PATHOGENESIS OF BACTERIAL INFECTION

GLOSSARY – Jawetz Medical Microbiology, 26th Ed., pp. 149-150 Characteristics of Pathogenic Bacteria:

1. Transmissibility2. Adherence to host cells3. Persistence4. Invasion of host cells and tissues5. Toxigenicity6. Ability to evade or survive the host’s immune system

Identifying Bacteria that Cause Disease1. KOCH’S POSTULATES (1884)2. MOLECULAR KOCH’S POSTULATES3. MOLECULAR GUIDELINES FOR ESTABLISHING MICROBIAL DISEASE CAUSATION

VIRULENCE Quantitative measure of pathogenicity Measured by the number of organisms required to cause disease

LD50 (50% lethal dose)- # of organisms needed to kill half of the hostsID50 (50% infectious dose)- # of organisms needed to cause infection in half of

the hosts Bacteria cause disease by:

1. Toxin Production2. Invasion And Inflammation3. Immunopathogenesis

Types of Bacterial Infection:EPIDEMIC – occurs much more frequently than usualPANDEMIC – worldwide distributionENDEMIC – constantly present at a low level in a specific populationINAPPARENT/SUBCLINICAL – detected only by demonstrating a rise in antibody titer or by isolating the organismLATENT STATE – reactivation of the growth of the organism and recurrence of symptoms may occurCHRONIC CARRIER STATE – organisms continue to grow with or without producing symptoms in the host

STAGES OF BACTERIAL PATHOGENESIS:1. TRANSMISSION from an external source into the portal of entry2. EVASION of primary host defenses (skin, stomach acid)3. ADHERENCE to mucous membranes usually by bacterial pili4. COLONIZATION by growth of the bacteria at the site of adherence5. DISEASE SYMPTOMS caused by toxin production or invasion accompanied by inflammation6. HOST RESPONSES (nonspecific, specific)7. PROGRESSION or RESOLUTION of the disease

GENOMICS & BACTERIAL PATHOGENICITYMechanisms used by bacteria to transmit virulence genes from one to another:1. Transformation- DNA from one organism is released into the environment and is taken up by a different organism that is capable of recognizing and binding DNA2. Mobile genetic elements- plasmids, transposons, bacteriophages

VIRULENCE FACTORS ENCODED BY GENES ON MOBILE GENETIC ELEMENTS

(Table 9-2, p153)

PATHOGENICITY ISLANDS (PAIs)Large group of genes that are associated with pathogenicity located on bacterial chromosomes; 10-

200 kbProperties:1. > 1 virulence genes2. present in the genome of pathogenic members of a species, absent in nonpathogenic members 3. large

4. different guanine + cytosine content (G+C) than the rest of the bacterial genome5. commonly associated with tRNA genes6. often found with parts of the genome associated with mobile genetic elements7. often have genetic instability8. often represent mosaic structures with components acquired at different times

DETERMINANTS OF BACTERIAL PATHOGENESISI. TRANSMISSION

II. ADHERENCE TO CELL SURFACESIII. INVASION, INFLAMMATION & INTRACELLULAR SURVIVALIV. TOXIN PRODUCTIONV. IMMUNOPATHOGENESIS

TRANSMISSIONAn understanding of the mode of transmission of bacteria and other infectious agents is important because interrupting the chain of transmission is an excellent way to prevent infectious diseases.

IMPORTANT MODES OF TRANSMISSIONMode of Transmission Clinical Example

I. HUMAN TO HUMAN A. Direct Contact Gonorrhea Intimate contact (sexual or passage through birth canal) B. No direct contact Dysentery Fecal-oral (excreted in human feces, then ingested in food or

water) C. Transplacental Congenital syphilis Bacteria cross the placenta and infect the fetus

D. Blood-borne Syphilis Transfused blood or IV drug use can transmit bacteria and virusesII. NONHUMAN TO

HUMANA. Soil Source Tetanus Spores in soil enter wound in skinB. Water Source Legionnaire’s

DiseaseBacteria in water aerosol are inhaled into lungs

C. Animal Source 1. Directly 2. Via insect

vector 3. Via animal

excreta

Cat-scratch FeverLyme Disease

HUS by E. coli 0-157

Bacteria enter in cat scratchBacteria enter in tick bite

Bacteria in cattle feces are ingested in undercooked hamburger

D. Fomite Source Staphylococcal skin infection

Bacteria on an object (towel) are transferred onto the skin

VERTICAL TRANSMISSION – from mother to offspring

Within birth canal/ at the time of birth

Streptococcus agalactiae (Group B streptococci)

Neonatal sepsis and meningitis

Escherichia coli Neonatal sepsis and meningitisChlamydia trachomatis Conjunctivitis and pneumoniaNeisseria gonorrhoeae Conjunctivitis

Herpes simplex type-2 Skin, CNS, disseminated infection (sepsis)

