Bacterial Infection and Immunity Symbioses Commensalism: one partner benefits and the other is...
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Bacterial Infection and Immunity
Symbioses
Commensalism: one partner benefits and the other is neither harmed nor benefited.
Mutualism: both partners benefit.
Parasitism: one partner benefits at the expense of the other.
Role of the resident flora1. Members of the resident flora in the intestinal trac
t synthesize vitamin K and aid in the absorption of nutrients.
2. Members of the resident flora on mucous membranes and skin may prevent colonization by pathogens and possible disease through “bacterial interference”.
3. The normal flora may antagonize other bacteria through the production of substances which inhibit or kill nonindigenous species.
4. The normal flora stimulates the development of certain tissues, i.e., the caecum and certain lymphatic tissues (Peyer's patches) in the GI tract
5. The normal flora stimulate the production of cross-reactive antibodies.
Hospital acquired infection
Infections acquired during hospital stays.
Pathgen: A microorganism capable of causing sisease.
Nonpathogen: A microorganism that does not cause disease; may be part of the normal flora.
Opportunistic pathogen: An agent capable of causing disease only when the host’s resistance is impaired (ie, when the patient is “immunocompromised”).
Pathogenicity: The ability of an infectious agent to cause disease
Virulence: The quantitative ability of an agent to cause disease. Virulent agents cause disease when introduced into the host in small numbers. Virulence involves invasion and toxigenicity.
LD 50 (age /sex /health /route of entry, etc )
LD50: The number of pathogens required to c
ause lethal disease in half of the exposed hosts is called an LD50.
ID50: The number of pathogens required to ca
use disease (or, at least, infection) in half of the exposed hosts is called the ID50
Adherence(adhesion, attachment): the process by which bacteria stick to the surfaces of host cells. Once bacteria have entered the body, adherence is a major initial step in the infection process. The terms adherence, adhesion, and attachment are often used interchangeably.
Invasion: The process whereby bacteria, animal parasites, fungi, and viruses enter host cells or tissues and spread in the body.
Toxigenicity: The ability of a microorganism to produce a toxin that contributes to the development of disease.
IDENTIFYING BACTERIA THAT CAUSE DISEASE
Koch’s Postulates Molecular Koch’s Postulates Molecular Guidelines for
Establishing Microbial Disease Causation
Koch's postulates
IIsolated solated diseased not healthy peoplediseased not healthy people
GGrowthrowthpure culturepure culture
IInduce disease nduce disease susceptible animalssusceptible animals
RRe-isolated e-isolated susceptible animalssusceptible animals
Pathogenesis
Pathogenesis is a multi-factorial process which depends on the immune status of the host, the nature of the species or strain (virulence factors) and the number of organisms in the initial exposure.
BACTERIAL VIRULENCE FACTORS
REGULATION OF BACTERIAL
VIRULENCE FACTORS
Environmental signals often control the expression of the virulence genes. Common signals include:
Temperrature Iron availability : C diphtheriae /low ion Osmolality : Growth phase: pH: Specific ions:
1. Adherence Factors
Specific Adherence of Bacteria to Cell and Tissue Surfaces
1. Tissue tropism:
2. Species specificity:
3. Genetic specificity within a species:
Nonspecific adherence
Hydrophobic interactions Electrostatic attractions Atomic and molecular vibrations resulting from
fluctuating dipoles of similar frequencies Brownian movement Recruitment and trapping by biofilm polymers i
nteracting with the bacterial glycocalyx (capsule)
Adhesion
adhesinadhesin
EPITHELIUMEPITHELIUM
receptorreceptor
BACTERIUMBACTERIUM
S. pyogenes
fibronectinfibronectin
lipoteichoic acidlipoteichoic acidF-proteinF-protein
E. coli fimbriae
mannosemannose
Type 1Type 1
• galactose galactose – glycolipids glycolipids – glycoproteins glycoproteins
P P
E. coli with fimbriae
2. Invasion of host cells & tissues
3. Toxins Exotoxins Endotoxins
Endotoxins Produce in vitro cause food poisoning: botul
in, staphylococcal enterotoxin, etc. Produce in vivo: Systematic toxic effects : e.g. diphtheria, tet
anus, and streptococcal erythrogenic toxins. Local toxic effects : e.g. cholera, and toxigeni
c E. coli enterotoxins.
