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141 Cards in this Set
- Front
- Back
Pathogenesis of ETEC?
|
Enterotoxic E. coli (traveler's diarrhea)
adheres to wall of small intestine, no histological changes secretes plasmid-encoded toxins into mucosa: LT1 cAMP cholera-like toxin + STa heat stable toxin |
|
Pathogenesis of EHEC?
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Enterohemhorragic E. coli
low ID (~100 cells) survives pH of stomach LEE pathogenicity island encodes adhesins phage-encoded SHIGA-LIKE TOXINS: Stx1, Stx2 --> halt protein synth --> cell death |
|
What are some of the sequelae of infection with EHEC?
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Stx-2 --> Hemolytic Uremic Syndrome (shiga toxins cause cell death in microvasculature of kidneys)
Brain damage, also due to cell death in vasculature of brain |
|
Most common source of EHEC?
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CATTLE.
99% of cattle infected with EHEC but lack vascular receptor so are immune to its toxins |
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Pathogenesis of UPEC?
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Uropathogenic E. coli
p-pili for attachment --> polynephritis FimH adhesin on end of p-pilus UTI caused by spread of bacteria from colon --> urethra/bladder |
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Which members of the Enterobacteraciae are NOT members of normal human flora?
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Salmonella
Shigella Yersinia pathogenic E. coli |
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What is O-antigen?
H-antigen? K-antigen? |
O = LPS
H = flagella K = capsular polysaccharides |
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Most infections by E. coli are from person's own flora. What are the two exceptions?
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-gastroenteritis
-neonatal meningitis |
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Pathogenesis of EPEC?
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Enteropathogenic E. coli
attaches to enterocytes --> destruction of villi "attaching and effacing" lesions in small intestines pedestal formation with TypeIII secretion system to inject effectors into host toxins increase Cl-, HCO3- secretion --> H2O efflux, diarrhea |
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Why is it important to avoid treating EHEC infections w/abx?
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abx induce phage excision, production of phage-encoded toxins by EHEC cells.
|
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Which E. coli virulence factors are plasmid or phage encoded?
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ETEC: LT1/2, STa/b on plasmid
EHEC: Shiga-like toxins phage-encoded |
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Dx of EHEC in lab?
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isolation of shiga-like toxins from stool
enrichment culture |
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Pathogenesis of EIEC?
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Enteroinvasive E. coli
attacks large bowel --> watery diarrhea progresses to bloody diarrhea invades, multiplies within, and spreads through intestinal epithelium |
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Pathogenesis of EAEC?
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Enteroaggregative E.coli
attacks small bowel, esp. in immunocompromised pts induce intestinal mucus secretion --> traps other EAEC, biofilm bundle-forming pili facilitate formation of microcolonies on epithelium w/o histological change presence of cytotoxin not confirmed |
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Reservoir of Shigella?
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human GI tract
humans are the only known reservoir. |
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Disease sx of Shigella infection?
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1-2 day incubation period; self-limiting and resolves in 7-10 days
high fever 10-100 bowel movements a day, perhaps dysentery no nausea or vomiting WBC seen in stool |
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Which Shigella spp. cause the worst disease? Which case milder disease?
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Worst: S. dysenteriae, flexeneri
Milder: S. sonnei (usually only watery diarrhea, no dysentery) S. flex/son in USA, S. dys in developing world |
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Virulence factors of Shigella?
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-acid tolerant--> survive stomach
-causes abscesses/ulceration on large bowel -VIRULENCE PLASMID: invasion loci, TypeIII secretion apparatus -bacteria spread laterally, directly bewteen cells -enterotoxins produced but not essential for invasion or disease (S. dysenteriae's Shiga-toxin is exception) |
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How does Shiga-toxin of S. dysenteriae cause "disease from a distance?"
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Causes Hemolytic Uremic Syndrome when it reaches the kidneys. Shigella itself never actually leaves the GI tract
|
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What are the primary mediators of tissue damage in a Shigella infection?
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-Shigella-induced apoptosis of infected host cells
-massive inflammatory response due to production of IL-1 and IL-8 |
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How does Shigella travel from cell to cell?
