emerging pathogens. emergence of infectious disease ~ habitat / niche boundarybarrier adaptation...
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Emerging pathogens
Emergence of infectious disease ~
habitat / niche
BoundaryBarrier
adaptationhost / bacteria
time
homeostasis emerginginfectiousdisease
re-establishbalance
homeostasisbacteria & host
Mechanisms of host adaptation
Analysis of host adaptation
Mechanisms of bacterial adaptation
Analysis of bacterial adaptation
Emerging bacterial disease
avoids host response aggressive pathogen
stealth route
overwhelm innate immune responserapid infection - no adaptive immunity
frontal attack strategies
engages innate immune responseavoids / manipulates adaptive immunity
carrier state / chronic infections
Development of stealth pathogens / bacteria
BoundaryBarrier
natural habitat
homeostasis colonizes inhost
goal -persistance
chronic infectionsymbiotic relationship
Mycobacterium tuberculosis - tuberculosisListeria monocytogenes - listeriosis
Salmonella typhi - typhoid fever Helicobacter pylori - gastric ulcers / cancer
Chronic infectious agents
Symbionts
Rhizobium spp. - nitrogen fixing bacteria on roots / legumes Wolbachia spp. - induce sex ratio distortions in insects
Mitochondria - energy production
Stealth bacteria / pathogens
Bacterial adaptation to host cells associated with lateral gene transfer (mobile and unstable genetic elements)
Establishment of chronic infections
(Batut et al, Nature Reviews Microbiology, 2004)
First contact with host cellAdherence / invasion
Life in the environment
Establishing life within the hostAvoid host defenses
Establishing life within the hostAdapt to host environment
Extending the nicheModulate host biology
Extending the nicheMultiply / survive in replication niche
Avoid host defenses:- Invade host cells rapid - Rho, Rac, Cdc42 mediated invasomes - engulf bacterial aggregates zipper - silent cell entry- Evade innate immunity lack TL4 reactive LPS- Block adaptive immunity- Evade adaptive immunity by genetic rearrangement
Establish life within host:- Within phagosome arrest - phagosome acidification / fusion redirect - phagosome trafficking utilize - phagosome environment lyse phagosome - move via actin tails- Induce host cell proliferation- Inhibit host cell apoptosis- Adapt to host conditions (stomach acidity)
Common strategies of stealth bacteria
Manipulate host cell:- Type III secretion- Type IV secretion
(J. Batut, S. Andersson, D. O’Callghan, Nature Reviews, 2004)
Proteobacteria
Chronic infection with Mycobacterium tuberculosis
(Wilson, McNab, Henderson, Bacterial Disease Mechanisms, 2002)
M. tuberculosis phagosome arrest
Development of aggressive pathogens
BoundaryBarrier
becomes
natural habitat
homeostasiscolonize in
new environment
aggressivepathogen
microorganism-rich environment(soil / water / intestine)
acquire new virulence genesprovide a survival advantage
competes against normal flora& host defenses
Vibrio cholerae
adhere / colonize in intestinerapid onset / severe diarrhea
massive fluid loss - dehydrationhypotension
collapse of the circulatory systembacteria eventually wash out
self-limiting disease
(www.cameroon-info.net/ img/news/cholera_victim)
Disease - cholera
(UCLA Department of Epidemiology website)
Transmission
contaminated waterraw seafood
Cholera pandemics - begin in coastal communities - link between marine environment (algal blooms) - V. cholerae survival / spread
(Source: Dr. Rita Colwell, Director, National Science Foundation and Professor of Microbiology, University of Maryland)
Sea surface temperature (SST) changes in Indian Ocean vs. number of cholera cases in Bangladesh.
