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