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IscA protein causes actin condensation behind cell to propel it into neighboring cells.
|
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Path of Shigella through intestinal mucosa?
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infect M-cell --> pass through to macrophage phagosome --> lyse phagosome and induce apoptosis in macrophage --> come out in lamina propria side, invade epithelial cell --> lateral spread.
pattern: replicate in vacuole, induce vacuole lysis, then host lysis, then move on to next cell |
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Most common route of spread of Shigella in USA?
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person to person fecal-oral route after contact with contaminated feces.
|
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Which pathogenic E. coli strains cause tissue damage? Which do not?
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Tissue damage: EHEC, EIEC, EPEC
No Tissue Damage: ETEC, EAEC, UPEC |
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What is the difference (disease) between non-typhoidal and typhoidal Salmonella strains?
|
non-typhoidal: cause enteritis, occasional systemic infections. Usually isolated to GI tract
typhoidal: serogroup TYPHI, no enteritis! "Typhoid Fever" with chills, malaise, constipation, fever, myalgias. Invades blood and lymph through GI tract. |
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Sequelae of non-typhoid Salmonellosis?
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-septicemia
-reactive/septic arthritis |
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Which strains cause the most cases of salmonellosis in USA?
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S. typhimurium, S. enteritidis (50%, two most common causes)
S. newport next most common |
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Epidemiology of salmonellosis in USA? (vector, # cases, # deaths)
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spread through contaminated food/water, contact w/infected animals
1.4million cases/year >500 deaths |
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Epidemiology of Typhoid Fever?
cases, deaths, vector, reservoir? |
~400/year in USA
21 million cases worldwide, 200,000 deaths 12-30% fatality rate CHRONIC CARRIER STATE POSSIBLE --> large human reservoir, may shed organisms for life! *live in gallbladder* outbreaks assoc w/contaminated H2O, street vendor food |
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Function of SP1 locus?
|
Only req. for initial invasion of M cell or CD18+ cell.
40kb Invasion locus. TypeIII secretion apparatus. Effectors SipA and SipC injected into host epithelial cells --> actin rearrangement/ruffling --> uptake of Salmonella. |
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How does SPI2 facilitate systemic infection?
|
SPI2 is for survival within phagocytes after passing into lamina propria.
encodes another TypeIII secretion apparatus. Inject effectors from vacuole into cytoplasm of host SPI2 effectors prevent assembly of NADPH oxidase on Salmonella-containing vacuole --> no ROI formation in vacuole |
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Function of SPI7?
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encodes genes for assembly of capsular Vi-Antigen
Genetically unstable when S. typhi cultured in vitro but stable in vivo |
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Vaccination strategies against S. typhi?
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Ty21 attenuated strain
Vi-antigen preparations used for quick protection in travel clinics |
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Major reservoir of Yersinia?
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pigs
main source of infection = undercooked chitterlings (small intestine) |
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What motility changes occur in Yersinia?
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become nonmotile in host.
|
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How is Yop production regulated in Yersinia?
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high T, low Ca++, low Fe++
signal that cell is inside a host --> produce Yops (Yersinia Outer membrane Proteins) |
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What more common infection does Yersinosis resemble?
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appendicitis
Yersinosis is rare; few clinical labs routinely check for it |
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List some Yersinia virulence factors.
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Invasin (surface protein that induces uptake)
TypeIII secretion apparatus (injects Yops into host) Yersiniabactin (siderophore, Fe++) Yops (on plasmid--kill phagocytes) |
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What is the function of each Yop?
|
general goal = kill phagocytes, inhibit macrophage function
Yop E, T: depolymerize actin Yop O, H: dephosphorylate signaling proteins --> impaired signal transduction YopP: inhibit macrophage apoptosis and TNFalpha release |
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What damage does Yersinia enterocolitica cause in humans?
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abscesses at the M cells in the small intestine.
|
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What percentage of Mtb infections become symptomatic? What are the symptoms?
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~5%
chills, weight loss, night sweats |
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Steps in Mtb granuloma formation?