A-B toxins
ActiveActive BindingBinding
AA
Cell surfaceCell surface
BB
Diphtheria toxin and Pseudomonas exotoxin A
ADP-ribosylate elongation factor (EF2) inhibit protein synthesis
Cholera toxin and E. coli labile toxin
ADP-ribosylate adenylate cyclase
cyclic AMP active ion and water secretion diarrhea
Shiga toxin - shigellosis Shiga-like toxin - enterohemorraghic E. coli
LysesLyses rRNA in ribosomerRNA in ribosome DeathDeath of epithelial cellsof epithelial cells PoorPoor water absorptionwater absorption DiarrheaDiarrhea
Tetanus toxin
inhibits glycine releaseinhibits glycine release inactivates inhibitory neuronsinactivates inhibitory neurons muscles over-activemuscles over-active rigid paralysisrigid paralysis
Botulinum toxin inhibits acetylcholine releaseinhibits acetylcholine release inhibits nerve impulsesinhibits nerve impulses muscles inactivemuscles inactive flacid paralysisflacid paralysis
Exotoxins - extracellular matrix of connective tissue
Clostridium perfringensClostridium perfringens - collagenase - collagenase
StStreptoreptococcus coccus - hyaluronidase- hyaluronidase
Membrane damaging toxins
• Proteases Proteases • PhospholipasesPhospholipases• Detergent-like actionDetergent-like action
C. perfringens phospholipase
DDestroys blood vessels estroys blood vessels SStops influx inflammatory cellstops influx inflammatory cells CCreates anaerobic environmentreates anaerobic environment AAllows growth of this strict anaerobe. llows growth of this strict anaerobe.
Exotoxins
Antibodies (anti-toxins)Antibodies (anti-toxins) neutralizevaccination
Endotoxins
LPS Lipopolysaccharide:
core or backbone of CHO
side chains of CHO: "O" antigen
Lipid A Cell wall lysis required formaldehyde and heat resistant poor antigen as free molecule
Endotoxins
Endotoxin effects Fever-pyrogen 1 microgram/ kg Leukopenia and leukocytosis ne
crosis Shwartzman phenomenon and
disseminated intravascular coagulation (DIC).
Endotoxemia and shockLethal 1 milligram/ kg Identification :Limulcyte assay
Endotoxins
NNon-specific inflammationon-specific inflammation. CCytokine releaseytokine releaseCComplement activationomplement activationB cell mitogensB cell mitogens
PPolyclonal B cell activators olyclonal B cell activators
AAdjuvantsdjuvants
Endotoxem
ia
Peptidoglycan of Gram-positive bacteria
May yield many of the same biologic activities as LPS.
4. Enzymes
Tissue-degrading enzymes IgA1 proteases: split IgA1, an important
secretory antibody on mucosal surfaces, and inactivate its antibody activity.
1.1. H. influenzaeH. influenzae2.2. S. pneumoniaeS. pneumoniae3.3. N. gonorrhoeaeN. gonorrhoeae4.4. N. meningitidisN. meningitidis
5. Antiphagocytic factors
Some pathogens evade phagocytosis or leukocyte microbicidal mechanisms by adsorbing normal host components to their surfaces. A few bacteria produce soluble factors or toxins that inhibit chemotaxis by leukocytes and thus evade phagocytosis.
Antiphagocytic Substances
1. Polysaccharide capsules of S. pneumoniae, Haemophilu
s influenzae, Treponema pallidum ; B. anthracis and Klebsiella pneumoniae.
2. M protein and fimbriae of Group A streptococci 3. Surface slime (polysaccharide) produced as a biofilm by Pseudom
onas aeruginosa 4. O polysaccharide associated with LPS of E. coli 5. K antigen (acidic polysaccharides) of E. coli or the analogous Vi a
ntigen of Salmonella typhi
6. Cell-bound or soluble Protein A produced by Staphylococcus aureus. Protein A attaches to the Fc region of IgG and blocks the cytophilic (cell-binding) domain of the Ab. Thus, the ability of IgG to act as an opsonic factor is inhibited, and opsonin-mediated ingestion of the bacteria is blocked.
Protein A inhibits phagocytosis
Protein AProtein Aimmunoglobulinimmunoglobulin
Fc receptorFc receptor
BACTERIUM BACTERIUM
PHAGOCYTEPHAGOCYTE
M protein inhibits phagocytosis
M proteinM protein
rrr
peptidoglycanpeptidoglycan
Complement Complement fibrinogenfibrinogen
6. Intracellular pathogenicity
Some bacteria live and grow within polymorphonuclear cells, macrophages, or monocytes by avoiding entry into phagolysosomes and living within the cytosol of the phagocyte, preventing phagosome-lysosome fusion and living within the phagosome, or being resistant to lysosomal enzymes and surviving within the phagolysosome.
7. Antigenic heterogeneity
Antigenic type of bacteria may be a marker for virulence, related to the clonal nature of pathogens, though it may not actually be the virulence factor.
Some bacteria may make frequent shifts in the antigenic form of their surface structures in vitro and presumably in vivo, allowing the bacteria to evade the host’s immune system.
8. The requirement for iron
For the host, the iron metabolism denies pathogenic bacteria an adequate source of iron for growth.
For the bacteria, they have developed several methods to obtain sufficient iron for essential metabolism, e.g., the low-affinity iron assimilation system or the high-affinity iron assimilation systems.
Bacterial siderophores compete effectively for Fe3+ bound to lactoferrin and transferrin.
• Immunity of host
Development of the Immune System
Development of the Immune System
ery pl
mye
neu mφ
lym
nk
thy
CD8+
CD4+
CTL
TH2
TH1
Cells of the Immune System
BasophilsNeutrophils
Eosinophils
Granulocytic
Langerhans &Macrophages
Kupffer cellsDendritic cells?
