03/06d Host-Pathogen Interactions & Vaccines Flashcards
What are the five general features of immune responses to microbes, and microbe responses to the immune system?
1) Always involve innate and adaptive immunity
2) Distinct and specialized responses to different types of microbes for maximum effectiveness
3) Microbes evade or resist effector mechanisms
4) Many microbes can establish latent infections, that the immune system can control but does not eliminate
5) Tissue injury and disease can be caused by the host response rather than the microbe itself
For what types of things are immune responses specialized to fight? Name five
Extracellular bacteria Intracellular bacteria Viruses Fungi Parasites
What are the innate and adaptive responses to extracellular bacteria?
Innate - activation of complement, phagocytes, and inflammation
Adaptive - humoral (antibodies block infection, opsonize microbes, and neutralize toxins) and CD4 helper T cells (enhance phagocytic and microbicidal activities of macrophages and neutrophils, and stimulate antibody production)
What types of effector T cells are stimulated by extracellular bacteria? What are their responses?
Th1 and Th17 cells
Th17 responses - IL-17 induces production of cytokines, which recruit neutrophils and monocytes
Th1 responses - IFN activates macrophages to destroy phagocytosed microbes and induces opsonization and complement-binding
What are four immune pathologies associated with extracellular bacterial infection?
Excessive inflammation
Abscess formation
Septic shock
Toxic shock
How does your immune system cause excessive inflammation?
Result of reactions of neutrophils and macrophages
Local production of ROS and lysosomal enzymes can kill bacteria AND damage tissue
What is an abscess? How is it formed?
An abscess is the creation of a new anatomical space for the purpose of containing a bacterial infection
Neutrophils accumulate (pus), but are not sufficient to eliminate the infection
NOT penetrated by antibiotics - require surgical drainage
How is an empyema different from an abscess?
An empyema is the accumulation of pus in a preexisting anatomical space, rather than the formation of a new anatomical space
What is septic shock? What causes it?
Consequence of disseminated infection by certain bacteria (many have LPS)
Caused by widespread release of cytokines (TNF, IL-6, IL-1) by activated macrophages
Results in circulatory collapse and intravascular coagulation
Treatment - ICU, antibiotics
What is toxic shock? What causes it?
Caused by Staph and Strep infections which produce toxins that are superantigens - activate many T cells and cause cytokine storm
Disseminated infection is not required
Associated with anything that predisposes to Staph and Strep infections (surgery, childbirth, skin wounds)
How do extracellular bacteria evade the immune system? List six ways
1) Resist phagocytosis (polysaccharide-rich capsule) and complement (sialic acid residues)
2) Catalase - scavenges ROS
3) Antigenic variation - extensive mutation of dominant epitopes to evade detection
4) Molecular mimicry - if bacterial antigens resemble self proteins, the immune response may be weak, or may be directed at self
5) Coagulase and clumping factor cause fibrin to clot and deposit on cell surfaces
6) Proteins produced by Staph and Strep bind up Ig
What are the innate responses to intracellular bacteria?
Expression of NK cell-activating ligands on infected cells
Activated NK cells kill infected cells
Stimulation of dendritic cells and macrophages to produce IL-12 and IL-15
Innate response often fails to eradicate the microbe
What are the adaptive responses to intracellular bacteria?
Th1 cells produce IFN
IFN activates macrophages to destroy phagocytosed microbes and induces opsonization and complement binding
Th1 cells also activate macrophages through CD40L
Macrophages produce IL-12, which stimulates NK cells
If the macrophages fail to eliminate the infection, CD8 cytotoxic T cells kill the infected cells
How do intracellular bacteria evade the immune system?
Able to survive inside cells - hide from antibodies and complement
Stimulate inappropriate T cell polarization - Th2 cells inhibit Th1 cells, thus preventing the destruction of intracellular bacteria
What is the major immune pathology associated with intracellular bacteria?
Granulomas
What are the innate responses to virus infection?
PRRs recognize viral PAMPs
Immediate response - production of Type I Interferon, which induces an antiviral state in adjacent uninfected cells
PAMPs also induce NK cell activating receptors - NK cells kill virus-infected cells
What are the humoral adaptive responses to virus infection?
Antibody production - neutralizing antibodies block virus binding and entry, which can prevent both initial infection and spread
Effective against viruses only during their extracellular stage
Major determinant of immunity to most viruses
IgA - important for neutralizing viruses at mucous membranes (respiratory and GI tracts)
What are the cell-mediated adaptive responses to virus infection?