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-uptake by CR3 on macrophage after Mtb coated in C3b or C2a
-macs migrate to deeper tissue -other macs surround infected macs, differentiate into epitheloid cells, form wall around caseous necrosis -other lymphocytes/fibroblasts recruited to granuloma |
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What components of the Mycobacterial cell wall are unique to the Mycobacteria?
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(outermost) capsule like material
*mycolic acids* *arabino-galactans* peptidoglycan |
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How are Mycobacteria transmitted?
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respiratory droplets (can stay airbone for hours after infected pt leaves room)
|
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Generation time of Mtb?
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~20hr under ideal conditions
E. coli: 20 MINUTES |
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What cytokines are involved in granuloma formation?
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IFN-gamma
IL-12 TNF-alpha |
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Function of Mycobacterial PknG protein?
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serine-threonine kinase prevents vacuole acidification after phagocytosis by macrophage.
|
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Why is BCG vaccine not used in areas of low Mtb infection?
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BCG removes ability to use tuberculin skin (Mantoux/PPD) test. Will produce constitutive positive result.
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What is BCG (Bacillus Calmette-Guerin) vaccine made of?
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attenuated strain of Myc. bovis
|
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How to dx primary Mtb infection?
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chest x-ray for granuloma formation
PPD mantoux test |
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What percentage of latent Mtb infections reactivate into secondary infections?
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~10%
|
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What factors predispose a patient to reactivation of a latent Mtb infection?
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old age (<50y/o males)
HIV/AIDS increases probability of reactivation 200-300X. |
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What is miliary Mtb infection?
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serious, disseminated infection
spreads to any organ via lymphatics granulomatous infiltration of tissues resembles millet. |
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Where in the body does Mtb like to grow?
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O2 rich areas
apices of lungs --> blood tinged sputum |
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What stains are used to detect Mycobacterial stains in sputum smears?
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auramine fluorescent stain
acid-fast stain with Kinyoun Ziehl-Neelson carbol-fuschin + methylene blue |
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How are Mtb host responses detected?
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ELISA
IFN-gamma production assay Quantiferon Gold (blood test containing artificial Mtb production, tests for IFN-gamma production by activated T cells) PPD mantoux |
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How are Mtb infections treated?
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rifampin (RNA pol inhibitor)
pyrazinamide, isoniazid, ethambutol (cell wall inhibitor) treat for 6 months need multiple drugs because high level of multidrug resistance |
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What is the frequency of Mtb drug resistance?
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10^-6 to 10^-8 per culture of 10^8 to 10^9 cells in a patient
|
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Natural reservoir of Mycobacterium leprae?
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9-banded armadillos
|
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Characteristics of tuberculoid leprosy?
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chronic granulomatous disease of peripheral nerves and nasal mucosa.
many granulomas few bacteria less severe form of the disease. |
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Chatacteristics of lepromatous leprosy?
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chronic granulomatous disease of peripheral nerves and nasal mucosa.
few granulomas many bacteria leonine facies highly invasive, more severe form of disease. |
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Tx of leprosy?
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dapsone
PABA folate metabolism antagonist, similar to sulfonamides |
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Epidemiology of Mtb infections?
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worldwide:
3,000,000 deaths/year = 351 deaths/hour 8,000,000 cases/year 913 new cases/hour USA: 400 cases/year? |
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Of the yearly cases of tuberculosis, what percentage are reactivation of latent infection?
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~50%
|
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Dx of Mtb infection?
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culture, then niacin production, nitrate reduction, catalase +
PCR of tissue biopsy/sputum specimen staining of respiratory specimen chest x-ray + PPD skin test host response assessment (IFN-gamma) |
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Factors contributing to high Mtb antimicrobial resistance?
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poor patient compliance:
longterm Rx costly side effects |
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What is the most common bacterial cause of diarrhea/gastroenteritis?
|
Campylobacter spp.
C. jejuni C. coli (2-5%) |
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Infectious dose of Campylobacter?
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400-500 cells
|
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Symptoms of Campylobacter infection?
