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Bacteriology/Virology

Bacteriology/Virology. 2008. Chlamydia trachomatis Chlamydia, “the Clam”, “gooey stuff”. #1 reported infectious disease in US Gm-, obligate intracellular (ATP parasite), PBP Serovariant D-K EB “spore” enters cell, becomes RB, replicates by binary fission, convert to EBs and released

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Bacteriology/Virology

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  1. Bacteriology/Virology 2008

  2. Chlamydia trachomatisChlamydia, “the Clam”, “gooey stuff” • #1 reported infectious disease in US • Gm-, obligate intracellular (ATP parasite), PBP • Serovariant D-K • EB “spore” enters cell, becomes RB, replicates by binary fission, convert to EBs and released • Untreated: PID, infertility, ectopic pregnancy • Reiter’s Syndrome: reactive arthritis >1 month (molecular mimicry?) • Screen women <25yo annually, Dxw/ IFA, ELISA • Tx: Doxycycline

  3. Chlamydia trachomatis Trachoma Lymphogranuloma Venereum Serovariant L1-3 Unnoticed painless herpetiform ulceration Inguinal syndrome in men: painful lymphadenitis Can lead to anogenitorectal syndrome, elephantiasis of genitalia (women, homosexual men) Africa, Asia, S. America • Serovariant A-C • Chronic conjunctivitis leads to blindness by causing eyelashes to turn inward and scratch the cornea • Disease of poverty • SAFE strategy (surgery, ATB, face washing, environment)

  4. Chlamydiophila C. Psittaci Parrot Fever C. Pneumoniae “Walking Pneumonia” Pear-shaped EB Human-only pathogen Atypical pneumonia with persistant cough, malaise Connection with athero-sclerosis? (foam cells) • Inhaling bird feces, urine (parrots, parakeet, poultry) • Mild, non-productive cough, lower respiratory tract • Can spread to liver, spleen, cause focal necrosis

  5. BorreliaburgdorferiLyme Disease • #1 vector borne illness in US (80% of all vector-) • Corkscrew motility through solid tissue • O-mem with lipoproteins (OspA), no LPS, no LTA • Deer ticks – 2 yr lifecycle, “accidental” hosts • Summer months, children + elderly, NE US • Bulls-eye rash, “flu-like” with no respiratory symptoms • Can lead to arthritis in single joint, bells palsy • Chronic disease – OspA, hLFA-1, autoimmune • ELISA, Western (OspC, BmpA, Fla) confirmation • Avoid area, protective clothing, DEET, survey/remove • Treat with doxycycline or IV ceftriaxone

  6. Relapsing Fever B. hermsii, B. duttonii (Endemic) B. Recurrentis (Epidemic) Body louse Africa/S. America Higher fatality rate • “Soft” ticks • Western US • Lower fatality rate • Replicate in blood • Genetic recombination(VMP-like proteins) • Reocurring fever, malaise • Tx: Tetracyclines • Jarisch-Herxheimer Rx“mild septic shock”

  7. LeptospirainterrogansLeptospirosis • Not obligate parasite (variety of animal hosts) • Shed through urine of infected host • Affects kidneys, liver, eyes • “Flu” like symptoms (LPS-like materal) • Well’s Syndrome (10%) Disseminated spirochetes, severe renal dysfunction, high fatality rate, aseptic meningitis • Treat early with tetracyclines/β-lactams

  8. TreponemapallidumSyphilis • Correlated with Yaws disease (Africa) • Infamous Tuskeegee study • Coat self with host proteins, exposed TROMPs • Wasserman test replaced with VDRL, RPR tests with cardiolipin (IgA), negative after treatment • Confirmatory tests expensive • Syphilis screen recommended for all pregnancies • Tx: 1 dose of penicillin

