Introduction to Microbial Pathogenesis

Infectious Agent

• “a single [type] of micro-organism could be isolated from all animals suffering from anthrax;

• the disease could be reproduced in an experimental host by infection with a pure culture of this bacterium; and

• the same [type] of micro-organism could subsequently be reisolated from the experimental host.”

(Proposed by Henle in 1840; demonstrated by Koch in 1876)

Infectious Agents in Humans

• Prion - scrapie

• Viruses – HIV, influenza

• Bacteria – Mycobacterium tuberculosis

• Fungi – Candida albicans

• Protozoa – Plasmodium falciparum

• Helminths – Schistosoma mansoni

normal abnormal

Prion

Virus

Bacteria

Fungi

Protozoa

Helminths

Ascaris lumbricoides : human intestinal roundworm

Barriers

Physical barrier: Skin, Mucosal gel overlaying epithelium (respiratory, gastrointestinal, urogenitary)

Microbiological barrier: Normal microbioflora

Initiation of Disease

Initiation of Disease

contact with pathogenic organism:human to human, animal to human

Transmission

• Aerosols to respiratory mucosa

• Fomite to nasopharyngial or conjungtive mucosa

• Fecal – Oral Route

• Mucosal surface to mucosal surface

Transmission

Multiplication

Dissemination

Invasion

Breach of epithelium

Colonization of mucosa

Infectious Disease Cycle

or

Attachment to target cells

to subepithelial or intracellular space

Evasion ofhost defense

Adherence/Attachment

Specific Adherence Non-specific Adherence

• Receptor-mediated adhesion • Hydrophobic/lipophilic-mediated adhesion

•Hydrophobic struture on microbial cell envelope

•Lipophilic area on host cell membrane

Specific Adherence

Bacterial

Viral

Fimbrial

Afimbrial

Microbial adhesin Host cell receptor

Herpes simplex 1 virus Epithelial cells of skin and mucosaglycoproteins B, C and D heparin sulfate

Measles virus Epithelial, endothelial cells, mononcytes-macrophages (and others)

hemagglutinin (H) protein CD46

Uropahogenic E coli Epithelial cell

P-pili glycolipid receptor globobiose

fibronectin binding protein

Staphylococcus aureus

fibronectin receptor integrin

Epithelial, endothelial, fibroblastic cells

Invasion

bacterial viral

•Transcytosis across superficial epithelium to subepithilial space

•Induce engulfment by non-phagocytic host cells

•Local reararrangement of host cell cytoskeleton

•Phagocytosis

•Utilization of membranous cell gateway

•Pass through plasma membrane

•Membrane invagination

•Clathrin

•Fusion with host cell plasma membrane

•HIV gp120/41

•T lymphocyte CD4

•Macrophage CCR5

Evasion/Manipulation of Host Defense

• Modulation of innate/inflammatory response

• Resistance to phagocytic killing in subepithelial space

• Serum resistance

• Antigenic variation

Modulation of Innate/Inflammatory Response

Adhesin-directed degranulation of mast cells

E. coli bound to mouse mast cell

mast cell

histamineproteoglycans

cytokines

degranulation

Resistance to phagocytic killing in subepithelial space

• Survive within phagocyte

• Inhibit phagocyte mobilization :(chemotaxis, complement activation)

Inhibit chemoattractants: Streptococcus pyogenes degrades C5a

Inhibit chemotaxis: Pertussis toxin causes intracellular rise in cAMP in neutrophils to impair chemotaxis

• Avoid ingestion

kill phagocytes: Streptolysin O lyses PMNs; Staphylococcus aureus alpha, beta and gamma toxins and leucocidin lyses PMNs

capsular protection from opsonization: M proteins, Streptococcus pyogenes

Bacterial capsules that resemble self: Neisseria meningitidis (sialic acid); Streptococcus pyogenes (hyaluronic acid)

Survival within phagocyte

Escape endosome or phagolysosome:

