Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Sexually transmitted infection wikipedia , lookup
Dirofilaria immitis wikipedia , lookup
Rocky Mountain spotted fever wikipedia , lookup
Oesophagostomum wikipedia , lookup
Neglected tropical diseases wikipedia , lookup
Listeria monocytogenes wikipedia , lookup
Sarcocystis wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Schistosoma mansoni wikipedia , lookup
Herpes simplex virus wikipedia , lookup
MICR 420 Emerging and Re-Emerging Infectious Diseases Lecture 7: C. trachomatis Dr. Nancy McQueen & Dr. Edith Porter Overview C. trachomatis The genus Chlamydia Morphology Growth and metabolic characteristics Virulence factors Diseases Diagnosis Direct antigen test Culture PCR Immune response Therapy Threats: Apparently under control Chlamydia Obligate gram-negative intracellular bacteria No peptidoglycan layer Major outer membrane protein accounts for 60% of all surface protein Small genome (~1.0 Mb) Depend on host molecules for replication Limited or no ATP synthesis Two forms exist Small elementary bodies (EB) Survives outside host cells Transferred to new host Similar in function to a spore RNA:DNA = 1:1 Larger reticulate bodies (RB) Grow within cells RNA:DNA = 3:1 Do not survive outside host Reticulate Elementary Chlamydia Developmental Cycle EB attach to epithelial host cell Endocytosis Prevention of fusion with lysosome Development into RB RB proliferation, formation of large inclusion bodies 48h – 72h Visible in light microscope Development into EB Rupture of host cell and release of EB Persistent Forms Chlamydia Species C. pneumoniae C. psittaci World wide ~ 10% of pneumonias and 5% of all bronchitis cases Psittacosis Zoonotic pneumonia Inhalation of droppings from infected birds Category B biological weapon C. trachomatis Various serotypes Eye infections STI Chlamydia Infection of the Eyes Inclusion conjunctivitis Transmitted to newborn's eyes during passage through the birth canal Spread through swimming pool water Preventive erythromycin Treated with tetracycline Trachoma Greatest cause of blindness worldwide Trachoma World wide ~ 80 (150?) million people infected and ~ 6 million blind Mostly in developing countries 3% of cause of all blindness world wide Transmitted eye-hand-eye, eye-fomite-eye, flies Infection occurs usually during childhood Chronic follicular conjunctivitis inversion of eyelashes irritation of cornea corneal ulcerations, scarring vision loss typically at age 30 – 40 Trachoma Histopathology of Trachoma http://www.lenntech.com/images/Water%2 0Borne%20Diseases/Trachoma.jpg Simplified WHO System to Assess Trachoma Grade Description TF Trachomatous inflammation—Follicular: The presence of five or more follicles (>0.5 mm) in the upper tarsal conjunctiva TI Trachomatous inflammation—Intense: Pronounced inflammatory thickening of the tarsal conjunctiva that obscures more than half of the deep normal vessels TS Trachomatous scarring: The presence of scarring in the tarsal conjunctiva TT Trachomatous trichiasis: At least one lash rubs on the eyeball CO Corneal opacity: Easily visible corneal opacity over the pupil (from Matthew J. Burton, British Medical Bulletin, 2007) Pathogenesis of C. trachomatis (A) Chlamydia elementary bodies (EB) translocate Tarp into an associated cell to orchestrate rearrangement of host cell actin. The Cterminal domain of Tarp directly nucleates small actin filaments followed by hostmediated signaling involving tyrosine phosphorylation (*P) cascades and ultimately Arp2/3 to mobilize actin assembly necessary for invasion. (B) Throughout development, chlamydial inclusions intercept host-derived vesicles via recruitment of Rab GTPases (Rabs 1, 4, 10, and 11) and SNARE (Vamp 3, 7, and 8) molecules through interactions with Inc proteins. (C) Established inclusions are able to interfere with NF-kB (p50 and RelA) activation through ChlaDub1-mediated prevention of IkBa ubiquitination (*Ub) or CT441-mediated degradation of RelA. This would be predicted to interfere with proinflammatory signals originating from ligand binding to TNF family (TNFR) or pattern recognition (PRR) receptors. Virulence Factors of C. trachomatis (CT) Contribute to intracellular survival and proliferation In part secreted via Type III secretion apparatus Tarp (Translocated actin recruiting phosphoprotein): effects actin rearrangement and endocytic uptake of CT CT inserts proteins (Inc and others) in inclusion (endosome) membrane that prevent fusion of host lysosomes CT releases proteins (ChlaDub1, CT441) into the cytoplasma that interfere with NFkB signal transduction, a key pathway of the acute inflammatory and innate immune response. Immune Response to C. trachomatis Not well understood Infection controlled by cell mediated immune response However: contributes also to the scarring Antibodies are formed Tear IgG actually enhance uptake Tear IgA appear to be protective (Matthew J. Burton, British Medical Bulletin, 2007) Diagnosis of Trachoma No “gold standard” test Direct antigen test PCR ELISA to measure patient antibodies against outer membrane proteins, conserved heat shock proteins Culture inoculating specimens onto cell culture monolayers Visualization of inclusion bodies after 48 – 72 h using fluorescent labeled monoclonal antibodies against CT LPS or MOMP Therapy and Prophylaxis of Trachoma Eyelid surgery Antibiotics to treat the infection Tetracycline WHO’s Global Alliance Azithromycin for the Elimination of Education about facial Blinding Trachoma by 2020 cleanliness and personal hygiene Environmental improvements Take Home Messages Chlamydia are obligate intracellular bacteria that have a unique life cycle alternating between infectious elementary bodies and proliferative reticulate bodies. Pathogenic factors include rearrangement of cytoskeleton promoting uptake, inhibition of fusion of lysosomes with endosomes and inhibition of NfkB activation. C. trachomatis serotypes A-C (-K) cause trachoma, a chronic conjunctivitis leading to blindness. Trachoma is diagnosed by direct antigen and nucleic acid based test and treated with tetracyline and azithromycin. Resources http://www.who.int/topics/trachoma/en/ http://www.cdc.gov Textbooks Microbiology: A clinical Approach (2010) Garland Science Prescott’s Principles of Microbiology (2009) McGrawHill Microbiology: An Evolving Science (2009) Norton Primary literature Betts et al., Current Opinion in Microbiology, 2009, 12:81–87 Matthew J. Burton, British Medical Bulletin, 2007