Bacterial Infection and

Pathogenesis

•  pathogenesis (how a disease develops) 

•  pathogenicity (disease causing ability of  microorganisms)

•  virulence (degree of pathogenicity) 

Section 1 Normal flora 

Microorganisms that 

live on or in human 

bodies, and ordinarily 

do not cause human 

diseases

– Mechanisms •  Competition for receptors on host cells •  Competition for nutrients •  Metabolic or toxic products 

•  Nutritional function •  Immunity 

 The medical significance of normal flora

•  Antagonism 

normal flora  that, under ordinary circumstances, cause no harm but can cause disease under certain conditions 

Opportunistic pathogen

•  Alteration of colonization sites 

•  Declination of the host immunity defense 

•  Dysbacteriosis –  the state in which the proportion of bacterial 

species and the number of the normal flora colonizing in a certain site of a host present large scale alteration 

Under what conditions will opportunistic pathogens cause human diseases?

Section 2 Bacterial infection

bacteriabacteria

Immune status of the host

inbodyouterbody

细菌细菌细菌细菌细菌细菌

bacteriabacteria

bbacteriaacteria

bacteriabacteria

bacteriabacteria

toxins Cause disease

Why do people get infectious diseases?

From the organism’s perspectives The number of organisms The virulence of these organismsFrom the host’s perspective Innate immunity acquired immunity

Antibody-mediatedcell-mediated

Pathogenicity of bacteria

Pathogenicity and virulence: refer to an organism's ability to cause disease.

LD50 (median lethal dose) or ID50 (median infectious dose): refers to the number of bacteria or amount of bacterial products, such as toxins, that cause death or bacterial disease in 50% of animals in a defined period after the bacteria are administrated by a designated route.

Pathogenicity of bacteria

pathogenicity （ decide by): virulence factors of the bacterium the number of infecting bacteria route of entry into the body

Portals of Entry and the size of the inoculum

If certain pathogen enter the wrong portal,they will not be infectious.

Occasionally,an infective agent can enter by more than one portal.e.g.mycobacterium tuberculosis.

Portals of entry

skin respiratory system ingestion system genitourinary system

C. tetani

The size of the inoculum

The quantity of microbes in the inoculating dose.

The originate and progress of infection

A.The source of the infection

B.routes of pathogen transmission

C.Patterns of infection

A.The source of infection

Living reservoirsPersons or animals with frank sympto

matic infection are obvious sources of infection

Nonliving reservoirs

Exogenous infections: Patients Carriers: those in whom pathogens are pres

ent and may be multiplying, but who shows no clinical response to their presence.

Contaminated animals Endogenous infections

Sources of infectious diseases

Carrier state Definition of carriers: those in whom path

ogens are present and may be multiplying, but who shows no clinical response to their presence

Definition of carrier state: a type of infections causing no signs of symptoms, in which pathogens multiply and may be transmitted to other individuals

two major types of carrier: Convalescent carriers: those who recover from

infectious disease and in whom the pathogens remain and multiply without causing overt symptoms.

Healthy carriers: those who do not have the clinical symptoms but carry pathogens indeed.

Typhoid Mary (Mary Mallon) 社会恶习的扩散者

B. Routes of pathogen transmission

1.respiratory infections: the tiny particles of liquid released into the air form aerosols or droplets

2.wound infectons: in soil and feces of human and animal

3.intestinal infections: contaminate drinking water and food or when used to fertilize crops

4.contact infection:directly contact between the skin and mucous membranes of the infected person or animal and that of healthy person

5.animal bites infections:the majority of animal vectors are arthropods such as fleas,mosquitos,flies,and ticks

acute infection chronic infection

C. Patterns of infection

Apparent infection

1.apparent infectionWhen an infection causes pathological changes leading to disease,it is often accompanied by a variety of signs and symptomsInfectons that come on rapidly,with severe but short-lived effects,are called acute infectionsThe infection persists several months to several years called chronic infection

Inapparent infection: also called subclinical infection that has no detectable clinical symptoms

local infection generalized/systemic infection

Localized infection stands for the case that the microbe enters the body and remains confined to a specific tissue

Generalized infection

Bacteremia Definition: a transitory disease in which bacteri

a present in the blood are usually cleared from the vascular system with no harmful effects.

Septicemia Definition: a disease in which the blood serves a

s a site of bacterial multiplication as well as a means of transfer of the infectious agent from one site to another.

