Lecture 20: Immunity to Bacteria and Fungi

Proliferation (infection process)

Host defense:

Phagocytosis (Ab- and C3b-mediated opsonization)

Complement-mediated lysis and localized inflammatory response

Ab-mediated agglutination

Attachment to host cells (Infection Process)

Host defense:

Blockage of attachment by secretory IgA antibodies

Invasion of host tissues (Infection Process)

Host Defense:

digestive

enzyme/phagosome/Lysosome

Toxin-induced damage to host cells (Infection Process)

Host Defense:

Neutralization of toxin by antibody

Getting sick or remaining well when exposed to a germ

is a balance

Development of disease is related to many factors:

• Response (resistance/immunity) of the host

• Virulence (dangerousness) of bacteria

Virulence (dangerousness) of bacteria

• Bind to host receptor

• Enter host

• Overcome host response

• Utilize a metabolite – such as iron

• Evade host response – even live inside immune system cells

Response (resistance/immunity) of the host:

Determined by location, physiological status of host, age, pre- exposure/damage tissue e etc.

Early innate response:

Recognition of bacteria through TLRs and other receptors induces inflammation, cytokine release, and complement activation

Adaptive response:

It work in association with innate response in clearing bacteria, generating immune memory, dendritic cells and macrophages ingest invading bacteria, and initiate adaptive immunity by producing cytokines and triggering both T and B cell responses

Innate immunity is critical to

adaptive immune response

In innate immunity, Type I Interferons are

readily produced in response to bacterial PAMPs, and boost macrophage responses enhancing their production of IFNγ, NO, and TNFα.

TLRs are responsible

in large part for the initial recognition of invading bacteria

TH17 cells confer protection against

extracellular bacteria and fungi, by triggering inflammation

Cells

Leukocytes (white blood cells)

Cells – Leukocytes (white blood cells)

Granulocytes

• Neutrophils, eosinophils, basophils, and mast cells

Phagocytes

• Neutrophils, macrophages/monocytes, Dendritic cells, NK cells

Complement – serum protein

Alternative – series of proteins directly bind and attack (proteins activate each other) – free floating C3b

Classic – antibody binds first

Lectin – binds to a sugar (mannose) on surface of bacteria

Opsonization

Primary (azurophilic) granules:

myeloperoxidase (MPO), defensins, lysozyme, and proteases.

Primary granules contribute in

direct microbial killing, along with reactive oxygen species (ROS)

Macrophages

Phagocytosis, Reactive oxygen species (ROS)/ Cytokine/ chemokine production, antigen presentation (Some intracellular bacteria can survive in macrophage, Rhodococcus equi, Mycobacterium tuberculosis, Salmonella

Natural Killer-NK cells play protective role in

some bacterial, protozoan and fungal infections.

NK cells do not express

antigen specific receptors

Some bacteria cause upregulated expression of NKG2D ligands on infected cells which causes activation of

NK cells

Complement:

Bacteria can be destroyed by Complement acting through the classical, alternate or lectin pathways. As a result these bacteria are either lysed(Membrane Attack Complex) or opsonized (phagocytosis)

Innate immunity to bacteria

Complement

Iron sequestering

Antimicrobial peptides

Example of an antimicrobial peptides

cathelicidins

Vitamin D receptors are up-regulated on

activated macrophages

5 basic mechanism of adaptive immunity

1. Neutralization of toxins or enzymes by antibody

2. Killing of bacteria by the classical complement pathway

3. Opsonization of bacteria by antibodies and complement, resulting in their phagocytosis and destruction

4. Destruction of intracellular bacteria by activated macrophages

5. Killing of bacteria by cytotoxic T cells and NK cells

Diseases caused by toxigenic bacteria

Clostridium tetani and Bacillus anthracis

In diseases caused by toxigenic bacteria

the immune response must not only stop the invading bacteria but also must neutralize the toxin

Neutralization occurs

when antibody prevents the toxin from binding to its receptor on a target cell

Neutralization process involves

the competition between receptor and antibodies for the toxin

Bacteria is able to get into bloodstream from

tissues

Protection against invasive bacteria is usually mediated by

antibodies directed against surface antigens

Antibodies not only are effective opsonins themselves but also increase the binding of C3b by

activating the classical complement pathway

Antibodies generated against capsular antigens

neutralize the antiphagocytic property of bacterial capsules, thus permitting their destruction of phagocytic cells

Antibodies generated against E. coli pilus antigen interfere with

their binding to intestinal wall

When exposed to fever from the host, bacteria express certain proteins when under heat stress =

Heat-shock protein

Heat-shock proteins (HSPs) are

highly antigenic

Protection against intracellular bacteria is mediated by

macrophages activated through the M1 pathway (classically activated macrophages)

M1 polarization of macrophages has been shown to be important in resistance to

Listeria monocytogenes, Salmonella enterica Typhi and Typhimurium, mycobacteria, and chlamydia

Immune response influences

the course and severity of an infection

Cell-mediated responses are required to control intracellular bacteria because

only activated macrophages can prevent their growth

Macrophage activation requires that

TH1 cells produce IFNγ

If an animal mounts an inappropriate TH2 response,

cell mediated immunity fails to develop, M2 macrophages are generated, and chronic progressive disease may result.

Three major types of fungal infections:

1. Primary infections by fungi that affect the skin or other surfaces (Microsporum or Candida)

2. Primary infections by dimorphic fungi that mainly cause respiratory infections (Histoplasma) 3. Secondary infections by opportunistic fungi (Pneumocystis)

IL 23 and IL 17 influence

Th17 cells that promote inflammation.

Neutrophils are activated by

IL-23/IL-17 axis during fungal infections, activates Adaptive immune response

Both TH1 and TH17 responses are important in

cellular immunity to fungi by enhancing pro inflammatory reactions

Mycobacterium avium subsp. paratuberculosis (MAP) agent of

Johne’s disease in cattle and other ruminants