marine reservoirVibrio cholerae
(www.hinduonnet.com/.../ 07/stories/0807048f.htm)
Tcp - (toxin coregulated pili) - adherence origin - filamentous phage (VPI)
cholera toxin - A-B toxin encoded on CTX phage Tcp = receptor for CTX phage
Acquisition of virulence factors
B5 - subunit (GM1 ganglioside)
A - subunit
(ADPRT activity - Gs)
Vibrio cholerae
1992 - novel epidemic strain emerged in India - serotype 0139 - Bengal strain carries conjugative transposon
allowed - horizontal gene transfer of DNA encoding 0139 antigenusurped El Tor until 1994
(Obtained from CDC)
The global spread of cholera during the seventh pandemic(1960 - 1990’s) - El Tor biotype
Emerging Vibrio cholerae disease
Epidemiologyremains a major problem in developing countries
155 serotypes most epidemics - serotype 01 Classical biotype - 1881-1896 & 1899-1923 pandemics
El Tor biotype - ongoing cholera pandemic
WHO estimates that officially reported cases represent~ 5-10% of actual cases worldwide
(www.who.int/topics/ cholera/surveillance/)
Areas reporting cholera cases in 2004Cholera, 2000-2001
Cholera
Epidemiology
Grey areas: countries with cholera cases Black dots: countries with imported cholera cases
Emergence of pathogenic Vibrio cholera
BoundaryBarrier
ancestral species lacked CTinfection excluded by normal flora
becomes
natural habitatsalt / fresh water
homeostasiscolonizes in
smallintestine
aggressivepathogen
acquired VPI phage encoded Tcpthen CTX phage encoded CT
allows bacteria to flourish in intestineshed in large numbers back to natural
habitat (salt / fresh water)
acquired virulence factors
Tcp / cholera toxin - phage0139 serotype - conjugation
Emergence of pathogenic Escherichia coli
Not colonized
Streptococcus, Lactobacillus
Streptococcus, Lactobacillus, Bacteroides, Bifidobacter
E. coli, Lactobacillus, Bacteroides, Bifidobacterium, EnterococcusClostridium,
40+ species, >90% anaerobesBacteroides, Eubacterium, Fusobacterium,Bifidobacterium, Peptostreptococcus,Ruminococcus, Enterococcus, Streptococcus, Clostridium, Enterococcus
Microbial GI tract ecosystem (probiotics)
Not colonized
Helicobacter pylori
E. coli - EHEC, ETEC, Vibrio choleraC. perfringes, B. cereus, S. aureus
E. coli - EHEC, EIEC, Shigella,Clostridium difficile
Pathogenic bacteria of the GI tract
E. coli - EPEC, Salmonella Campylobacter jejuni
(Dennis Kunkel Microscopy, 2001)
Escherichia coli
Associated disease:diarrhea / hemorrhagic colitis
Transmission:contaminated food or water
Bacteriology:Gram-negative rod - motilefacultative anaerobeserotype - based on O, H, K antigens - LPS; H - flagellum (hauch); K - capsule (i.e. O157:H7)virotype - based on virulence factors (i.e. ETEC)
(www.geocities.com/ CapeCanaveral/3504/gallery.htm)
Emergence of pathogenic Escherichia coli
ancestral species not pathogenic
not cleared by host
becomes
natural habitatGI tract - warm-blooded
animals
homeostasisexposed toGI bacteria
acquired phage / plasmid encoded virulence factors from intestinal pathogenic
bacterianow competes more effectively in
host shed into environment
transferred to other hosts
virulence factors
virotype dependent
aggressivepathogen
Escherichia coli enteropathogens
Enteropathogenic E. coli (EPEC)
Enterotoxigenic E. coli (ETEC)
Enteroaggregative E. coli (EAggEC)
Enterohemorrhagic E. coli (EHEC)
Enteroinvasive E. coli (EIEC)
EPEC - Enteropathogenic E. coli
Disease:major cause of diarrhea in children(> 1 million children die / year from EPEC)
associated with attaching-effacing (A/E) lesion
loss of microvilli host actin-mediated pedestal formation
(Knutton et al, Oxford University Press, 1998)
EPEC bundle forming pili
(Anantha et al, Infect. Immun., 1998)
Virulence:not toxigenic / not invasive
type III secretion - genes encoded - chromosomal pathogenicity island (PAI) (35 kb - LEE - locus of enterocyte effacement)
adhesion - contact with host cell induces: bundle-forming pilus - (plasmid encoded)
EPEC - Pathogenesis
Type III secretion: Apparatus - EspA, EspB, EspD (EspF)
Tir- phosphorylated by host tyrosine kinase, becomes receptor for bacterial adhesin - intimin leads to intimate attachment - activation PKC (PLCIP3)