Hepatitis B virus Hepatitis BHuman immune-deficiency virus Asymptomatic infectionCandida albicans Thrush

Breast milk Staphylococcus aureus Oral or skin infectionsCytomegalovirus Asymptomatic infectionHuman T-cell leukemia virus Asymptomatic infection

Transplacental Treponema pallidum Congenital syphilis

Listeria monocytogenes Neonatal sepsis and meningitisCytomegalovirus Congenital abnormalitiesParvovirus Hydrops fetalisToxoplasma gondii Toxoplasmosis

IMPORTANT PORTALS OF ENTRY

1. respiratory tract(upper and lower airways)2. GIT (primarily mouth)3. genital tract4. urinary tract

Portal of Entry Pathogen DiseaseRespiratory Tract Streptococcus pneumoniae Pneumonia

Neisseria meningitides MeningitisHaemophilus influenza MeningitisMycobacterium

tuberculosisTuberculosis

Influenza virus InfluenzaRhinovirus Common coldEpstein-Barr virus Infectious mononucleosisCoccidiodes immitis CoccidiodomycosisHistoplasma capsulatum Histoplasmosis

GIT Shigella dysenteriae DysenterySalmonella typhi Typhoid feverVibrio cholera CholeraHepatitis A virus Infectious hepatitisPoliovirus PoliomyelitisTrichinella spiralis Trichinosis

Skin Clostridium tetani TetanusRickettsia rickettsi Rocky Mountain Spotted FeverRabies virus RabiesTrichophyton rubrum Tinea pedis (athlete’s foot)Plasmodium vivax Malaria

Genital Tract Neisseria gonorrhoeae GonorrheaTreponema pallidum Syphilis

Chlamydia trachomatis Urethritis

Human papilloma virus Genital warts

Candida albicans Vaginitis

TRANSMISSION OF IMPORTANT WATERBORNE DISEASESPortal of Entry Pathogen DiseaseRespiratory TractInhalation of water aerosol Legionella pneumophila Pneumonia (Legionnaire’s disease)SkinPenetration through skin Pseudomonas aeruginosa Hot-tub folliculitis

Schistosoma mansoni Schistosomiasis

NosePenetration through

cribriform plateNaegleria fowleri Meningoencephalitis

Gastrointestinal Tract

1. Ingestion of drinking water

Salmonella species Diarrhea

Shigella species Diarrhea

Campylobacter jejuni Diarrhea

Norovirus (Norwalk-like viruses)

Diarrhea

Giardia lambllia DiarrheaCryptosporidium parvum Diarrhea

2. Ingestion of water while swimming

Leptospira interrogans Leptospirosis

DIARRHEAL DISEASES TRANSMITTED BY FOODBacterium Typical Food Main Reservoir Disease

Diarrheal DiseasesGram-positive cocci Staphylococcus aureus Custard-filled pastries,

potato, egg, tuna fish salad

Humans Food poisoning, esp. vomiting

Gram-positive rods Bacillus cereus Clostridium perfringens Listeria monocytogenes

Reheated riceCooked meat, stew and

gravyUnpasteurized milk

products

SoilSoil, animals or

humansSoil, animals or

plants

DiarrheaDiarrhea

Diarrhea

Gram-negative rods Eschericia coli E. coli O157:H7 strain

Salmonella enteritidis

Salmonella typhi Shigella species Vibrio cholera Vibrio parahaemolyticus Campylobacter jejuni Yersinia enterocolitica

Various foods and waterUndercooked meat

Poultry, meats and eggs

Various foodsVarious foods and waterVarious foods and waterSeafoodVarious foodsVarious foods

HumansCattle

Domestic animals (esp. poulty)

HumansHumansHumansWarm salt waterDomestic

animalsDomestic

animals

DiarrheaHemorrhagic colitis

Diarrhea

Typhoid FeverDiarrheaDiarrhea (dysentery)DiarrheaDiarrheaDiarrhea

Nondiarrheal DiseasesGram-positive rods

Clostridium botulinum

Listeria monocytogenes

Improperly cannedvegetables and smoked

fishUnpasteurized milk

products

Soil

Cows

Botulism

Sepsis in neonate or mother

Gram-negative rodsVibrio vulnificusBrucella speciesFrancisella tularensis

SeafoodMeat and milkMeat

Warm salt waterDomestic

animalsRabbits

SepsisBrucellosisTularemia

Mycobacteria Mycobacterium bovis

Milk Cows Intestinal tuberculosis

BACTERIAL DISEASES TRANSMITTED BY INSECTSBacterium Insect Reservoir Disease

Gram-negative rods Yersinia pestis

Francisella tularensis

Rat fleas

Ticks (Dermacentor)

Rodents (rats, prairie dogs)

Many animals (rabbits)

PlagueTularemia

Spirochetes Borrelia burgdorferi Borrelia recurrentis

Ticks (Ixodes)Humans

MiceHumans

Lyme diseaseRelapsing fever

Rickettsias Rickettsia rickettsia Rickettsia prowazekii Ehrlichia chaffeensis

Ticks (Dermacentor)LiceTicks (Dermacentor, Ixodes)

