chapter 25 lecture outline microbial pathogenesis

Chapter 25Lecture Outline

Microbial Pathogenesis

Microbiology: An Evolving Science © 2009 W. W. Norton & Company, Inc. 2

Overview

25.1 Host Pathogen Interactions 25.3 Virulence factors: Microbial attachment 25.4 Toxins: A way to subvert host cell function 25.5 Type III protein secretion and pathogenesis 25.6 Finding virulence genes with signature

tagged mutagenesis 25.7 Surviving within the host 25.8 Viral pathogenesis


Pathogens and Parasites Pathogens: bacterial,

viral, and fungal agents of disease

Parasites: protozoans and worms causing disease

Definitions are typically used in microbial pathogenesis

Filaria Wucheria bancrofti causing elephantiasis.

Fungus Trichophyton rubrum causing athletes’s foot.


Host-Pathogen Interactions: Definitions (1)

Colonization Presence of microbes on body surfaces

Infection Entry and growth of pathogen or parasite Infection does not always cause disease Most infections removed by immune system

Primary pathogens Have ability to penetrate host defenses and cause disease in a healthy

host Opportunistic pathogens

Cause disease only in compromised hosts Immune system defective Break in tissue barrier allows organism access to new site Loss of normal microbiota allows organism to bloom


Host-Pathogen Interactions: Definitions (2) Virulence

Measure of degree or severity of disease Rate of lethal infections Lethal dose = LD50

Number of organisms to kill 50% of hosts

Infectious dose (for organisms that do not cause death) = ID50

Number of organisms to colonize 50% of hosts

Pathogenicity of organism Measure of ability to cause disease A function of infectivity and virulence

Determined by genetic makeup of organism


Measurement of Virulence


Infection Cycles

Transmission Entry

Colonization Invasion

Dissemination Exit

Adherence factors

ToxinsImmune evasion

Pathogenicity factors


Transmission of Infections (1) Spread via direct contact

Example: common cold Indirect contact

Contact with fomites Inanimate objects Example: S. aureus infection

Via vectors Example: Mosquitoes (malaria) Reservoir for disease organism

May not show disease symptoms


Transmission of Infections (2)


Port of Entries

Skin Hard to penetrate (keratin) Requires usually lesion or injection

Mucosal surfaces Respiratory tract Intestinal tract Urogenital tract

Exit site is usually same as entry site


Adherence Factors Serve microbial attachment Human body expels invaders

Mucosa, dead skin constantly expelled Liquid expelled from bladder Coughing, cilia in lungs Expulsion of intestinal contents

Bacteria must adhere to host tissue Pili (fimbriae)

Hollow fibrils with tips to bind to host cells

Adhesins surface proteins that bind to host cells


Microbial Attachment via Pili Type I pili adhere to mannose

Grows from outer membrane New subunits added at base

E.g. uropathogenic E.coli

Type IV pili Grow from inner membrane Can grow and retract Twitching motility E.g. Neisseria gonorrhoeae


Microbial Attachment via Adhesins

Streptococcus pyogenes uses M protein to attach to respiratory cells B. pertussis uses pertactin and

filamentous hemagglutinin to bind to respiratory ciliated cells


Toxins Subvert Host Function Exotoxins

SecretedTypically proteinsSpecific targets and effects

EndotoxinSame as lipopolysaccharidePart of the outer membrane Activates host defense resulting in acute

inflammatory response including fever


Exotoxins Five target of protein exotoxins

Cell membrane Leakage

Protein synthesis Inhibition

2nd messenger pathway Disruption

Immune system Overstimulation (superantigens)

Proteases Degrade host proteins


Mode of Action of Selected Exotoxins

Pore forming toxinsE.G: S. aureus alpha toxinTransmembrane, oligomeric, beta barrel pore

AB toxinB: mediates binding to hostA: subunit with toxic activity cleaving 28S rRNA in eukaryotic ribosomes

E. coli enterotoxigenic heat stable toxinStimulates guanylate cyclaseIncreases cGMP levelsAffects electrolyte flux, increases water efflux.