  9. TreponemapallidumSyphilis • 1⁰ - localized painless chancres, high # of spirochetes, neutrophil response, few weeks • 2⁰ - disseminate in blood, “great pox” rash on palms/soles, flu-like symptoms with arthritis • Latency – High Ab titers, 30% progress to 3⁰ • 3⁰ - “gummas” (granulomatous lesions)neurosyphilis: general paresis (insanity),tabesdorsalis (demyelination of posterior columns - sensation)

  10. Bartonella B. henselae Cat Scratch Disease B. henselae and B. quintana Bacillary Angiomatosis Immunocompromised patients (AIDS) Mainly skin (also bone, GI, reproductive, LN, CNS) Reddish vascular nodules, lesions similar to Kaposi’s Proliferation of vascular endothelial cells (HIF-1, VEGF from macrophages) Tx: Erythromyin • Pustule at scratch, large, painful lymph nodes • Parinaud’sOculoglandular Syndrome (2-17%)conjunctivitis, b.v. proliferation, resolves • Encelphalitis/Meningitis/Myelitis (1-7%) cranial/ peripheral nerves, convulsion, resolves • Tx: Doxycycline

  11. Bartonella B. quintana Trench Fever B. bacilliformisCarrion’s Disease Bartonellosis Oroya fever (40% fatal febrile anemia) with hemolysin, pain in shins, erythrocyte lysis Verruga peruana (skin angiomatosis) chronic Tx: Chloramphenicol • Spread by human louses, scratching skin • Poor hygiene: homeless, alcoholics • Pain in shin bones, 5 day fever cycle, non-fatal • Tx: Erythomycin, Doxy- • Silver Stain, ELISA, 16S rRNA

  12. Anaplasmataceae Ehrlichiachaffeensis Human MonocyticEhrlichosis (HME) Anaplasmaphagocytophilum Human Granulocytic Anaplasmosis (HGA) Neutrophilic intra-cytoplasmic inclusions Transmitted by deer ticks Severe febrile illness Similar distribution to Lyme Increased incidence w/ age • Monocytic intracytoplasmic inclusions • Transmitted by lone star tick • Significant left-shift • Southeastern US • Military dogs from VN war • Symptoms similar to RMSF • Tx: Doxycycline

  13. HTLVAdult T-cell Leukemia/Lymphoma (ATLL) • Oncovirus, icosahedral capsid, dsRNA+ • Decades long latency period • ATLL develops in 3-5%, fatal in one year,oncogene activation in CD4+ helper cells • Immune mediated neurological symptoms • Same treatment as HIV (HAART)

  14. HIV-1, HIV-2Acquired Immunodeficiency Syndrome (AIDS) • Lentivirus, truncated cone capsid, dsRNA+ • Gene groups: gag (structural proteins), pol (enzymes), env(envelope glycoproteins) • gp120, gp41 bind to CD4 and coreceptors CCR5 (macrophages), CXCR4 (T-cells) • tax (trans-activator factor), rex (regulates mRNA) • High mutation rates yields drug resistance • ELISA, Western blot to confirm, CD4 count for severity • Drug target gp41 fusion, reverse transcription, polyprotein proteolysis; (non)-nucleoside analogs

  15. HIV • Nucleotide RT Inhibitors (NRTIs) • Zidovudine (AZT) and Lamivudine (3TC) • Used for HIV, 3TC also for chronic Hep B • Didanosine (ddiA) • AZT resistant HIV, causes pancreatitis (5%) • Stavudine (d4T) • NucleoTide RT Inhibitor • Tenofovir • targets viral RT, can replace NRTI

  16. HIV • Non-Nucleoside RT Inhibitors (NNRTI) • Nevirapine • Binds to RT, steric hindrance to Tri-P, hepatotoxicity • HIV Fusion Inhibitor • Enfuvirtide (Fuzeon) • Binds to HIV-1 gp41 and prevents fusion

  17. HIV • Protease Inhibitors • Inhibit viral “maturation” by blocking cleavage of gag viral polyproteins by protease • Lipodystrophy, induce/worsen diabetes • Kidney stones, diarrhea, increased serum TG • Indinavir, Saquinavir, Ritonavir, Lopinavir, Nefinavir, Amprenavir • HAART • AZT, 3TC, NNRTI, Protease Inhibitor

