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.