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24-48hr incubation period
mucusy/bloody diarrhea bacteria in stool (darting motility) |
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Vector and seasonal trends of Campylobacter infections?
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most frequent in summer months (more picnic food...)
transmitted by feces-contaminated H2O, food (undercooked chicken), unpasteurized milk p2p spread rare |
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Reservoirs of Campylobacter?
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zoonotic infection.
asymptomatic colonization of birds, cattle, pets. |
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How to dx Campy infection?
|
-microscopic examination of stool: darting motility of curved rods
-culture on Campy plate at 42 degrees C in microaerophilic conditions |
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What was the 5th Koch's postulate proposed by Barry Marshall?
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Antibiotic treatment must eradicate organism and disease.
|
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Treatment of Campylobacter infections?
|
nothing (self-limiting dz)
abx may be necessary if dissemination has occurred in an immunocompromised patient. |
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Campylobacter virulence factors?
|
adhesion to wall of small intestine
Cytolethal Distending Toxin (CDT): arrests cells at G2/M phase interface. endo/transcytosis: invade cells and spread laterally via tubulin polymerization. flagella LOS/LPS variability (immune evasion) |
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Etiology of Guillian-Barre Syndrome?
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Campylobacter infection --> crossreactive ab's to GM1 ganglioside on myelin sheaths.
|
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Symptoms of Guillain-Barre Syndrome?
|
ascending bilateral paralysis
inflammation of myelin sheath = acute idiopathic (spontaneous) polyneuritis |
|
Treatment of Guillain-Barre syndrome?
|
no cure
plasmaphoresis to remove anti-GM1 ab's self-limiting, no sequelae in 90% of cases |
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Why does Campylobacter infection sometimes lead to Guillain-Barre syndrome?
|
MOLECULAR MIMICRY
LPS/LOS sometimes contains sialic (= N-acetylneuraminic) acid (component of connective tissue) |
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Which serotypes of Campylobacter are most commonly associated with Guillain-Barre Syndrome?
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O:19
O:41 |
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What are some complications of Campylobacter infections?
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recurrent colitis
reactive arthritis acute cholecystitis (inflammation of the gallbladder) meningitis Guillain-Barre Syndrome |
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What was considered the definitive proof that Helicobacter pylori caused stomach ulcers?
|
resolution of ulcers after treatment of Abx + omeprazole but not omeprazole alone.
|
|
What diseases are caused by Helicobacter pylori?
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-gastritis (usually asymptomatic)
-gastric ulcers (atrophic gastritis) -duodenal ulcers -gastric carcinomas -B-cell MALT lymphomas |
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Natural reservoirs of Helicobacter pylori?
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humans ONLY.
other spp of Helicobacter infect animals but humans only for H. *pylori* specifically |
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What pattern of inflammation is associated with gastric carcinomas? With ulcers?
|
corpus inflammation --> IL-1Beta --> increased pH (less acid) --> gastric cancer
antrum inflammation --> gastrin --> decreased pH (more acid) --> ulceration |
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Epidemiology of H. pylori infections?
infection rate geography of infection and cancer incidence |
50% of humans infected in childhood
infection most prevalent in developing countries cancers most prevalent in Japan and China. |
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Dx of H. pylori infections?
|
endoscopy and biopsy of stomach
culture tested for urease production serology fecal antigen assay breath urease test |
|
Tx of H. pylori infections?
|
Triple therapy: antacid + 2 abx
|
|
What are some reasons for tx failure when treating H. pylori infections?
|
-abx are pH sensitive and are deactivated by stomach cid
-patient stupidity -chromosomally encoded abxR |
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Virulence factors of H. pylori?
|
urease
VacA toxin Cag pathogenicity island Adhesins BabA, SabA LPS/molecular mimicry NAP (neutrophil activating protein) SOD/Catalase to protect from ROI's flagella/corkscrew motility |
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Function of Cag pathogenicity island?
|
-encodes Type IV secretion system
-inject CagA into host --> change cell shape, motility via growth receptor signaling pathways -induce inflammatory CK's --> ulceration, cancer |
|
Function of VacA toxin?