results in chloride secretion - causing diarrhea -
(Wilson, McNab, Henderson, Bacterial Disease Mechanisms, 2002)
Acquisition of virulence: type III secretion - encoded on LEE PAI
bundle forming pilis - plasmid encoded
ETEC - Enterotoxigenic E. coli
Disease:childhood diarrhea in developing countries‘traveler’s’ diarrhea’
(From: info.med.yale.edu/ library/zeiss)
Virulence:toxigenic - heat labile toxin (LT) heat stable toxin (ST)
(both toxins - plasmid encoded)
fimbriae CFA - colonization factor antigen (plasmid encoded)
ETEC - pathogenesis
ST- heat-stable toxin
guanilyn hormone-like) - stimulates guanylate cyclase retains toxicity - 100o C for 30 min processed 18-19 amino acid peptide / stabilized by disulfide bonds
ST1a
ST1b
LT- heat-labile toxin
cholera-like (AB5) toxin B-subunit receptor - GM1 gangliosideA-subunit enzyme - ADP-ribosyltransferase ADP-ribosylates / activates Gsstimulates - adenylate cyclase
secondary effects - stimulates prostaglandins, leukotrienes, cytokines
AB5-toxin
Acquisition of virulence:LT / ST - plasmid encodedfimbriae CFA - plasmid encoded
ETEC - pathogenesis
Disease:childhood diarrhea in developing countries- linked to growth retardation
mucous diarrhea - can persist for > 14 days
persistent colonization - forms mucous biofilm
EAggEC - Enteroaggregative E. coli
(J. Nataro, T. Steiner, R. Guerrant Emerging Infectious Diseases, 1998)
EAEC adherence to HEp-2 cells
Virulence:Adhesion / mucous biofilm relatedAAF/I - (aggregative adherence fimbriae) characteristic - adherence to epithelial cells as aggregates - plasmid encoded
EAST1 - heat stable (ST) enterotoxin encoded on 100 kD plasmid
Acquisition of virulence: - AAF/I and EAST1 - plasmid encoded
Disease:watery followed by bloody diarrheaintense abdominal pain
O157:H7 - most important serotype
hemorrhagic colitis (HC)
severe cases - hemolytic uremic syndrome (HUS)
edema, hemorrhage, acute kidney failurehemolytic anemia, thrombocytopenia(5-10% mortality rate)
EHEC - Enterohemorrhagic E. coli (STEC)
Virulence:Toxigenic / non invasiveShiga-like toxin (Stx1, Stx2-vero toxins) bacteriophage encoded
EAST1 - heat stable toxinLEE - pathogenicity island - A/E lesion
(www.yamagiku.co.jp/pathology/case/case006)
Bacteria attached to crypt epithelium in region of active inflammation (HE, high power)
Colon biopsy patient suffering from O157:H7 infected patient shows focal
inflammation in lamina propria (HE, low power)
Shiga-like (Stx) AB5- toxin
L enzyme activity N-glycosidase
A-subunit B-subunit receptor bindingGb3 (glycolipid globotriaosylceramide)
Receptor - Gb3 (not on enterocytes - high expression on kidney cells)
Enzyme activity - N-glycosidase - cleaves adenine from residue 4324 of 28S rRNA - inhibits protein synthesis
- retrograde transfer to cytosol - ERAD (ER associated protein degradation)
(Wilson, McNab, Henderson, Bacterial Disease Mechanisms, 2002)
Acquisition of virulence:Stx - phage encodedT3S - encoded on LEE PAIEAST 1 - plasmid encoded
EHEC - Pathogenesis
EIEC - Enteroinvasive E. coli
Disease:inflammatory diarrhea - closely related to Shigellosis(infectious dose 2-3 logs higher than Shigella)
E. coli - biochemical characterization
Shigella - genotype / phenotype characterization
Virulence:
Invasive disease
invasion genes - located on 140 MDa plasmid encodes type III secretion system - mxi / spa loci
does not produce Shiga toxin
EIEC invasion
(Prasadarao et al, Infect. Immun. 1999)
Virulence relates to:
- hybrid - Shigella - E. coli organism
- type III secretory process - affecting invasion plasmid encoded
Summary emerging Escherichia coli pathogens
normal flora E. coli - host
GI homeostasis
ETECplasmid -
LT / ST
LT - CT-like
EAggECplasmid -
AAF/1 fimbriae
EHECLEE PAI - T3Sphage - Stx
Stx - Shiga-like toxin
EIECShigella-like
plasmid - T3S
Shigellaaggressive
GI pathogen
EPECLEE PAI - T3Splasmid - bfp
SalmonellaAggressive
GI pathogen
100 million years
Concepts - emerging pathogens
• How new bacterial diseases emerge
• Strategies used by stealth / chronic pathogens
• Origin / strategies used by aggressive pathogens
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