Bacterial Infection and Immunity Symbioses Commensalism: one partner benefits and the other is...

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


Peristalsis, low pHbile salts, fatty acids

columnar cells

GI tract

Skin squamous cellssweat

desquamationflushing, fatty acids

tracheal ciliaLung mucociliary elevator

surfactants




Nasopharynxand eye

mucus, saliva, tears flushing, lysozyme

PhagocytesBlood andLymphiodorgans

phagocytosis and intracellular killing

K, NK & LAK cells

direct and antibody dependent cytolysis




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.

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