|
-cytostatic toxin
-autotransporter (translocates self into cell) -induces vacuole formation in host cell -increase permeability of epithelial layers -induce apoptosis if it messes w/mitochondria |
|
Theory behind Urea Breath Test?
|
1. feed pt C14 labeled urea
2. Hp's urease converts urea --> CO2 + NH3 3. 14C labeled CO2 present in pt's breath/burps 4. collect breath in balloon, test for C-14 in mass spectrometer. |
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Function of H. pylori urease?
|
Urea + H2O --> CO2 + <B>2 NH3</B>
-protects Hp from stomach HCl -causes cell damage -nitrogen source for bacteria |
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Define selective toxicity.
|
target organism killed with relatively little harm to the host.
exploits differences between pathogen and host. |
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Define Therapeutic Index.
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TI = lethal dose ÷ therapeutic dose
the higher the better. |
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What is a semi-synthetic antibiotic?
|
natural molecule chemically modified via rational drug design
increase efficacy spectrum or bioavailability |
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How are naturally-occurring antibiotics found?
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microbial ecology, mass screening of natural compounds derived from fungi, molds, etc.
|
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Drawback of naturally occurring antibiotics?
|
intrinsic resistance is common.
|
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Which abx have a high Therapeutic Index? Which have a low TI?
|
high (~safe): penicillins, cephalosporins
low (dangerous): aminoglycosides |
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Define Minimum Inhibitory Concentration.
|
minimum concentration of abx that achieves ~80% inhibition of growth in vitro under standard conditions.
|
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Define Minimum Bactericidal Concentration.
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minimum concentration of abx required to achieve 99.9% killing in vitro under standard conditions.
|
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Which abx are bacteriostatic? What is the relationship between bacteriostatic MBC and MIC?
|
bacteriostatic: macrolides, tetracyclines
MBC >>> MIC |
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Which abx are bactericidal? What is the relationship between bactericidal MBC and MIC?
|
bactericidal: beta-lactams, aminoglycosides, daptomycin (lipopeptide). rapid kill.
MBC ~ MIC or slightly higher. |
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In most clinical situations, bacteriostatic abx will suffice. When is bactericidal activity necessary?
|
-immunocompromised pts
-CNS infections (meningitis) -endocarditis (heart valves) |
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What factors influence the activity of abx in vivo vs. in vitro?
|
protein binding
enzyme activity diffusion/tissue distribution absorption |
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What is time-dependent killing and which abx exhibit it?
|
efficacy depends on how long [abx] > MIC of target organism
i.e. after a certain point increasing [abx] won't help any more beta-lactams |
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What is concentration-dependent killing and which abx exhibit it?
|
efficacy depends on how high the concentration of the antibiotic is relative to the MIC of the organism
(aminoglycosides, quinolones) |
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What does it mean when two abx have additive effects in therapy?
|
combined activity is equal to sum of individual activities.
|
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What does it mean when abx have synergistic effects in therapy?
|
combined activity is greater than the sum of individual activities.
|
|
Reasons for combining abx in therapy (>1 drug at a time)?
|
-achieve synergistic effects
-reduce probability of selecting for resistant bugs -broadened spectrum (empiric therapy) |
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What is the difference between intrinsic and acquired resistance?
|
intrinsic--resistance conferred by native property of organism.
acquired--resistance obtained through gene transfer, mutation, plasmid acquisition, etc. |
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Describe resistance via drug modification. Which abx are vulnerable to this?
|
enzymes chemically inactivate drug molecules.
GNR beta-lactamases x beta-lactams aminoglycoside modifying enzymes |
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How do bacteria decrease access to abx target sites?
|
-efflux pumps (macrolides)
-decreased permeability of membrane (carbapenems/PSAR) -upregulation of target site (VISA) |
|
Problems in detection of resistance in vitro?
|
• Heteroresistance
– MRSA – AmpC “SPICE” organisms • Inducible expression – β-lactamase in Enterococcus – erm methylase in S. aureus • Alternate pathways – uptake of exogenous folate by Enterococcus |
|
What is Cross-resistance and how is it conferred?
|
• Association of resistance between antimicrobial agents.