Dogs, rodents, ticks

ADHERENCE TO CELL SURFACESPILI (Neisseria gonorrhoeae, Escherichia coli)CAPSULESGLYCOCALYCES (Staphylococcus epidermidis, viridans streptococci)Various molecules that mediate adherence to cell surfaces are called ADHESINS

INVASION, INFLAMMATION & INTRACELLULAR SURVIVALENZYMES1. COLLAGENASE – degrade collagen 2. HYALURONIDASE – degrade hyaluronic acid3. COAGULASE – accelerates the formation of fibrin clot from fibrinogen; clot protects the bacteria from phagocytosis by walling off the infected area and coating the microorganism

4. IMMUNOGLOBULIN A (IgA) PROTEASE – degrades IgA5. LEUKOCIDINS – destroy neutrophilic leukocytes and macrophages

VIRULENCE FACTORS1. CAPSULE– Streptococcus pneumoniae, Neisseria meningitidis

6. CELL WALL PROTEINS OF GRAM (+) COCCI – M protein (group A streptococci Streptococcus pyogenes, Protein A of Staphylococcus aureus)

INTRACELLULAR SURVIVALMycobacterium, Legionella, Brucella, Listeria, Histoplasma

1. inhibition of the fusion of phagosome with the lysosome (avoid degradative enzymes in the lysosome)

2. inhibition of acidification of the phagosome (reduces activity of lysosomal degradative enzymes )

3. escape from phagosome into the cytoplasm (no degradative enzymes )

Bacteria cause disease by: INFLAMMATION and TOXIN PRODUCTION

TOXIN PRODUCTIONMAIN FEATURES OF EXOTOXINS AND ENDOTOXINS

EXOTOXINS have A-B subunit A (active)- possesses the toxic activityB (binding)- responsible for binding the exotoxin to specific receptors on the

membrane of the human cell) A-

subunit: act by ADP-ribosylation (A-subunit is an enzyme that catalyzes the addition of adenosine diphosphate ribose- ADP-ribose- to the target protein in the human cell INACTIVATES or HYPERACTIVATE THE CELL SYMPTOMS

EXOTOXINS are released from bacterial by SECRETION SYSTEMS INJECTOSOME/TYPE III SECRETION SYSTEM – “molecular syringe” (needle-like projection) &

transport pumps in the bacterial cell membrane

PROPERTY EXOTOXIN ENDOTOXIN

Source Certain species of G(+) & Gram (-) bacteria

Cell wall of G(-) bacteria

Secreted from cell Yes No

Chemistry Polypeptide LipopolysaccharideLocation of genes Plasmid or bacteriophage Bacterial chromosomeToxicity High LowClinical effects Various Fever, shock

Mode of action Various Includes TNF, IL-1Antigenicity Induces high-titer antibodies

(antitoxins)Poorly antigenic

Vaccines Toxoids used as vaccines No toxoids formed and no vaccines available

Heat stability Destroyed rapidly at 60oC (except staphylococcal enterotoxin)

Stable at 100oC for 1 hour

Typical diseases Tetanus, botulism, diphtheria Meningococcemia, sepsis

EFFECTS OF ENDOTOXINSCLINICAL FINDINGS MEDIATOR/MECHANISM

FEVER IL-1, IL-6

HYPOTENSION (SHOCK) TNF, NITRIC OXIDE, BRADYKINININFLAMMATION C5a produced by the alternative pathway of complement attracts

neutrophilsCOAGULATION (DIC) Activation of tissue factor

IMPORTANT MECHANISMS OF ACTION OF BACTERIAL EXOTOXINS

IMPORTANT BACTERIAL EXOTOXINS

MECHANISM OF ACTION EXOTOXIN

ADP- ribosylation Diphtheria toxin, cholera toxin, Escherichia coli heat-labile toxin, pertussis toxin

Superantigen TSST, staphylococcal enterotoxin, erythrogenic toxinProtease Tetanus toxin, botulinum toxin, lethal factor of anthrax toxin,

scalded skin toxin

Lecithinase Clostridium perfringens alpha toxin

BACTERIUM MECHANISM OF ACTIONCorynebacterium diphtheria Inactivates EF-2 by ADP-ribosylation (inhibits protein synthesis)Clostridium tetani Blocks the release of the inhibitory NT GLYCINE by proteolytic

cleavage of releasing proteins

Clostridium botulinum Blocks release of ACETYLCHOLINE by proteolytic cleavage of releasing proteins

Clostridium difficile Exotoxins A and B inactivate GTPases by glycosylation

Clostridium perfringens Alpha toxin is a lecithinase; enterotoxin is a superantigen

Bacillus anthracis Edema factor is an adenylate cyclase; lethal factor is a protease that cleaves MAP kinase (required for cell division)