Toxemia Definition: the presence of microbial t

oxins in the blood Pyemia Definition: the presence of pyogenic b

acteria in the blood as they are being spread from one site to another in the body

毒素

血液

毒素

toxin

toxin

special toxic symptom

e.g.tetanus

Toxemia

局部病灶

局部病灶

pathogenic bacterium can grow in blood

BacteremiaBacteremia

Defense function↓↓

毒素毒素毒素毒素毒素毒素toxin

Organism is seriously damaged, toxic symptom all over the body 。

Septicemia

Local lesion

blood

局部病灶

局部病灶

毒素toxin

毒素 毒素

toxin

New pyosis focus of infection

Pyosepticemia

When Pyosis bacteria cause Septicemia ， multiple pyosis focus of infection will happen.e.g. staphylococci aureus

A microorganism that causes disease 

Pathogen

Section 3. Bacterial pathogenicity

•  Virulence 

•  The amount of entry 

•  The portal of entry 

What factors determine bacterial pathogenicity?

What is virulence

The ability of any agent of infection to

produce disease. The virulence of a

microorganism (such as a bacterium or virus)

is the measurement of the severity of the

capable of disease.

Invasiveness

ToxinVirulence

1. Invasiveness

Definition The ability of microorganisms to enter the

body and spread in the tissues.

Invasiveness 

•  Adherence factor – Pilus 

– LTA 

•  Capsule  

•  Invasive enzyme

1.1 Material foundation of invasiveness

1.1.1 Adherence factor( 粘附因子 )

Definition of adherence: 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. It is a general cellular microbiology

phenomenon take place at the early stage of infection.

The terms adherence, adhesion or attachment are

often used interchangeably

1.2 Adherent mechanisms

Electrostatic attraction( 静电吸引 )

Hydrophobic interaction (疏水作用 )

Cationic bridge( 阳离子桥联 )

Nonspecific adherence

ligand-receptor(配体 -受体 )bonding Specific adherence

(Reversible)

(Irreversible )

Microbe Adhesin Receptor

S. Aureus LTA Unknown

S. epidermidis Slime Unknown

Streptococcus, group A LTA-M protein complex

Fibronectin

S. pneumoniae Surface protein N-acetylhexosamine-gal

E. coli Type 1 fimbriae d-Mannose

  Colonization factor antigen fimbriae

GM1 ganglioside

  P fimbriae P blood group glycolipid

Other Enterobacteriaceae Type 1 fimbriae d-Mannose

N. gonorrhoeae Fimbriae GD1 ganglioside

T. pallidum P1, P2, P3 Fibronectin

Chlamydia sp. Cell surface lectin N-acetylglucosamine

M. pneumoniae Protein P1 Sialic acid

V. cholerae Type 4 pili Fucose and mannose

Examples of Bacterial Adherence Mechanisms

Examples of tissue tropism for bacterial infection

Bacteria TissueTissue

N. meningitidis Nasopharynx epithelium 、、 blood vessel endothelium

N. gonorrhoeae Urethro-epithelium

V. cholerae Enteric epithelium

B. pertussis Respiratory epithelium

H. pylori Gastric mucosa

Group A Streptococcus Nasopharynx epithelium

C. Jejuni Enteric epithelium

M. Pneumoniae Respiratory epithelium

Tissue tropism

Different bacteria adhere to different

host cell by different ligand

1.3 Invasive mechanisms1.3.1 Capsule and microcapsule

1.3.2 Invasive EnzymeInvasive Enzyme(( 侵袭性酶类侵袭性酶类 ))

1.3.3 Microcolony( 微菌落 ) and biofilm( 生物膜 )

1.3.3.1 Microcolony

By microcolony we mean a colony of bacteria

visible only under a low power microscope, and its

formation is an event preceding mature of biofilm

formation.

Microcolony( 微菌落 )

Bacterial biofilms are highly interactive, ubiquitous

bacterial ecosystems consisting of individual bacterium

bound to a foreign surface by complex matrix of

extracellular polysaccharides. They can be thought of as

“bacterial communities or cities.” Within these

communities live groups of bacteria constituting multiple

species. Individual bacterium coalesce by linking

extracellular polysaccharides on their cell walls. In nature,

biofilms constitute a protected growth modality that

allows the bacteria to survive in hostile environments.