• Common mechanisms – similar target (macrolides & lincosamides) – linkage of resistance determinants on the same genetic elements (e.g., transposons, plasmids) – inactivation by the same enzyme (aminoglycosides) – similar modes of cell entry (porins) or efflux (multidrug transporters) |
|
Function of YopJ?
|
acetylate MAPKK --> disrupt cell signaling --> apoptosis
Y. pestis only |
|
Function of YopH?
|
dephosphorylates host signaling proteins --> disrupts signaling
|
|
Function of YopO?
|
phosphorylates host signaling proteins --> disrupts signaling
|
|
Function of YopE, T?
|
depolymerize actin --> host cytoskeletal disruption
|
|
Function of YopP?
|
inhibition of mac apoptosis
partially by preventing TNFalpha release Y. enterocolitica, pseudotuberculosis only |
|
Function of Y. pestis hms?
|
hemin storage locus
aids in biofilm formation in flea foregut --> flea vomits blood into host |
|
Pathogenesis of Y. pestis?
|
systemic infection, disrupts immune response and host cell signaling.
invades via M cell, enters macrophage, is carried to LN. proliferates in lymph nodes --> lymphadenitis |
|
Distribution of Mycobacterial infections in UW HMC lab?
|
85% = Mycobacterium tuberculosis (40%)
Mycobacterium avium-complex (60%) 15%= M. gordonae (20%) others (80%) |
|
Function of Yersiniabactin?
|
siderophore; iron chelating agent.
|
|
Function of Yersinia Invasin?
|
surface protein that facilitates uptake by host cells.
|
|
What environmental factors regulate Yersinia virulence gene expression?
|
Temperature
[Ca++] [Fe++] |
|
Most virulent serotypes of V. cholerae?
|
O1
O139 "Bengal" (encapsulated) |
|
What is the host cell receptor for Cholera Toxin?
|
GM-1 ganglioside.
|
|
Structure of cholera toxin?
|
A2:B5
CtxA1 catalytic subunit CtxA bound to CtxA1 by disulfide bond 5 CtxB binding subunits |
|
Mechanism of cholera toxin action?
|
B subunits bind to host GM-1
A1 cleaved from A2 via reduction of disulfide bond A1 enters host cell, ADP ribosylates G-protein --> Adenylate cyclase ON, +cAMP --> + intestinal permeability. |
|
Significance of GM-1 ganglioside?
|
host receptor for cholera toxin
autoantibodies formed against GM-1 in Guillain-Barre syndrome following C. jejuni infection |
|
Function of TCP (toxin-controlled pilus)?
|
V. cholerae pathogenesis: adheres to intestinal epithelium, facilitates toxin entry
|
|
How are TCP, Ctx genes regulated?
|
ToxS periplasmic sensor protein
ToxR TM receptor, activates Ctx genes and ToxT ToxT cytoplasmic protein, activates TCP gene transcription |
|
What does ToxS detect?
|
pH
mucus (indicates Yersinia is in a host) osmolarity temeprature |
|
Typical site of V. parahemolyticus infection?
|
colon.
self-limiting diarrhea, mostly in summer/early fall. |
|
Types of infections caused by V. vulnificus?
|
diarrhea
septicemia (sometimes fatal) wound infections |
|
Which serotype of V. cholerae is associated with recently emerging recurrent infections?
|
O139.
prior infection with O1 offers no protective immunity. |
|
Difference between immune response to typhoidal and non-typhoidal Salmonella?
|
NTS interacts with innate immune system
Typhoidal Salmonella indifferent to innate immune response. Probably b/c Vi-antigen is non-immunogenic. |
|
Describe TLR-5 signaling events in host immune response.
|
TLR-5 detects flagellin
--> secrete IL-8 --> recruitment of neutrophils --> local inflammation. |
|
What cells and cytokines are involved in immune response to Mtb?
|
innate + adaptive CD4/CD8 both involved.
TNF-a, IFN-g, IL-12 phagocytes activated --> oxidative burst, NO2 |