  18. Herpesviruses • Kinase puts first sugar on bases (AMP, GMP) • Acyclovir • Valacyclovir • Ganciclovir • Penciclovir • Famciclovir • Foscarnet • Vidarabine

  19. Herpesviruses • Acyclovir • Open ring, chain terminator • HSV > VZV >> CMV (non-theraputic?) • Reduces mortality 50% in herpes encephalitis • Renal, CNS toxicity • Poor GI absorption (20%) • Valacyclovir • Prodrug for Acyclovir • Increased GI absorption (60%)

  20. Herpesviruses • Ganciclovir • Treats CMV • Prevention of disease in immunocompromised • CNS toxicity • Penciclovir • Treats Zoster (longer half-life) • Famciclovir • Prodrug for Penciclovir, increases GI absorption • Rapid resolution of zoster-associated pain

  21. Herpesviruses • Foscarnet • Block polymerase by blocking PPi site • Treat acyclovir-resistant, CMV retinitis • Toxic, used only in life-threatening situations • Vidarabine • Topical for HSV keratoconjunctivitis

  22. Herpesvirus – Eye Infections • Formivirsen • Intravitreal injection • Antisense oligonucleotides, RNA silencing • Trifluridine, Idoxuridine, Vidarabine Solutions • Nucleoside analogs • Chain terminators • Treat Herpes keratitis

  23. Influenza Virus • Type A,B,C (same internal M, N proteins) • A: pandemics, antigenic shift, B: epidemic, drift • Subtypes Hemagglutinin, Neuraminidase • H5, H7, H9 are avian-derived strains • Amantadine and Rimantadine • only works on type A (needs pH <6 to fuse) • Inhibits M2 proton pump (buffers pH >6) • Rimantadinemore potent, less CNS toxicity • Oseltamivir (Tamiflu) and Zanamivir • Neuramidase inhibitor (cleavage off sialic acid) • Targets type A and B, approved treatment of flu

  24. Hepatitis • Recombinant Interferon Alpha 2b • Hepatitis B, Kaposi’s sarcoma, HCV • Peg-Interferon Alpha (Pegasys) • Hepatitis C • More stable in circulation • Combination with ribavirin

  25. RSV, Lassa • Palivizumab (Synagis) • Monoclonal Ab to neutralize RSV F-glycoprotein • Blocks fusion • Treats infants <2yo • Ribavirin • Guanosine analogue • Causes mutations (base substitutions) • Combination with IFN for HCV

  26. Evading Host Defenses Divergent Evolution • E. coli (O157:H7) from commensal strains Convergent Evolution • Listeria + Shigella destroy phagosome w/ proteins Common strategies • Leukocidins kill phagocytes (streptolysin O, α toxin, adenylylcyclase) • Proteases degreate proteins (C3a, C5a, sIgA) • Host proteins (Ig, lactoferrin, transferrin, S-layer, heparin, hyaluronic acid, sialic acid, H-factor) • Membranes (Gm+, LPS) • Block intracellular signalling, lysosome fusion, respiratory burst, escape phagosome, inhibit Ag presentation • Antigenic variation (convergence: VMP&VSG) • Super Ags

  27. Vaccination Schedule • Hepatitis B • Birth • 1-2 months • 9-18 (next well child visit) • Rota, DTaP, HiB, PCV, IPV • 2, 4, 6 months • DTaP, HiB, PCV, MMR-Chicken Pox, Varicella, Hepatitis A • 12-15 months • Influenza (H3N2, H1N1, B) • Annually (6-60 months) • >60 months if high risk • Hepatitis A • 18-24 months (>6mo after) • DTaP, IPV, MMR-Chicken Pox, Varicella • 4-6 years • PPV, HepA, MCV4 • >2 years if high risk

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