1.3.3.2 Bacterial biofilms( 生物膜 )

S. epidermidis biofilm colonized on surface of venous duct

The characters of bacterial biofilm

※ There is a circulation system in biofilm, so bacterial

in this community can exchange nutrition and metabolic

product each other

※ Counteract the defense system of the host and toxic

effect of antibiotics

※ Transfer antibiotic resistant gene rapidly.

What is virulence

The ability of any agent of infection to

produce disease. The virulence of a

microorganism (such as a bacterium or virus)

is the measurement of the severity of the

capable of disease.

Invasiveness

ToxinVirulence

2. Toxin

•ExotoxinExotoxin

•EndotoxinEndotoxin

An exotoxin is a soluble protein excreted by a

microorganism. An exotoxin can cause damage to the

host by destroying cells or disrupting normal cellular

metabolism. most G+ and few G- bacteria produce

exotoxins. They are highly potent and can cause major

damage to the host. Exotoxins may be secreted, or,

similar to endotoxin, may be released during lysis of

the cell.

ExotoxinExotoxin

Exotoxin 

Origin G +  bacteria (most) 

G    bacteria 

Release 

Secreted by living bacteria

Physical and chemical properties 

•  Protein 

• Heat resistance : Sensitive 

Thermolabile （ inactivated after treated

with 60 ～ 80 ℃ for 30 minutes).

Exception ： staphylococcal enterotoxin can

resist

the treatment of 100 ℃ for 30 minutes ， and it is also resist the digestion of digestive

enzymes.

ActiveActive BindingBinding

AA

Cell surfaceCell surface

BB

A-B toxinsA-B toxins

Structure

B subunit

（ Binding ）• Determine the tissue

specificity of the toxin

• Powerful antigenicity

• can not be inactivated by

formaldehyde, while it can

be purified for subunit

vaccine.--Toxoid 

A subunit

(Toxic)

• Determine the toxic

of the toxin

• weak antigenicity

• can be inactivated

by formaldehyde

A-B toxinsA-B toxins

Immunity 

•  Antitoxin –  An antibody that specifically interacts with and 

neutralizes a toxin –  Application: treatment or urgent prevention 

measure 

•  Toxoid –  An exotoxin modified so that it is no longer toxic 

but is still able to induce antibody formation –  Application: vaccine

Toxicity 

•  High 

•  Tissue specificity

• Powerful antigenicity ： antitoxin and toxoid

Types

Enterotoxin

–enterotoxin (Staphylococcus aureus)

cytotoxin

– diphtheria toxin (Corynebacterium  diphtheriae)

neurotoxin

– tetanospasmin (Clostridium tetanus)

Mechanism of C. tetaniMechanism of C. tetani Organisms produces neurotoxin (tetanospasmin)Organisms produces neurotoxin (tetanospasmin)

Toxin travel along peripheral nerve to Toxin travel along peripheral nerve to anterior horn cells of spinal cordanterior horn cells of spinal cord

Inhibit neurotransmitter from inhibitory neuronInhibit neurotransmitter from inhibitory neuron Continuous muscle contractionContinuous muscle contraction

TrismusTrismus or lockjaw, risus sardonicus , opisthotonos, dysphagia, dyspnea or lockjaw, risus sardonicus , opisthotonos, dysphagia, dyspnea [dɪs'feɪdʒɪə][dɪs'feɪdʒɪə] 咽下困难 咽下困难 [dɪsp'niːə][dɪsp'niːə] 呼吸困难呼吸困难 [əʊ'pɪsθəʊtənəʊz][əʊ'pɪsθəʊtənəʊz] 角弓反张角弓反张

neurotoxin

sardonic smile (risus sardonicus)sardonic smile (risus sardonicus)

lockjawlockjaw

Rigid paralysis Rigid paralysis

Clostridium botulinumClostridium botulinum

Botulinum toxinBotulinum toxin

- inhibits acetylcholine release - inhibits acetylcholine release

- inhibits nerve impulses- inhibits nerve impulses

-muscles inactive-muscles inactive

-flacid paralysis-flacid paralysis

Toxin Gene LocationSubunit Structure

Target Cell Receptor Biologic Effects

Anthrax toxins

Bacillus anthracis

Plasmid Three separate proteins (EF, LF, PA)

Unknown, probably glycoprotein

EF + PA: increase in target cell cAMP level, localized edema; LF + PA: death of target cells and experimental animals

Bordetella adenylate cyclase toxin

Bordetella sp.

