Immunity to Infectious Agents:

Bacteria and Fungi

Dyah Ayu Oktavianie, DVM., M. Biotech

PKH-UB

Immunity to bacteria and fungi

Mechanisms of protection from bacteria can be deduced from their
structure and pathogenicity.
Lymphocyte-independent (innate) bacterial recognition pathways
have several consequences.
Antibody provides an antigen-specific protective mechanism.
(specific)
Ultimately most bacteria are killed by phagocytes.
Infected cells can be killed by CTLs.
Successful pathogens have evolved mechanisms to avoid
phagocyte-mediated killing.
The response to bacteria can result in immunological tissue damage.
Fungi can cause life-threatening infections.

 Yersinia pestis: killed of European

population in the Middle Ages.
Myocbacterium tuberculosis: infect 1/3 of
the world population

Immune defenses against pathogenic

bacteria are determined by their
Surface chemistry
Mechanism(s) of pathogenicity
Extracellular or intracellular parasite

Different immunological mechanisms have evolved to

destroy cell wall structure of different groups of bacteria
There are four types
7
6

8. Impede C and
phagocytosis
Targets for Ab

5. Compound cell wall extremely

resistant to breakdown

4. Lysis by cationic proteins and complement

Killing by phagocytosis

2. Lysosomal enzymes
Asterisk (*) are recognized by the innate immune
system as a non-specific danger signal
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2005 Elsevier

Neutralizing antibody
is protective

Protection requires cellmediated immune

responses

Antibody and cellmediated responses

are required

 The first lines of defense do not need antigen recognition: skin, epithelial
surfaces, fatty acid, ciliary action in trachea, low pH in stomach and vagina.
Commensals limits pathogen invasion

The second line of define is mediated by recognition of bacterial

components. (innate)
Microbial components bearing pathogen-associated molecular pattern (PAMPs)
(danger signal)
PAMPs are recognized by the pattern recognition molecules of the innate immune
system
Collectins and ficolins
Toll-like receptors
NOD proteins

Pattern recognition molecules

Toll-like receptor (TLR) family
At least ten TLRs: TLR1, 2, 4, 5, 6 and 9
Express on phagocytes, dendritic cells, epithelial cells with a
different combination
Mannose receptor
Scavenger receptors
Complement
C-reactive protein
Mannose-binding lectin
Surfactant protein A in lung

LPS is the dominant activator of innate immunity in Gram (-) bacteria

Endotoxin shock

1
2

Acute
phase
response

4. release

3. transfer to

II

TLR4

TLR4

III

Other bacterial components as

immune activators
Cell wall components: peptidoglycans and lipoteichoic acids
TLR2, 1, 6
Lipid components from mycoplasma, mycobacteria, and
spirochetes LBP, CD14
Mycoplasma lipoproteins TLR2/6
Flagellin TLR5
DNA (CpG motifs) TLR9 (express in phagosomes)
Peptidoglycans of G(+) and G(-) NOD-1 and NOD-2 proteins
in cytosol

1. Inflammation
2. Activation of clotting system, fibrin formation

= innate

Limit bacterial spreading

1. Recognition
molecules in blood

2.Alternative

5. PAMPs
8

6. Recognition
receptors on cells
i.e., TLRs

What happen after bacterial recognition?

Activation of the alternative pathway of complement

Lytic complex (C5b-9): kill bacteria with outer lipid bilayer
C5a: attracts and activates neutrophils and cause mast cell degranulation (histamine and LTB4)
C3 derivatives: opsonization
Proinflammatory cytokines production
TNF, IL-1 (from macrophages): increase adhesive properties
Chemokines: attracts leukocytes
TNF, IL-1, IL-6: induce acute phase responses (complements)
IL-12, IL-18: stimulate NK cells to release IFN to activate macrophages
Induction of lymphocyte-mediated response (innate to acquired)
Immature DCs in periphery migrate to draining lymph nodes to prime T cells
Activated macrophages at site of infection act as APC to further activate effector T cells
TLR activation induces a local environment rich in IFN , IL-12, and IL-18 which favors TH1
pathway

Alternative
complement
pathway only

Most bacteria are killed by phagocytes

A few Gram-negative bacteria are killed by complement
Most bacteria are killed by phagocytes
Neutrophils in blood
Resident macrophages in tissues

Phagocytes are attracted by bacterial components and

complement products to site of infection
Cellular composition: pyogenic = acute, rich in neutrophils;
granuloma = chronic, rich in macrophages

PAMPs

LPS : TLR4
Flagellin : TLR5
LP/PG : TLR2/1/6

Pattern recognition molecules

Complement
components

Complement-fixing antibody:
IgM > IgG3 > IgG1

Bacterial components

Trigger uptake, cytokine secretion, and kill mechanisms

Killing pathways of phagocytes

Oxygen dependent
Reduction of oxygen to superoxide anion, formation of
free radicals and toxic derivatives
Formation of nitric oxide (inducible NO synthase)

Oxygen independent

Defensins
Acidification of phagosomes
Lysosome
Lactoferrin and Lactoferricin

Macrophage killing enhanced on activation by (1) microbial

products via TLRs (induce TH1 response) and (2) cytokines
(IFN)
NK cells, NK T cells, and
macrophages produce IFN.
Th1 T cells are the major
source of IFN.

In lymph nodes

TLRs
Direct cell contact

High
IL-12 low
High IL-10
and TGF
Th2
Treg

In site of infection

Bacteria-infected cells can be killed by CTLs

(viruses, Listeria spp)

Cross-presentation
MHC class I (ER); See Fig7.11

FasL -Fas

(Mtb
)

MHC class I

Other T cell populations can contribute to

antibacterial immunity
Non-conventional T cells (cytotoxic activity and
secrete IFN)
T cells
Epithelial surfaces
Recognize phospholigands

CD1-restricted T cells
Recognize glycolipids
Presented by CD1 (non-polymorphic homologs of MHC
class I) on DC

Some tissue cells express

antimicrobial mechanisms
Secrete defensins by epithelial cells
Infected cells as targets of CTLs
Restrict the growth of intracellular
microbial

1. Toxins
inhibit
chemotaxis

2. Capsule repel
attachment

3. Inhibit phagosomelysosome fusion;

Inhibit proton pump
4. Catalase
neutralize H2O2

8. Resident in
cytoplasma

5. Resistant coating

6. LAM blocks
IFN signal

7. Block antigen
presentation

Pathogenic bacteria escape the effects of

antibody
1.Avoid the effects of antibody
2.Alter antigenic composition
(b
)

(4) Adsorb and deplete

local Ab

(a
)

(3
)

(c
)

(2
)

(1
)

Pathogenic bacteria escape the effects of

complement

O antigen on
LPS

shedding
Sialic acid
Factor H and I
Smooth surface of G(-)

C5a protease Group A

Strept

Resist
insertion

2005 Elsevier

Response to bacteria can result in

immunological tissue damage

Endotoxin shock
Schwartzman reaction
Koch phenomenon
Superantigens induce massive cytokine
release

Superantigens
of G(+) bacteria
G(-)
bacteria

Diffuse intravascular coagulation (DIC)

Defective clotting, increase vascular
permeability, loss of fluid in tissues, full in
blood pressure, circulatory collapse,
hemorrhagic necrosis

(1)

(2
)

A cytokine-mediated tissue damage in a site of previous

inflammation

Local inflammation and upregulation

of cytokine receptors by IFN
secreted by NK and NK T cells

Systemic cytokine release

(TNF)

(hemorrhagic rash)

Systemic infection
Extracellular

Intracellular