ADP-Ribosylating Toxins

Often AB toxins Active toxin is an ADP-ribosyltransferase Found among toxins that inhibit protein

synthesis (e.g. diphteria toxin) and among toxins that disrupt 2nd messenger pathways (e.g. cholera toxin)

ADP-ribosylated proteins may be inhibited or activated


Cholera toxin Ribosylates to overactivate

adenylate cyclase cAMP activates ion transport,

water follows Uncontrollable diarrhea

Diphtheria toxin Ribosylates elongation factor 2 Blocks ribosome function, cell

dies Forms pseudomembrane over

trachea

ADP-Ribosylating Toxins

C. diphtheriae

V. cholerae


ADP-Ribosylating ToxinsAnimation: Cholera Toxin Mode of Action

Click box to launch animation


Type III Protein Secretion Injects proteins directly into host cell

“Hypodermic needle” similar to base of flagellum!Genes on pathogenicity island

Injected proteins cause host toengulf bacterium

Salmonella injects over 13 toxinsAlters fusion of vesicles in cellCauses diarrhea in host


The Needle Complex of the Type III Secretion System

Proteins are directly injected into host cytoplasma

Apparatus is related to flaggela assembly proteins


Immune Evasion

Prevent uptake Allow uptake but prevent degradation by

hostFacultative intracellular organismsObligate intracellular organisms

Change surface Inhibit immune defenses


Surviving within the Host Outside host cell, how to avoid death?

Complement, antibodies bind pathogen and enhance uptake by phagocytes (opsonization)

Some pathogens secrete thick capsule Streptococcus pneumoniae, Neisseria meningitidis

Some pathogens make proteins to bind antibodies Staphylococcus aureus cell wall Protein A

Antibodies attach “upside down” Prevents opsonization

Some pathogens cause apoptosis (suicide) of phagocytes


Surviving within the Host Once inside host cell, how to avoid death?

Cell ingests pathogens in phagosome Some pathogens use hemolysin to break out

Shigella dysenteriae, Listeria monocytogenes

Phagosome fuses with acidic lysosome Some pathogens secrete proteins to prevent fusion

Salmonella, Chlamydia, Mycobacterium Some pathogens mature in acidic environment

Coxiella burnetii—Q fever


How do Bacteria Recognize Host Environment?

Two-component signal transductionDetect magnesium concentration, pH

Both low in host cell vacuole

Quorum sensing Detect exotoxins made by other cells Delays toxin synthesis until many bacteria present

Possible pathway for preventing pathogen growth?


Selected Viral Pathogenesis:Immune Evasion Change of capsid alteration allows virus to re-infect

Creates novel epitopes Influenza virus antigenic drift

Subtle changes in surface structure RNA Polymerase does not correct replication errors Frequent mutations in haemagglutinin gene If allows virus to avoid immune system, virus spreads New flu vaccine needed every year

Influenza virus antigenic shift Major changes in surface proteins

Infection of the immune system HIV infects T helper cells

Central regulators of our adaptive immune system


Concept QuizBacteria prevent being flushed from the intestine by means of

a. The Type II secretion system

b. Inhibition of immune system cells

c. Type IV pili and adhesins


Concept QuizCholera toxin A subunit causes ADP-ribosylation of its target, and is an example of

a. A neurotoxin, which inhibits neural function

b. An enterotoxin, which disrupts function of the intestine

c. A cytotoxin, which kills infected host cells


Concept QuizMost bacteria avoid the lysosome. One bacterium that welcomes lysosome acidity is

a. Shigella flexneri

b. Legionella pneumophila

c. Coxiella burnetii


Concept QuizNew vaccines to influenza virus must be taken each year, because this virus undergoes

a. Antigenic drift

b. Binding to multiple receptors

c. Inhibition of p53 to allow unchecked growth

chapter 25 lecture outline microbial pathogenesis

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