1. Immune response against pathogens
Professor Pongsak Utaisincharoen
Department of Microbiology, Faculty of Science

2. Immune response to pathogen
Defense against microbes is mediated by the mechanisms of innate and adaptive immunity
innate provides early defense
adaptive provides more sustained and stronger response
The immune system responds in distinct and specialized way to different types of microbes
The survival and pathogenicity of microbes are critically influenced by the ability of microbes to evade immunity
In many infection tissue injury and disease may caused by host response to microbe rather than microbes itself
Many microbes established latent or persistent infection in which the immune response controls but does not eliminate the microbe
Inherited and acquired defect in innate and adaptive immunity are important causes of susceptibility to infection

4. Immunity to Extracellular Bacteria
Disease is caused by 2 principal mechanisms
Induce inflammation leading to tissue damage at the site of infection
Many of these bacteria produce toxins e.g. LPS

5. Innate immune response to extracellular bacteria
Principal mechanism is complement activation, phagocytosis (PMN, macrophages)
e.g. Peptidoglycan of gram (+) bacteria activate alternative pathway of complement
Adaptive immune response to extracellular bacteria
Humoral immunity is the principal protective and its function is to eliminate the microbes and neutralize their toxin
Ab response are directed against cell wall Ag and their toxin
Ab to combat these infection include
Neutralization
Opsonization which lead to enhance phagocytosis activation of complement by classical pathway
Protein Ag of extracellular bacteria also activate TH to produce cytokine which can stimulate Ab production, IFN-γ to activate macrophage, TNF-α to induce inflammation

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7. The principal injurious consequences are inflammation and septic shock which are caused by cytokines produced from macrophages.
Septic shock (sepsis)
is severe cytokine-induced pathogenic consequence of infection by g(-)bacteria and some g(+) bacteria
characterized by fever, hypotension, thrombocytopenia abnormality of coagulation
TNF-α is principal mediator
Super antigen
a toxin that directly activate
MHC class II
restricted to T (regardless of peptide specificity)
produce massive T cell stimulation
release large amount of cytokines (e.g. IL-2, TNF- α)

8. Conventional TCR recognition of peptide-MHC
T cell
T cell
TCR
Peptide X
MHC class II
Any peptide
Superantigen
Vβ3
APC
APC
Conventional TCR recognition of peptide-MHC
Superantigen binding to class II MHC and TCR Vβ3

9. Toxic shock, Food poisoning
T cell
TCR
Peptide X
MHC class II
Any peptide
Superantigen
Toxic shock,
Food poisoning
IL-2
TNF-α
IL-1β
TNF-α
APC

10. Consequences:
Toxic shock reaction
e.g. staphylococcal enterotoxins from S.aureus

11. Complication of humoral immune response maybe by the generation of Ab
e.g. Streptococcus gr A
- M protein structure similar to Myosin of cardiac muscle
- Ab (to M protein) react with myosin
- Rheumatic fever

12. Evasion of immune mechanism by extracellular bacteria
Antigenic variation: change of Ag so Ab of host can not recognized them e.g. N.gonorrhoeae, E. coli
Inhibition of complement activation: capsule of many g(-) and g(+) bacteria contain sialic acid residues that inhibit complement activation
Resistance to phagocytosis: bacteria that have polysaccharide-rich capsules resist to phagocytosis e.g. Pneumococcus

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15. Intracellular Listeria infection
Immunity to Intracellular Bacteria
facultative intracellular bacteria is able to survive and multiply inside the cells including phagocytic cells
Staying inside the cells, the bacteria are able to avoid Ab attack
Intracellular Listeria infection

16. Innate immune response to intracellular bacteria
mainly is phagocytes and NK cells
initially PMN and later macrophages ingest and attempt to kill the bacteria but microbes are resistant to degradation within the cells
bacteria can activate NK cell by directly interact or by stimulation of IL-12 production from infected macrophages
the activated NK cell release IFN-g which in turn activate macrophages to become more aggressive
innate immunity may limit bacterial growth but fails to eliminate the pathogen
Adaptive immune response to intracellular bacteria
the major protective is cell-mediated immune response
2 major types reaction
macrophage activation by CD4+T cell through IFN-g which results in killing phagocytosed microbe
cytotoxic T cell (CD8+T cell) interacted to infected macrophage and induce lysis of the infected cells

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20. Patient with tuberculoid leprosy have strong cell-mediated immunity but low antibody levels (reflected in granulomas that form around nerves and secondary traumatic skin lesions but less tissue destruction.
Patient with lepromatous leprosy has high specific antibody but poor cell-mediated response therefore high bacterial growth and persistent but inadequate macrophage activation result in destructive lesion in the skin and underlying tissue.

21. This injury is called delayed type hypersensitivity (DTH).
The macrophage activation that occurs in response to intracellular microbes is also capable of causing tissue injury.
This injury is called delayed type hypersensitivity (DTH).

