Microbial Microbial Mechanisms of Mechanisms of PathogenesisPathogenesis

PathogenesisPathogenesis The word comes from the The word comes from the GreekGreek pathospathos, ,

"disease", and "disease", and genesisgenesis, creation. , creation.

The term pathogenesis means step by step The term pathogenesis means step by step development of a disease.development of a disease.

The chain of events leading to that disease The chain of events leading to that disease due to a series of changes in the structure due to a series of changes in the structure and /or function of a cell/tissue/organ.and /or function of a cell/tissue/organ.

Caused by a microbial, chemical or physical Caused by a microbial, chemical or physical agent. agent.

Pathogenicity - Pathogenicity - Ability to Ability to cause diseasecause disease

Virulence - Virulence - Degree of Degree of pathogenicitypathogenicity

Many properties that determine a Many properties that determine a microbe’s pathogenicity or virulence are microbe’s pathogenicity or virulence are unclear or unknownunclear or unknown

But, when a microbe overpowers the But, when a microbe overpowers the hosts defenses, disease results!hosts defenses, disease results!

Portals of EntryPortals of Entry 1. Mucus Membranes1. Mucus Membranes

2. Skin2. Skin

3. Parenteral3. Parenteral

1. Mucus Membranes1. Mucus Membranes A. Respiratory TractA. Respiratory Tract

Sticky mucous secretionSticky mucous secretion Muco polysachharidesMuco polysachharides Cough reflexCough reflex Phagocytic cellsPhagocytic cells

Common Diseases Common Diseases contracted via the contracted via the Respiratory TractRespiratory Tract

Common coldCommon cold FluFlu TuberculosisTuberculosis Whooping coughWhooping cough PneumoniaPneumonia MeaslesMeasles Strep ThroatStrep Throat DiphtheriaDiphtheria

Mucus MembranesMucus Membranes

B. Gastrointestinal TractB. Gastrointestinal Tract Microbes gain entrance Microbes gain entrance

thru contaminated food & thru contaminated food & water or fingers & hands.water or fingers & hands.

Most microbes that enter Most microbes that enter the G.I. Tract are destroyed the G.I. Tract are destroyed by HCL & enzymes of by HCL & enzymes of stomach or bile & enzymes stomach or bile & enzymes of small intestine.of small intestine.

Common diseases contracted via the Common diseases contracted via the

G.I. TractG.I. Tract SalmonellosisSalmonellosis Salmonella sp.Salmonella sp.

ShigellosisShigellosis Shigella sp.Shigella sp.

CholeraCholera Vibrio choloreaVibrio cholorea

UlcersUlcers Helicobacter pyloriHelicobacter pylori

BotulismBotulism Clostridium botulinumClostridium botulinum

Fecal - Oral DiseasesFecal - Oral Diseases

These pathogens enter the G.I. Tract at These pathogens enter the G.I. Tract at one end and exit at the other end.one end and exit at the other end.

Spread by contaminated hands & fingers Spread by contaminated hands & fingers or contaminated food & wateror contaminated food & water

Poor personal hygiene. Poor personal hygiene.

Mucus Membranes of the Genitourinary System

Acidic urine

Vaginal secretion- Acidic due to fermentation of glycogen by lactobacillus

Gonorrhea

Neisseria gonorrhoeae

Syphilis

Treponema pallidumChlamydia

Chlamydia trachomatis

HIV

Herpes Simplex II

Mucus MembranesMucus Membranes

D. Conjunctiva D. Conjunctiva ––

Lacrymal secretionLacrymal secretion LysozymeLysozyme

TrachomaTrachoma Chlamydia Chlamydia

trachomatistrachomatis

2. Skin2. Skin Skin - the largest organ of the body. Skin - the largest organ of the body. Sebaceous secretion-containing fatty acidsSebaceous secretion-containing fatty acids Resident floraResident flora When unbroken is an effective barrier for most When unbroken is an effective barrier for most

microorganisms.microorganisms.

Some microbes can gain entrance thru Some microbes can gain entrance thru openings in the skin: hair follicles and sweat openings in the skin: hair follicles and sweat glandsglands

3. Parentarel3. Parentarel

Microorganisms are Microorganisms are depositeddeposited into the into the tissues below the skin or mucus membranestissues below the skin or mucus membranes

PuncturesPunctures injectionsinjections bitesbites scratchesscratches surgerysurgery splitting of skin due to swelling or drynesssplitting of skin due to swelling or dryness

Number of Invading Number of Invading MicrobesMicrobes

LDLD50 50 - Lethal Dose of a microbes toxin - Lethal Dose of a microbes toxin that will kill 50% of experimentally that will kill 50% of experimentally inoculated test animalinoculated test animal

IDID50 50 - infectious dose required to cause - infectious dose required to cause disease in 50% of inoculated test animalsdisease in 50% of inoculated test animals Example: IDExample: ID5050 for for Vibrio cholerea Vibrio cholerea 10 1088 cells cells

(100,000,000 cells) (100,000,000 cells) IDID50 50 for Inhalation Anthrax - 5,000 to 10,000 for Inhalation Anthrax - 5,000 to 10,000

spores spores

How do Bacterial Pathogens penetrate Host Defenses?

