Download Chapter 11: Immunological Responses to Microbes

Chapter 11: Immunological Responses to Microbes
General Features
- Microbes must surpass physical and chemical barriers and then deal with innate
and adaptive immune systems in order to establish an infection
- Intracellular bacteria use the macrophage to grow by preventing fusion of the
lysosome with the phagosome (Classic example is Mycobacterium tuberculosis
 causative agent of TB)
- Extracellular bacteria with polysaccharide capsule prevent phagocytosis
(remember proteins usually antigenic meaning that only proteins cause a good
immune response)
- Other extracellular bacteria secrete toxins that cause diarrhea or massive
proliferation followed by cell death (apoptosis).
Host Defenses to Extracellular Bacteria
General features
- eliminated by soluble mediators and phagocytosis
- Examples of extracellular bacteria
1. Borrelia burgdorferi  Lyme’s disease; transmitted by ticks and enter
bloodstream
2. Staphylococcus aureus  localized skin infections (boils, furuncles);
becomes pathogenic when intact skin barriers are broken
3. Neisseria gonorrhea  gonorrhea; eliminated by complement mediated
osmotic lysis it prevents both direct and opsonin mediated phagocytosis
4. Streptococcus pneumonia  bacterial pneumonia
Physical and chemical barriers
- Physical barriers: intact skin, mucosal surfaces, mucosal secretions have
bactericidal and bacteriostatic proteins (e.g. lactoferrin  binds iron required for
bacteria to grow; lysozyme  cleaves bacterial cell wall); mucus layer
Phagocytes, phagocytosis, and cytokines
- Phagocytosis is the primary mechanism by which extracellular bacteria are
eliminated
- Opsonins enhance phagocytosis (e.g. C3b, IgG)
- Opsonins do not affect the destruction of the organism; this depends on the fusion
of the phagosome with the lysosome, and release of bactericidal products 
reactive oxygen intermediates (via activation of NADPH oxidase), nitric oxide,
and reactive nitrogen intermediates
- Activated macs secrete cytokines
- Production of many bactericidal factors enhanced by the cytokine IFN- & TNF.
Complement
- opsonin (C3b)
- MAC  destruction by osmotic lysis
Antibodies
- activate classical pathway (IgM & IgG  IgM better)
- opsonins
- neutralize toxins
CD4+ T cells and cytokines
- Type 1 cytokines (IFN- and TNF) enhance killing by phagocytes
- T cell derived cytokines required for B-cell activation which leads to isotype
switching and differentiation to plasma cells which secrete antibody.
Resistance to Immunity: Extracellular Bacteria
Streptococcus pneumonia
- polysaccharide capsule prevents phagocytosis
- B cell activation occurs but mostly IgM produced (Why? Type II T-independent
response (Remember: pneumococcal polysaccharide) which isn’t very effective)
- Polysaccharide not processed by MHCII (remember: only protein is)  CD4s not
activated  no B cell help  no isotype switching
- T-independent antigens lack memory so this infection can prove fatal
- No IgG produced  no opsonization (no activation of innate immunity)
Host Defenses to Viruses
General features
- Epstein-Barr Virus (causative agent of mononucleosis) encodes an IL-10-like
molecule that inhibits cytotoxic T cells required to kill virally infected cells
(Why? IL-10 inhibits Th1 response since it is a Type 2 cytokine  no IL-2
produced  no activation of Thp)
- Requires either NK cells or cytotoxic T cells
- IL-2 (type 1 cytokine) required to activate cytotoxic T cells (CD8)
- When viral particles bud from the cell antibodies or phagocytes effective
Phagocytes, phagocytosis and cytokines
- if virus is found in blood, lymph or interstitial fluid they may be phagocytosed
- viruses only found in fluids during the initial infectivity stage or when released
from cell
- phagocytosis is not a primary mechanism to eliminate viral infections
Natural killer cells and osmotic cell lysis
- Two ways in which NKs kill virally infected cells:
1. Direct: NK receptor  recognizes viral proteins on infected cell surface
2. Indirect: FcgR  ADCC = antibody-dependent cellular cytotoxicity (Fc
portion Ab bound to virus binds to NK cell)
- NK cell  perforin  osmotic lysis
- Perforin does not kill NK cell
- NKs most effective during the early phase of infection
-
NKs have killer inhibitory receptor (KIR)  binds to MHCI  no killing 
CD8s kill virally infected cells by binding to MHCI
Increased expression of MHCI by the action of IFNturns off NKs
CD4+ T cells and cytokines
- dendritic cells dectect viral particles in interstitial fluid, blood or lymph, antigen
presentation occurs ONLY during the initial infectivity stage or when virus is
released
- differentiation to Th1 required to secrete IL-2 in order for naïve CD8s to
differentiate into CTLs
B cells and antibody production
- IgG neutralize free virus by binding to receptor for virus so that it can’t bind and also
promote its phagocytosis
CD8+ T cells and osmotic cell lysis
- use perforin to cause osmotic lysis of the virally infected cell
Comparison of CTL and NK cell responses to viral infections
- lethal hit is the same (both use perforin and death by osmotic lysis)
- IL-12 promotes differentiation of type1 cytokine producing cells
- IL-12 also gives a proliferative and stimulatory signal to NK cells
- NKs can deliver the lethal hit without further differentiation (pCTLs must
differentiate to CTL  requires antigen contact and IL-2)
- IL-2 enhances NK cytotoxicity
- NK cells have a broad specificity receptor. CD8s recognize infected cells by
MHCI
- NK cell is inhibited by MHCI expression on the target cell (mediated by KIR).
