LECTURE 2
INFECTION IMMUNITY AND PROTECTION
IMMUNE RESPONSES TO BACTERIAL PATHOGENS
Normal flora of humans inhabit:
Nose and nasal pharynx (Staphylococci).
Oropharynx (Streptococci).
Mouth (Actinomyces, yeast).
Skin (Staphylococci, Streptococci, diptheroids).
Gastro-intestinal tract (small and large intestine).
Genito-urinary tract (kidneys, bladder, vagina and cervix).
IMMUNE SYSTEM IN HEALTH AND DISEASE
Infectious diseases – the result of a less effective human immune
system
Infection verses disease
Latent infections and carrier state – source of infection to other
individuals
Knowledge of immune response and pathogen evasive strategies
- important for developing preventive and therapeutic measures
IMMUNE RESPONSE TO INFECTIOUS DISEASES
A pathogen establishes an infection in a susceptible host when both innate
and adaptive host defenses are circumvented.
Innate immunity and pathogen recognition
Innate immunity forms the 1st and 2nd line defense against pathogens.
Innate immunity recognizes the invading pathogens.
Recognition is through pattern recognition receptors (PRRs).
PRRs are located on cells of innate immune system i.e. macrophages,
33
Pattern recognition receptors (PRR) are a class of innate immune
response proteins that respond to invasion of host tissue by
foreign particles and tissue destruction signals.
Foreign particles or pathogens are recognized by their pathogen-
associated molecular patterns (PAMPs).
Tissue destruction signals e.g. endogenous stress signals are
recognized as danger-associated molecular patterns (DAMPs).
Pathogen-associated molecular patterns (pamps)
They are small molecular sequences or patterns that are highly
conserved and consistently found on pathogens. These molecular
patterns are recognized by Pattern recognition receptors (PRRs)
of innate immune cells.
Some examples of PAMPs include:
●Bacterial lipopolysaccharide or toxins e.g. LPS found on gram –
ve bacteria
●Bacterial flagellin
●Bacterial lipoteichoic acid
●Bacterial lipoproteins and peptidoglycan (PDG)
●Mannose residues and N-formylmethionine,
●Fungal glucans,
●Viral nucleic acids associated with viruses ssRNA, ds RNA, DNA
●Bacterial DNA and unmethylated cytosin-guanosin dinucleotide
(CpG)
Residues
Damage associated molecular patterns (damps)
They are endogenous danger signal molecules produced in response to
tissue damage (inflammation), cell death and activation of antigen
presenting cells (APCs) and lymphocytes.
They may function as primal initiators or simply give positive-feedback to
enhance or modify an ongoing response.
34
Examples of DAMPs include: Heat shock proteins (HSPs), altered
membrane phospholipids and uric acid (produced by necrotic cells)
Pathogen recognition receptors (prrs)
PRRs are present in most cells of the immune system.
PPRs are commonly found in macrophages, dendritic cells,
endothelial cells, mucosal endothelial cells and lymphocytes.
PPRs may be located in three areas in the cells: On the cell
membrane to recognize exogenous PAMPs.
In the phagolysosome of phagocytic cells to recognize PAMPs in
phacytosed material.
In the cytosol of the cells to recognize endogenous PAMPs and
DAMPs.
Types of mammalian Pathogen recognition receptors
(prrs)
●Toll-like receptors
●NOD-like receptors
●Mannose receptors
●Receptor kinases
●RIG-like receptors
●RNA helicases
●CD14
●Mannan binding lectin
●Complement receptors
e.t.c
Toll-like receptors
Are the most characterized PRRs
There are about 10 human TLRs which are known i.e. TLR1, TLR2
…… – TLR10
TLRs members of the interleukin-1 receptors (IL-1Rs) family.
TLRs are transmembrane PRRs – span the cell membrane of
immune cells
35
Structure of toll-like receptors
TLRs have two domains: Intracellular and extracellular
The intracellular domain or cytoplasmic region is conserved
across all TLRs and is known as known as the Toll/IL-1R (TIR)
domain.
The extracellular domain contains a leucine-rich repeat (LRR)
motif which is distinct across the TLRs.
LRR domains are directly involved in the recognition of PAMPs.
TLRs recognize PAMPs either as monomers or a dimers. E.g. TLR1
forms heterodimers with TLR2 and TLR6 to recognize different
PAMPs.
36
Pattern recognition by Toll-Like Receptors
TLR PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS)
TLR1 Tri-acyl lipopeptides (bacteria, mycobacteria); Soluble factors (Neisseria spp)
TLR2 Lipoprotein/lipopeptides (a variety of pathogens); Peptidoglycan & Lipoteichoic acid
(Gram + bacteria); Lipoarabinomannan (mycobacteria); A phenol-soluble modulin
(Staph. epidermidis); Glycoinositolphospholipids (Tryp. cruzi); Glycolipids
(Trep. maltophilum); Porins (Neisseria); Zymosan (fungi); Atypical LPS
(Leptospira interrogans, Porphyromonas gingivalis)
HSP70 (host)
TLR3 Double-stranded RNA (virus)
TLR4 LPS (Gram-negative bacteria); Fusion protein (RSV); Envelope proteins
(MMTV); HSP60 (Chlamydia pneumoniae); Taxol (plant);
HSP60; HSP70 (host); Type III repeat extra domain A of fibronectin;
Oligosaccharides of hyaluronic acid; Polysaccharide fragments of
heparan sulfate; Fibrinogen (host)
TLR5 Flagellin (bacteria)
TLR6 Di-acyl lipopeptides (mycoplasma)
TLR-1/ bind uniquely bacterial lipopeptides and glycosylphosphatidylinositol (
TLR-2 GPI)-anchored proteins in parasites
TLR-2/ bind lipoteichoic acid from gram-positive cell walls, bacterial lipopeptides, and peptidoglycan.
