplex virus)
EVASION OF THE IMMUNE DEFENCES
Molecules interfering with complement
Enzymes that break down C3a/C5a (Pseudomonas)
Molecules that inhibit complement activation (Vaccinia/smallpox virus)
EVASION OF THE IMMUNE DEFENCES
Molecules binding cytokines
E.g. Vaccinia (small pox,IFNγ)
EVASION OF THE IMMUNE DEFENCES
Subvert responses by producing molecules with cytokine activity
E.g. Epstein Barr Virus produces vIL-10 (downregulates TH1 Response)
Epstein Barr virus causes glandular fever
IL-10 made by T-regs – downregulates response using vIL-10 – increases chance of the virus surviving
EVASION OF THE IMMUNE DEFENCES
Inhibition of phagocytic killing
E.g. M. tuberculosis
Stops fusion of phagosome & lysosome
Results in granulomas
What does infectious disease pathology result from?
Direct effects of pathogen (e.g. toxins)
Host responses (innate or specific)
Pathological consequences of INNATE immune responses
- LPS induces macrophage cytokine secretion (IL1, TNF-alpha & TLR4)
- Systemic effects: fever, endotoxic shock
- Possible can lead to death
- TNF-alpha is the most potent one produced
- Local infection contained = successful outcome
- Systemic infection, sepsis & mass cytokine release = death
Pathological consequences of SPECIFIC immune responses
- Antibodies and/or T cell reactions may contribute to pathology
- E.g. skin rashes in measles due to T cell response
- E.g. granuloma formation in TB due to chronic macrophage activation
What is ebola?
Filovirus: enveloped, non-segmented negative stranded RNA with filamentous particles
Causes hemorrhagic fever
Outbreak in West Africa is the largest in history
• High fatality rate: around 70% reported
Ebola & evasion of immune responses
- Infects immune cells including dendritic cells and macrophages
- Inhibits maturation of infected dendritic cells so they do not present antigen effectively
- Causes apoptosis leading to reduced numbers of circulating T lymphocytes and NK cells and weakened immune responses
- Interferes with the production of type I interferon
- Also interferes with the cellular response to interferon
What is immunopathogenesis?
The process of disease development involving an immune response or components thereof