Chromosomal A-B Unknown, probably glycolipid

Increase in target cell cAMP level, modified cell function or cell death

Botulinum toxin

Clostridium botulinum

Phage A-B Possibly ganglioside (GD1b)

Decrease in peripheral, presynaptic acetylcholine release, flaccid paralysis

Cholera toxin

Vibrio cholerae

Chromosomal A-5B Ganglioside (GM1)

Activation of adenylate cyclase, increase in cAMP level, secretory diarrhea

Diphtheria toxin

Corynebacterium diphtheriae

Phage A-B Growth factor receptor precursor

Inhibition of protein synthesis, cell death

Heat-labile enterotoxins

Escherichia coli

Plasmid Similar or identical to cholera toxin

 

Properties of A-B Type Bacterial Toxins

Pertussis toxin

Bordetella pertussis

Chromosomal

A-5B Unknown, probably glycoprotein

Block of signal transduction mediated by target G proteins

Pseudomonas exotoxin A

Pseudomonas aeruginosa

Chromosomal

A-B Unknown, but different from diphtheria toxin

Similar or identical to diphtheria toxin

Shiga toxin Shigella dysenteriae

Chromosomal

A-5B Glycoprotein or glycolipid

Inhibition of protein synthesis, cell death

Shigalike toxins

Shigella sp., E. coli

Phage Similar or identical to Shiga toxin

 

Tetanus toxin

Clostridium tetani

Plasmid A-B Ganglioside (GT1)

and/or GD1b

Decrease in neurotransmitter release from inhibitory neurons, spastic paralysis

Toxin OrganismGene Location

Subunit Structure

Target Cell Receptor Biologic Effects

Properties of A-B Type Bacterial Toxins

Endotoxin 

Origin  G    bacteria 

Release  Cell wall lysis required

Physical and chemical properties 

•  LPS Lipopolysaccharide: Lipid A • Heat resistance : Resistance

Low poor antigen poor antigen , no toxoid EEndotoxin effects:ndotoxin effects: no tissue specificity  FeverFever--pyrogen 1 microgram/ kgpyrogen 1 microgram/ kg leukocytosisleukocytosis hypotensionhypotension ShwartzmanShwartzman phenomenon and disseminated phenomenon and disseminated

intravascular coagulation (DIC).intravascular coagulation (DIC). Endotoxemia and shockEndotoxemia and shock

Toxicity 

Lipid A of lipopolysaccharide is responsible for endotoxin activity

Pathogenesis of sepsis (septicemia)

Endotoxin (LPS)-mediated toxicity

Fever,

leukopenia followed by leukocytosis,

activation of complement, thrombocytopenia,

disseminated intravasacular coagulation,

decreased peripheral circulation and perfusion to

major organs (multiple organ system failure),

Shock and death.

Peptidoglycan, teichoic and lipoteichoic acids of gram-positive bacteria stimulate pyrogenic acute phase responses and produce endotoxin-like toxicity

Back

Endotoxin-mediated toxicity

Endotoxins

Detection of endotoxin: The Limulus lysate test

Low, no toxoid 

Low, no tissue specificity 

High, antitoxin, toxoid 

High, tissue specificity 

Immunity 

Toxicity 

Resistance Heat resistance  Sensitive 

LPS Protein composition 

Secreted from living cells or  Released upon released upon bacterial lysis  bacterial lysis 

Release 

Endotoxin 

G   

Exotoxin 

G +  and G   

Properties 

Origin 

The difference between exotoxin and endotoxin

Virulence  

invasiveness 

Virulence 

Adherence factor 

exotoxin 

toxin endotoxin 

Capsule and slime layer

Invasive enzyme 

Virulence of pathogenic bacterial

Infection Infection determinantdeterminant interaction interaction Infection Infection

typetype immunity >Virulence

immunity <Virulence

immunity ≈Virulence

Inapparent infection

Apparent infection

latent

infection

environment

Host immunity

Pathogenicity

(Virulence, number , Portal)

Exercises

•  Definitions:  normal flora, opportunistic pathogen,  exotoxin, endotoxin, antitoxin, toxoid, bacteremia, septicemia, toxemia, endotoxemia, carrier 

1.The medical significance of normal flora 2.The conditions causing opportunistic infections 3.Virulence of bacteria