24. Immunity to Fungal Infection
Innate Immune Response to fungal infection
innate immunity is central to host defense against fungal infection
macrophages, PMN are essential mechanisms include, opsonization, phagocytosis complement activation (alternative pathway)
macrophages and DC produce IL-12 to activate NK and T cell
NK cells not play a major role in fungal infection but can support the macrophage killing by releasing IFN-g to activate macrophages
Immunity to
Fungal Infection
Adaptive Immune Response to fungal infection
Ab against fungal surface protein or polysaccharide can be protective for infection
T cell play a critical role in fungal infection by producing IFN-g to activate macrophages

25. Evasion of Immune Response by Fungal infection
can inhibit cytokines production (IL12, TNF-a)
stimulate IL-10 production (anti-inflammatory cytokines)
**Therefore, fungal can inhibit macrophage activation and prevent
T cell to be activated**
block leukocyte recruitment to the site of infection

26. Immunity to Viral Infection
Viruses typically infect various cell type by using cell surface molecule as receptor to enter the cell.
Viral replication interferes with normal cellular protein synthesis and
function leads to injury and cell dead.
Surface protein of the virus
Influenza virus
Receptors on cell surface
Influenza virus infection. The surface proteins of the virus bind to receptors on cell surface.

27. Innate Immune Response to Viral Infection
2 major function of innate immune responses
To mediate antimicrobial effects while adaptive immune responses are being activated
To provide conditions promoting the subset of adaptive immune responses most effective in defense against virus
The principal mechanisms of innate immunity against viruses are inhibition of infection by type I IFN (a and b) and NK cell-mediated killing of the infected cells
Type I IFN is produced by infected cells such as (any nucleated cells), macrophages, DC, epithelium, endothelium
Type I IFN can inhibit viral replication inside the cells
Adaptive Immune Response to Viruses
Adaptive immunity against viral infection is mediated by antibodies which block virus binding and entry into cells and by CTL which eliminate the infection by killing infected cells

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29. In some viral infection, tissue injury may be caused by CTLs
In latent infection, viral DNA persist in host cells, but the virus does not replicate or kill infected cells.
In some viral infection, tissue injury may be caused by CTLs

30. Immune Evasion by Viruses Alter their antigens
antigenic drift
antigenic shift
Inhibit class I MHC
Inhibit the immune response

31. Antigenic shift Antigenic drift
Virus undergo mutations in the genes that encode surface proteins
Antigenic shift
The segmented RNA genomes of virus that normally inhabit different host species can recombine in host cell and these reasserted viruses can differ from prevalent strains (e.g. influenza virus)

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36. Immunity to Parasites Infection
Include: Protozoa, Helminthes and ectoparasites
Innate Immunity to Parasites
phagocytes
complement activation
The organisms are often able to survive and replicate. They can adapt to host defenses.
Adaptive Immunity to Parasites
Different parasites elicit distinct adaptive immune responses.
Cell mediated immunity, macrophages activation by Th1
Helminthic infection is mediated by Th2 resulting in IgE production and activation of eosinophils

37. The principal defense mechanism against protozoa that survive within macrophages is cell-mediated immunity, particularly macrophage activation by Th1 (e.g. Leismania, malaria)
Defense against many helmithic infection is mediated by activation of Th2 cells resulting in IgE Ab production and activation of eosinophils

41. Parasites change their surface antigen during their life cycle.
Two forms of antigenic variation are defined.
Stage specific change in antigen expression
e.g. the mature tissue stages of parasites produce Ag
different from those of the infective stage
Antigenic variation in parasites is continuous variation of major surface antigen
Parasites become resistant to immune effector mechanisms during their residence in vertebrate hosts.
Protozoa parasites may conceal themselves from immune system either by living inside host cells by developing cysts that resistant to immune effectors.

43. Most vaccine in use today work by inducing humoral immunity (Ab)
Strategies for vaccine development
Depending on the properties of microbes the infectious agent does not establish latency
Does not undergo much or any antigenic variation
Does not interfere with host immune response
Most vaccine in use today work by inducing humoral immunity (Ab)

44. Types of Vaccines
Attenuated and inactivated bacterial and viral vaccines
vaccines composed of intact non-pathogenic microbes and treating the microbes in such a way that they no longer cause disease or killed microbes.
Advantage of attenuated microbial vaccines is that they elicit all the innate and adaptive immune responses.
Live attenuated vaccines are more effective than killed microbes.
Purified antigen (subunit) vaccine
composed of antigen purified from microbes or inactivated toxins.

45. Types of Vaccines Synthetic antigen vaccines
use synthesized microbial antigen or epitopes to immunize
Live viral vaccines involving recombinant viruses
introduce genes encoding microbial antigen into a non-cytopathic virus and to infect individuals with this virus
DNA vaccines
inoculation of plasmid containing complementary DNA (cDNA) encoding a protein antigen leads to humoral and cell-mediated immune response.

46. Types of Vaccines Adjuvants and immunomodulators Passive immunization
T cell-dependent immune response against protein antigen requires the Ag be administered with adjuvant which elicit innate immune responses with increased expression of co-stimulators and production of IL-12
Passive immunization
transfer specific antibody into the body