Increased MHCI expression enhances CTL cytotoxicity
Resistance to Immunity: HIV
General features
- HIV  causative agent of AIDS
- HIV destroys CD4+ T cells directly or indirectly
- Opportunistic infections and malignancies
- Destruction of CD4 mediated by normal host defenses that destroy virally
infected cells
Transmission of HIV
- sexual intercourse
- exposure to contaminated blood or body fluilds
- perinatally
- HIV binds to CD4 on T cells, dendritic cells, and macrophages
- Binding to coreceptor (CCR5) required for macrophage tropic strains of HIV
- T cell tropic strains of HIV use CXCR4
Seroconversion
- antibodies dectected in serum
- not a useful marker for anti-viral immunity
Productive infection of CD4+ T cells
- replication in T cells occurs primarily in activated T cells
Syncytia formation and cell destruction
- CD4 molecules react with viral proteins on the infected cell membrane leading to
fusion and functional destruction of the two cells
- May contribute to decrease in uninfected CD4+ T cells during HIV infection
Disease progression
- decline in CD4+ T cell numbers and non-antigen specific immunosuppression
Host Defenses to Intracellular Bacteria
General features
- found in macrophage phagolysosome
- cellular immunity is primary effector mechanism (not humoral immunity)
- key cells in immunity: cytokine activated macrophages
Food borne/oral-fecal intracellular bacteria
- food borne intracellular bacteria removed by peristalsis but some bacteria escape
by binding to M cells
- some bacteria use macrophage as their niche
Airborne intracellular bacteria
- bacteria that escape mucus enter lung by transcytosis through the epithelial cells
or inside macrophages (Trojan horse)
- Mycobacterium tuberculosis prevents fusion of phagosome/lysosome and
replicate within the phagosome
Resistance to Immunity: Intracellular Bacteria
Mycobacterium tuberculosis
- bacteria reactivated when person becomes immunocompromised
- PPD  previously infected individuals develop a skin reaction mediated by
memory CD4+ T cells (DTH – Mantoux reaction)
Host defense
- Key cells  IFN-, TNF activated macs
- IL-12 stimulates IFN- production by NK cells
- IFN- enhances the production of ROI, nitric oxide, and RNIs
- M. leprae scavenges reactive oxygen species
-
Granulomas: macrophages surrounded by CD4+ T cells secreting type 1
cytokines particularly IFN-
Shigella dysenteriae
- escape peristalsis by binding to M cells; escapes into M cell cytoplasm where they
replicate and spread laterally to infect adjacent epithelial cells
Host Defenses to Fungi
General features
- mycoses: fungal infections
- problem in immunocompromised (opportunistic infections  e.g. Candida
albicans, Aspergillus)
- superficial infections  ringworm, athlete’s foot
- systemic infections  Cryptococcus neoformans
- Cryptoccocus neoformans is a common infection in AIDS patients
- polysaccharide capsule prevents phagocytosis
- eliminated by opsonin-mediated phagocytosis
- after sequestration in macs, IFN- required for optimal activation of
intracellular killing; patients with low CD4+ T cell counts have impaired killing
Resistance to Immunity: Fungi
Candida albicans  candidiasis
- in immunosuppressed hosts, oral infection presents as white plaques (thrush)
- vaginal infections manisfest as thick discharge and itching of the vulva
- phagocytosis is the main mechanism by which candida is destroyed (better if
opsonin mediated)
- chronic mucocutaneous candidiasis: hole in T cell repertoire
Important: Look at Figure 11.8 on page 231