1. Adherence - almost all pathogens have a means to attach to host tissue

Binding Sites

adhesins

ligands

How Bacterial Pathogens Penetrate How Bacterial Pathogens Penetrate Host DefensesHost Defenses

1. Adherence1. Adherence 2. Capsule2. Capsule 3. Enzymes3. Enzymes

A. leukocidinsA. leukocidins B. HemolysinsB. Hemolysins C. CoagulaseC. Coagulase D. KinasesD. Kinases E. HyaluronidaseE. Hyaluronidase F. CollagenaseF. Collagenase G. Necrotizing FactorG. Necrotizing Factor

Adhesins and ligands are Adhesins and ligands are usually on Fimbriaeusually on Fimbriae Neisseria Neisseria

gonorrhoeaegonorrhoeae ETEC ETEC

(Entertoxigenic E. (Entertoxigenic E. coli)coli)

Bordetella pertussisBordetella pertussis

2. Capsules2. Capsules Prevent phagocytosisPrevent phagocytosis AttachmentAttachment Streptococcus Streptococcus

pneumoniaepneumoniae Klebsiella pneumoniaeKlebsiella pneumoniae Haemophilus Haemophilus

influenzaeinfluenzae Bacillus anthracisBacillus anthracis Streptococcus mutansStreptococcus mutans Yersinia pestisYersinia pestis

K. pneumoniae

3. Enzymes3. Enzymes

Many pathogens secrete enzymes that Many pathogens secrete enzymes that contribute to their pathogenicitycontribute to their pathogenicity

A. LeukocidinsA. Leukocidins

Attack certain types of WBC’sAttack certain types of WBC’s

1. Kills WBC’s which prevents 1. Kills WBC’s which prevents phagocytosisphagocytosis

2. Releases & ruptures lysosomes2. Releases & ruptures lysosomes lysosomes - contain powerful hydrolytic lysosomes - contain powerful hydrolytic

enzymes which then cause more tissue enzymes which then cause more tissue damage damage

B. Hemolysins - cause the lysis of RBC’s

Streptococci

1. Alpha Hemolytic Streptococci

- secrete hemolysins that cause the incomplete lysis or RBC’s

2. Beta Hemolytic Streptococci

- Secrete hemolysins that cause the complete lysis of RBC’s

C. Coagulase - C. Coagulase - cause blood cause blood to coagulateto coagulate

Blood clots protect bacteria from Blood clots protect bacteria from phagocytosis from WBC’s and other host phagocytosis from WBC’s and other host defensesdefenses

Staphylococci - are often coagulase Staphylococci - are often coagulase positivepositive boilsboils abscessesabscesses

D. Kinases - D. Kinases - enzymes that enzymes that dissolve blood clotsdissolve blood clots

1. Streptokinase - Streptococci1. Streptokinase - Streptococci 2. Staphylokinase - Staphylococci2. Staphylokinase - Staphylococci

Helps to spread bacteria - Helps to spread bacteria - BacteremiaBacteremia

Streptokinase - Streptokinase - used to dissolve blood clots in the used to dissolve blood clots in the Heart (Heart Attacks due to obstructed coronary blood Heart (Heart Attacks due to obstructed coronary blood vessels)vessels)

E. HyaluronidaseE. Hyaluronidase

Breaks down Hyaluronic acid Breaks down Hyaluronic acid (found in (found in connective tissues)connective tissues)

““Spreading Factor”Spreading Factor”

Mixed with a drug to help spread the Mixed with a drug to help spread the drug through a body tissuedrug through a body tissue

F. CollagenaseF. Collagenase

Breaks down collagen Breaks down collagen (found in many (found in many connective tissues)connective tissues)

Clostridium perfringens - Clostridium perfringens - Gas GangreneGas Gangrene uses this to spread thru muscle tissueuses this to spread thru muscle tissue

G. Necrotizing Factor- Causes death (necrosis) to tissue cells

“Flesh Eating Bacteria”