Activation of CD8 cytotoxic T cells, which recognize viral peptides presented on MHC I
If dendritic cells are not infected, they phagocytose infected cells and transfer viral peptides from the phagosome to MHC I (cross-presentation)
CD8 cells undergo massive proliferation
CTLs require cytokines produced by CD4 helper cells
How do viruses evade the immune system? List five ways
1) Can alter their antigen through mutation until they no longer evoke immune responses
2) Some inhibit MHC I-associated presentation of viral peptides
3) Produce MANY molecules that inhibit immune responses (cytokine and interferon production in particular)
4) Infect and kill/inactivate immunocompetent cells
5) Establish latency
What is antigenic drift?
Constant mutation of viruses, combined with strong selection pressure of the immune system, that leads to neo-epitopes that are not recognized by the immune antibodies
What is antigenic shift?
Different variants of a virus that both infect a single host, and are thereby able to exchange genetic material, possibly resulting in a “super virus” (one with multiple devastating characteristics)
What is viral latency?
Persistence of viral DNA in a host cell, without viral replication of destruction of the host cell (state of balance)
Virus reactivates when host immunity diminishes
Common with EBV and certain DNA viruses in the herpesvirus family
What are the immune pathologies associated with virus infection?
Anti-viral responses are extremely strong! can destroy local (uninfected) cells and induce systemic effects
CTLs may kill virus-infected cells even when the virus is not cytopathic (HBV)
What are the innate and adaptive response to fungi?
Innate - activation of phagocytes
Adaptive - activation of CD4 helper T cells (Th1 or Th17 responses)
Often have a combination of responses
How do fungi evade the immune system?
Produce molecules that inhibit the immune response - inhibit production of TNF and IL-12, and stimulate production of IL-10 (anti-inflammatory)
Inhibit the function of the phagolysosome and result in formation of granulomas
What are the innate and adaptive responses to parasites?
Innate - activation of phagocytes and complement
Adaptive - intracellular parasites lead to Th1 responses, helminths lead to Th2 responses with IgE fixation and eosinophils
What cytokines are released by Th2 cells in response to helminthic infections?
IL-4, IL-5, and IL-13
What are the humoral effects of IL-4 and IL-13?
Stimulate maturation of naive B cells and production of IgE
What happens when IgE is cross-linked by helminthic antigens?
Mast cell activation
What are the three responses of activated mast cells?
Degranulation - release of histamine and proteases
Synthesis and secretion of lipid mediators (leukotrienes and prostaglandins)
Synthesis and secretion of TNF
What are the five major anti-parasite responses effected by mast cells?
1) Increased vascular permeability and inflammation
2) Gut and bronchial constriction to expel parasites
3) Mucous production to trap parasites
4) Direct parasite toxicity
5) IgE-dependent cellular toxicity (eosinophils)
How do parasites evade the immune system?
Stage-specific changes in antigen expression - parasites produce different antigens during different life cycles
Continuous variation of major surface antigens
Concealment in host cells or within cysts
Production of molecules that inhibit the immune response
How do most vaccines work?
By inducing humoral immunity
What two things are required for a vaccine to induce immunity?
1) Antigen
2) Something to stimulate an immune response
In some cases, one substance can do both
What are the six types of vaccines?
1) Live attenuated or killed bacteria
2) Live attenuated viruses
3) Subunit
4) Conjugate
5) Synthetic
6) Viral vectors
What are attenuated and inactivated vaccines? What are some of their advantages and disadvantages?
Composed of intact nonpathogenic microbes
Advantages - elicit all the normal innate and adaptive immune responses (the ideal way of inducing protective immunity)
Disadvantages - may cause disease in some patients, and killed bacterial vaccines in use today tend to induce limited protection
What are subunit or purified vaccines?
Composed of antigens purified from microbes or toxin
Non-immunogenic - require an adjuvant
Often used with toxoids
What is a toxoid?
Toxin that is inactivated without loss of immunogenicity
What are conjugate vaccines?
Used for bacterial polysaccharides (T-independent antigens that tend to elicit weak antibody responses)
Polysaccharides are couple to proteins to form a conjugate, and are injected with adjuvant
Stimulate T-B cell cooperation to generate higher-affinity antibodies
What are synthetic antigen vaccines? What are some examples of these types of vaccines?
Identification and production of antigens by recombinant DNA technology
Require adjuvant
Hepatitis, herpes simplex, and HPV have synthetic antigen vaccines
What are live viral recombinant vaccines?
Composed of genes that encode pathogen antigens inserted into non-cytopathic viruses, that are then used to infect individuals and induce full immunity
Some safety concerns have limited widespread use
What is an adjuvant? What does it do?
Something that stimulates an innate immune response (takes the place of a PAMP)
Generate “depots” that trap antigen at infection site, which enhances persistence and results in a more and longer antigen presentation
Encourage antigen uptake by dendritic cells
What is the only adjuvant approved by the FDA in the last 80 years? What are its effects?
Aluminum hydroxide salts (alum)
Produces the depot effect, promotes phagocytosis, activates APCs, and stimulates Th2 cell responses