- Shigella, Listeria monocytogenes

Inhibit phagosome-lysosome fusion- Legionella pneumophila, Mycobacterium tuberculosis, Salmonella

Survive within phagolysosome (resist enzymatic degration or neutralize toxic products)

- Inactivate reactive oxygen species: Salmonella, via superoxide dismutase, catalase, recA

- Resist antimicrobial peptides: Host cationic peptides complexed with SapA peptide

Serum Resistance

complement resistance

covalent binding of activated sialic

acid

LPS galactose residue

N. gonorrhoeaechanges to carbohydrate portion of lipo-

oligosaccharide

prevent insertion of C9 complex

into outer membrane

long O-side chains of LPS

outer membrane protein Rck

Salmonella

inhibit deposition of C3

incorporate host plasma proteins

(decay accelerating factors) into membrane

Schistosoma mansoni

prevent C3 convertase formation

sialic acid in LPS O antigen

hydrolyzing enzymes

intracellular lifestyle

inhabit blood cells to avoid exposure to humoral factors (e.g.complement)

PMN cellslymphocytes macrophages

red blood cells

Staphylococci

HIV

Mt

Plasmodiumium

Antigenic variation

Phase variation Genetic variation

Transmission of genetic information via mobile genetic elements

Gene recombination

- Pili genes: Neisseria gonorrhoeae

Gene reassortment

- Influenza viruses A, B, C

High mutation rate

- RNA virus: Influenza viruses A, B, C

Recombination of replication products

- DNA virus: terminal redundancy in linear genome

VSG in Trypanosoma brucei

Cell and Tissue Damage

• Induction of apoptosis and necrosis

• Virus-induced cytopathic effect

• Induction of damaging host immune response

Induction of apoptosis

Phase variation Genetic variation

Transmission of genetic information via mobile genetic elements

Gene recombination

- Pili genes: Neisseria gonorrhoeae

Gene reassortment

- Influenza viruses A, B, C

High mutation rate

- RNA virus: Influenza viruses A, B, C

Recombination of replication products

- DNA virus: terminal redundancy in linear genome

VSG in Trypanosoma brucei

Induction of Cell Death

Induction of apoptosis Induction of necrosis

Virus-induced apoptosis:

HIV (CD4+ T cell), EBV, adenoviris

Interfere with cellular regulation of cAMP

-Bordetella pertussis (macrophage)

Activation of caspase-1

Salmonella (macrophages, DC)

SipB binds and activates caspase-1

Sigella flexneri (macrophages) Invasion Plasmid antigen B (IpaB) binds and activates host caspase-1

Bacterial toxins:

Diptheria A-B toxin

Cell lysis

accumulation of reactive oxygen intermediates

macrophages

virusesaccumulation of nitrogen

intermediates

accumulation of intracellular calcium

Rotavirus, cytomegalovirus, HIV

Syncytia formation

Paramyxoviruses (respiratory syncytial virus, parainfluenza

viruses, measels virus, herpesvirus, some

retroviruses)

viral-encoded fusion proteins

Virus-Induced Cytopathic Effect: Part 1

production of eosinophilic or

basophilic inclusion bodies

viruses

host cell transformation

DNA viruses

Burkitt's lymphoma

(EBV)

inactivation of p53 and Rb, chromosomal destabilization, enhancement of foreign DNA integration and mutagenecity

cervical carcinoma

(human papilloma viruses)

retroviruses

adult T-cell leukemia

(human T-cell lymphotropic virus type 1)

Virus-Induced Cytopathic Effect: Part 2

Induction of Damaging Host Immune Response

autoimmune response

cross-reactivity between self and mycobacterial heat shock

proteins

cross-reactivity between components of endocardium and joint synovial membrane molecules and antigens in the

streptococcus cell wall

Acute rheumatic fever after group A

streptococcal pharyngitis

hypersensitivity reactions

granuloma formation

Mycobacterium tuberculosis

septic shock/sepsis

bacteria

LPS, peptidoglycan, lipoteichoic acid, toxins acting as superantigenstoxic shock