Bacterial ToxinsBacterial Toxins Poisonous substances produced by Poisonous substances produced by

microorganismsmicroorganisms Toxins - Toxins - primary factorprimary factor - pathogenicity - pathogenicity 220 known bacterial toxins 220 known bacterial toxins

40% cause disease by damaging the Eukaryotic 40% cause disease by damaging the Eukaryotic cell membranecell membrane

Toxemia Toxemia Toxins in the bloodstreamToxins in the bloodstream

Types of ToxinsTypes of Toxins 1. Exotoxins1. Exotoxins

Exotoxins are generated by the bacteria and Exotoxins are generated by the bacteria and actively secreted actively secreted

Secreted outside the bacterial cellSecreted outside the bacterial cell

2. Endotoxins2. Endotoxins Part of the outer cell wall of Gram (-) bacteriaPart of the outer cell wall of Gram (-) bacteria The body's response to endotoxin can involve The body's response to endotoxin can involve

severe inflammation.severe inflammation.

ExotoxinsExotoxins Mostly seen in Gram (+) BacteriaMostly seen in Gram (+) Bacteria Heat labile, can be inactivated by heating at Heat labile, can be inactivated by heating at

60-8060-80 ۠۠ C.C.

Excreted [ secreted] from the microbial cells Excreted [ secreted] from the microbial cells into the surrounding ie culture media or into the surrounding ie culture media or circulatory systemcirculatory system

Don’t require bacterial death or cell lysis for Don’t require bacterial death or cell lysis for their release.their release.

Types of Exotoxins Types of Exotoxins 1. Cytotoxins1. Cytotoxins

Kill cells- shigella, vibrioKill cells- shigella, vibrio

2. Neurotoxins2. Neurotoxins Interfere with normal nerve impulsesInterfere with normal nerve impulses Clostridium botulinumClostridium botulinum Clostridium tetaniClostridium tetani

3. Enterotoxins3. Enterotoxins Effect cells lining the G.I. TractEffect cells lining the G.I. Tract E. coliE. coli SalmonellaSalmonella

Response to ToxinsResponse to Toxins

If exposed to exotoxins: antibodies against the If exposed to exotoxins: antibodies against the toxin (toxin (antitoxinsantitoxins))

Exotoxins inactivated ( heat, formalin or Exotoxins inactivated ( heat, formalin or phenol) no longer cause disease, but stimulate phenol) no longer cause disease, but stimulate the production of antitoxinthe production of antitoxin altered exotoxins - altered exotoxins - ToxoidsToxoids

Toxoids - injected to stimulate the production Toxoids - injected to stimulate the production of antitoxins and provide immunityof antitoxins and provide immunity

Endotoxins Endotoxins Part of the Gram (-) Bacterial cell wall.Part of the Gram (-) Bacterial cell wall. Biological activity or toxicity of endotoxin is Biological activity or toxicity of endotoxin is

largely due to lipid A.largely due to lipid A. Relatively heat stable can withstand heat over Relatively heat stable can withstand heat over

6060 ۠۠ C for many hours.C for many hours. Released upon cell lysis or death.Released upon cell lysis or death. Less potent than exotoxins, active in large Less potent than exotoxins, active in large

doses only.doses only. Pyrogenic often produce fever in hosts.Pyrogenic often produce fever in hosts. Salmonella, Shigella, Escherichia, Neisseria.Salmonella, Shigella, Escherichia, Neisseria.

BacteriocinBacteriocin Bacteriocins were first discovered by A. Gratia in Bacteriocins were first discovered by A. Gratia in

1925.1925. He called his first discovery a He called his first discovery a colicinecolicine because it because it

killed killed E. coli.E. coli.

BacteriocinsBacteriocins are proteinaceous toxins produced are proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely by bacteria to inhibit the growth of similar or closely related bacterial strain(s). related bacterial strain(s).

They are typically considered to be narrow They are typically considered to be narrow spectrum antibiotics, though this has been spectrum antibiotics, though this has been debated. debated.

Classification:Classification:

Class I: Small peptide inhibitors .Class I: Small peptide inhibitors .

Class II: Small heat-stable proteins .Class II: Small heat-stable proteins .

Class III: Large, heat-labile protein bacteriocins Class III: Large, heat-labile protein bacteriocins

Medical significance Medical significance

Bacteriocins are of interest in medicine Bacteriocins are of interest in medicine because they are made by non-pathogenic because they are made by non-pathogenic bacteria that normally colonize the human bacteria that normally colonize the human body. body.

Loss of these harmless bacteria following Loss of these harmless bacteria following antibiotic use may allow opportunistic antibiotic use may allow opportunistic pathogenic bacteria to invade the human body.pathogenic bacteria to invade the human body.