Monocytic
CytotoxicHelper
Suppressor
T-cells
Plasmacells
B-cells Dendriticcells?
lymphoid cellsMyeloid cells
Components of the Immune System
Components of the Immune System
Humoral Cellular Humoral Cellular
SpecificNonspecific
complement, interferon, TNF etc.
macrophages, neutrophils
T cells; other effectors cells
antibodies
Balance between Infection and Immunity
Balance between Infection and Immunity
infection immunity
Bolus of infection x virulenceimmunity
Disease =
Response to InfectionResponse to Infection
infection
x
disease
Innate immunity no
disease
recove
ry
adaptive immunity
re-infectio
n no disease
x
Beneficial:
Protection from Invaders Elimination of Altered Self
Detrimental:
Discomfort (inflammation) Damage to self (autoimmunity)
Beneficial:
Protection from Invaders Elimination of Altered Self
Detrimental:
Discomfort (inflammation) Damage to self (autoimmunity)
Significance of the Immune SystemSignificance of the Immune System
Innate Immunity Adaptive Immunity
Characteristics of Innate and Adaptive Immunity
Characteristics of Innate and Adaptive Immunity
No Immunologic
memory
Antigen independent
No time lag
Not antigen specific
Antigen dependent
A lag period
Antigen specific
Development
of memory
Innate Immunity Adaptive Immunity
Components of Innate and Adaptive Immunity
Components of Innate and Adaptive Immunity
skin, gut Villi, lung cilia,etc
many protein andnon-protein secretions
phagocytes, NK cell eosinophils, K cells
physical barriers
soluble factors
cells
none
Immunoglobulins(antibody)
T and B lymphocytes
Physical Barriers to ResistancePhysical Barriers to Resistance
Site Component Functions
Effector mechanisms in Innate Immunity -1
Effector mechanisms in Innate Immunity -1
Peristalsis, low pHbile salts, fatty acids
columnar cells
GI tract
Skin squamous cellssweat
desquamationflushing, fatty acids
tracheal ciliaLung mucociliary elevator
surfactants
Site Component Functions
Effector mechanisms in Innate Immunity -2
Effector mechanisms in Innate Immunity -2
Nasopharynxand eye
mucus, saliva, tears flushing, lysozyme
PhagocytesBlood andLymphiodorgans
phagocytosis and intracellular killing
K, NK & LAK cells
direct and antibody dependent cytolysis
Site Component Functions
Effector mechanisms in Innate Immunity -3
Effector mechanisms in Innate Immunity -3
Serum and other serous
fluids
lactoferrin, transferrin
iron deprivation
interferons, TNF-
antiviral proteins phagocyte activation
lysozyme peptidoglycan hydrolysis
Fibronectin & complement
opsonization, enhanced phagocytosis, inflammation
Macrophage Attacking E.coli (SEM x8,800)
Chemotactic response to inflammatory stimulus
Adaptive Immunity
Adaptive Immunity, which occurs after exposure to an antigen ( eg. An infectious agent) is specific and is mediated by either antibody or lymphoid cells. It can be passive or active.
Immunity of extracellular bacterial infection: antibodies (IgG, IgM, SIgA); phagocytes (neutrophils); complement; humoral immunity mainly.
Immunity of intracellular bacterial infection: cell-mediated immunity (delayed-type hypersensitivity, DTH response (DTH) involving TH1and macrophages) mainly.
INADEQUATE IMMUNE RESPONSES TO INFECTIOUS AGENTS
Causes immune suppression—an example is infection with HIV, which alters T cell immunity and allows further infection with opportunistic pathogens.
Release toxins that function as superantigens, initially stimulating large numbers of T cells to proliferate but, because of the release of cytokines from T cells, ultimately suppressing the immune response and allowing the pathogen to multilply.
Evade the immune defenses by altering their antigenic structure—an example is that influenza virus undergoes antigenic variation by two mutational mechanisms called antigenic shift and antigenic drift that creat new antigenic phenotypes which evade the host’s current immunity and allow reinfection with the virus.
Original and devolopment of Bacterial Infection
Source of infection
Exogenous infection : patient, carrier, diseased animal or animal carrier.
Endogenous condition : most are normal flora, cause infection under abnormal condition.
Transmission
• AAirborne dropletsirborne droplets• FFoodood• WWater ater • SSexual contactexual contact
Routes of infection
Respiratory Gastroenteric
Genitourinary tract closely contact insect bitting
blood transfusion Parenteral route
Mucous membranes
According to infectious state
Inapparent or subclinical infection
Latent infection Apparent infection : cause app
arent clinic syndrome Carrier state: carrier
According to infectious sites
Local infection Generalized or systemic infection1. Toxemia : is the presence of exotoxins in the blo
od.2. Endotoxemia : is the presence of endotoxins in
the blood.3. Bacteremia : is an invasion of the bloodstream
by bacteria.4. Septicemia : illness that occurs when poisonous
substances (toxins) produced by certain bacteria enter the bloodstream.
5. Pyemia : is caused by pyogenic microorganisms in the blood.