bacterial infection and immunity xiao-kui guo symbioses commensalism: one partner benefits and the...
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Bacterial Infection and Bacterial Infection and ImmunityImmunity
Xiao-Kui GUO
SymbiosesSymbioses
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 floraRole of the resident flora• Members of the resident flora in the intestinal tract
synthesize vitamin K and aid in the absorption of nutrients.
• Members of the resident flora on mucous membranes and skin may prevent colonization by pathogens and possible disease through “bacterial interference”.
• The normal flora may antagonize other bacteria through the production of substances which inhibit or kill nonindigenous species.
• The normal flora stimulates the development of certain tissues, i.e., the caecum and certain lymphatic tissues (Peyer's patches) in the GI tract
• 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 cause lethal disease in half of the exposed hosts is called an LD 50.
ID50: The number of pathogens required to cause 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.
Koch’s Postulates Molecular Koch’s
Postulates Molecular Guidelines for
Establishing Microbial Disease Causation
Koch's postulates IIsolated solated
– diseased not healthy diseased not healthy peoplepeople
GGrowthrowth– pure culturepure culture
IInduce disease nduce disease – susceptible animalssusceptible animals
RRe-isolated e-isolated – susceptible animalssusceptible animals
PathogenesisPathogenesis
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.
Source ofSource of infectioninfection Exogenous infection : patient, carrier,
diseased animal or animal carrier. Endogenous condition : most are normal flora,
cause infection under abnormal condition.
• AAirborne dropletsirborne droplets• FFoodood• WWater ater • SSexual contactexual contact
TransmissionTransmission Respiratory Gastroenteric
Genitourinary tract closely contact insect bitting
blood transfusion Parenteral route
Mucous membranes
Routes of Routes of infectioninfection
According to According to infectious sitesinfectious sites
Local infection Generalized or systemic
infection
1. Toxemia : is the presence of exotoxins in the blood.
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.
Inapparent or subclinical infection
Latent infection Apparent infection : cause
apparent clinic syndrome Carrier state: carrier
According to According to infectious stateinfectious state
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
BACTERIAL VIRULENCE FACTORSBACTERIAL VIRULENCE FACTORS
1. Adherence Factors1. Adherence Factors
1. Tissue tropism:
2. Species specificity:
3. Genetic specificity within a species:
Hydrophobic interactions Electrostatic attractions Atomic and molecular vibrations resulting from
fluctuating dipoles of similar frequencies Brownian movement Recruitment and trapping by biofilm polymers
interacting with the bacterial glycocalyx (capsule)
AdhesionAdhesion
adhesinadhesin
EPITHELIUMEPITHELIUM
receptorreceptor
BACTERIUMBACTERIUM
fibronectinfibronectin
lipoteichoic acidlipoteichoic acidF-proteinF-protein
mannosemannose
Type 1Type 1
galactose galactose – glycolipids glycolipids – glycoproteins glycoproteins
P P
E. coliE. coli fimbriae fimbriae
2. Invasion of host cells & tissues2. Invasion of host cells & tissues
3. Toxins 3. Toxins ExotoxinsEndotoxins
Exotoxins Produce in vitro cause food poisoning:
botulin, staphylococcal enterotoxin, etc. Produce in vivo: Systematic toxic effects : e.g. diphtheria,
tetanus, and streptococcal erythrogenic toxins.
Local toxic effects : e.g. cholera, and toxigenic E. coli enterotoxins. ActiveActive BindingBinding
AA
Cell surfaceCell surface
BB
Antibodies (anti-toxins)Antibodies (anti-toxins) neutralize– vaccination
EEndotoxinsndotoxins 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 Endotoxin effects Fever-pyrogen 1 microgram/ kg Leukopenia and leukocytosis
necrosis Shwartzman phenomenon and
disseminated intravascular coagulation (DIC).
Endotoxemia and shock Lethal 1 milligram/ kg Identification:
Limulcyte assay
NNon-specific inflammationon-specific inflammation.
CCytokine releaseytokine release CComplement activationomplement activation B cell mitogensB cell mitogens
PPolyclonal B cell activators olyclonal B cell activators
AAdjuvantsdjuvants
Peptidoglycan of Gram-Peptidoglycan of Gram-positive bacteriapositive bacteria
May yield many of the same biologic activities as LPS.
4. 4. EnzymesEnzymes
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
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.
5. Antiphagocytic 5. Antiphagocytic factorsfactors
AAntiphagocytic ntiphagocytic SSubstancesubstances
1. Polysaccharide capsules of S. pneumoniae, Haemophilus
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 Pseudomonas
aeruginosa 4. O polysaccharide associated with LPS of E. coli 5. K antigen (acidic polysaccharides) of E. coli or the analogous Vi
antigen 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 phagocytosisProtein A inhibits phagocytosis
immunoglobulinimmunoglobulin Protein AProtein A
Fc receptorFc receptor
BACTERIUM BACTERIUM
PHAGOCYTEPHAGOCYTE
rrr
peptidoglycanpeptidoglycan
Complement Complement fibrinogenfibrinogen
M proteinM protein
M protein inhibits phagocytosisM protein inhibits phagocytosis
6. Intracellular 6. Intracellular pathogenicitypathogenicity
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 heterogeneity7. 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.
Bacterial siderophores compete effectively for Fe3+ bound to lactoferrin and transferrin.
8. The requirement for iron8. 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.
Development of the Immune Development of the Immune SystemSystem
Development of the Immune Development of the Immune SystemSystem
ery pl
mye
neu mφ
lym
nk
thy
CD8+
CD4+
CTL
TH2
TH1
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 Balance between Infection and ImmunityImmunity
Balance between Infection and Balance between Infection and ImmunityImmunity
infection immunity
Bolus of infection x virulenceimmunity
Disease =
Response to InfectionResponse to InfectionResponse 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 SystemSignificance of the Immune SystemSignificance of the Immune System
Innate Immunity Adaptive Immunity
ComponentsComponents of Innate and Adaptive of Innate and Adaptive ImmunityImmunity
ComponentsComponents of Innate and Adaptive of Innate and Adaptive ImmunityImmunity
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
Chemotactic response to inflammatory stimulus Macrophage Attacking E.coli (SEM x8,800)
Adaptive ImmunityAdaptive Immunity
Innate Immunity Adaptive Immunity
CharacteristicsCharacteristics of Innate and of Innate and Adaptive ImmunityAdaptive Immunity
CharacteristicsCharacteristics of Innate and of Innate and Adaptive ImmunityAdaptive Immunity
No Immunologic
memory
Antigen independent
No time lag
Not antigen specific
Antigen dependent
A lag period
Antigen specific
Development
of memory
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 INADEQUATE IMMUNE RESPONSES TO INFECTIOUS AGENTSTO 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.