TLR6
TLR7 Imidazoquinoline; Loxoribine, Bropirimine (synthetic compounds)
37
TLR8 ssRNA
TLR9 CpG DNA (bacteria)
TLR10 ?
TLR SIGNALLING CASCADE
All TLR signal through MyD88 – universal adapter. Individual TLR
also induce pathogen-specific immune response. TLR2 & TLR4
also signal through TIRAP/Mal. TLR3 (?TLR4) also signal through
TRIF. Induction of IFNα/β expression through IRF3 by TLR3 & TLR4
is MyD88-independent.
38
RECOGNITION OF DANGER SIGNALS BY DAMPS
PATHOGEN ESCAPE STRATEGIES
-Intracellular growth – sequestered from immune attack.
-Shedding their membrane antigen.
-Camouflage by mimicking host cell surface.
-Selective suppression or regulation of immune response.
-Continual variation in surface antigens.
IMMUNE RESPONSE TO BACTERIAL INFECTIONS
Bacteria may enter the body either through natural or unnatural
routes
Recognition of most bacteria is through the innate system via the
TLRs, after which innate responses as phagocytosis are triggered
Different levels of host defense enlisted depending on number of
bacteria invading and their virulence.
39
Small size inoculum of low virulence – phagocytic elimination –
2nd line innate responses.Larger organisms of greater virulence –
adaptive specific immune response.For extracellular bacteria,
adaptive response are triggered especially antibody-mediated
responses
BACTERIAL TOXINS
Exotoxin Endotoxin
Produced by both Gram- Produced only by Gram-
positive and Gram- negative bacteria
negative bacteria
Released from cell Integral part of cell wall
Protein Lipid A of
lipopolysaccharide
Many types of exotoxin Only one type of endotoxin
based on structure and
function
Toxoids can be made by Toxoids cannot be made
treating with formalin
Heat labile Heat stable
IMMUNE RESPONSES TO BACTERIAL INFECTIONS
Extracellular bacteria induce antibody-mediated immune
responses. These antibodies act in several ways; Removal of
bacteria.
Inactivation of bacterial toxins (neutralization)
40
Effective antibody protection should be sufficient in quantity and
must be produced faster than the bacterial toxin.
Immunological memory due to previous exposure to the
organism or its products by natural infection or artificial
immunization.
ANTIBODIES IN MUCOUS SECRETIONS – ROLE OF IgA
Enteric bacterial infections (e.g. Salmonella typhi and Vibrio
cholerae) – antibodies secreted into intestinal lumen.
IgA is present in many mucous secretions in higher concentration
than in serum. Hence IgA plays an important role in mucosal
immunity and immunity against enteric bacteria.
FUNCTIONS ATTRIBUTED TO IgA
-Anti-toxin together with IgG in protection against cholera infection.
-Reacts with gut bacteria preventing adherence to gut wall.
-Enhances lysis together with complement.
-Enhances clumping/agglutination by coating bacteria.
ACQUIRED CELLULAR IMMUNITY IN BACTERIAL INFECTIONS
41
Innate immunity - not effective against intracellular bacterial pathogens..
Intracellular bacteria activate NK cells – provide early defense.
Intracellular infections induce cell-mediated immune response - delayed
type hypersensitivity.
Cytokines secreted by CD4+ T cells are important, notably IFNγ - activates
macrophages to kill ingested pathogens.
BACTERIAL EVASION OF HOST DEFENSE MECHANISM
4 primary steps in bacterial infection:
Attachment to host cells.
Proliferation.
Invasion of host tissue.
Toxin-induced damage to host cells.
Host defense at each steps and many bacteria have evolved
evasive mechanisms.
BACTERIA EVASIVE STRATEGIES
-Surface structures for attachment (pilli in gram negative bacteria).
-Secretion of adhesion molecules (Bordetella pertussis).
-Secretion of proteases that cleave IgA..
-Changing surface antigens (N. gonorrhoeae).
-Possess surface structures that inhibit phagocytosis.
-Mechanisms for interfering with Complement.
-Survive within phagocytic cells (Listeria species).
IMMUNE RESPONSE AND AGGRAVATION OF BACTERIAL
PATHOGENESIS
Disease may be caused by the immune response to the pathogen.
42
Pathogen stimulated overproduction of cytokines - bacterial septic
shock, food poisoning and toxic shock syndrome. Chronic
antigenic activation of CD4+ T cells leads to tissue destruction.
Cytokines secreted by the activated CD4+ T cells may cause
granuloma and tissue necrosis.
43
