?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F28095%2F&rft.title=Identification+of+cellular+factors+involved+in+Neisseria+gonorrhoea+induced+enhanced+HIV-1+transmission+in+a+cervical+tissue+based+organ+culture+model&rft.creator=Sanyal%2C+Anwesha&rft.description=The+presence+of+sexually+transmitted+infections+(STI)+such+as+Neisseria+gonorrhoeae+(NG)+can+enhance+the+transmission+of+HIV-1.+Our+goal+in+this+study+is+to+elucidate+mechanism+by+which+NG+induces+enhanced+HIV-1+transmission.+A+cervical+tissue+based+organ+culture+system+was+developed+to+study+the+interaction+between+NG+and+HIV-1+which+provided+a+unique+opportunity+to+elucidate+mechanism+of+NG+induced+enhanced+HIV-1+transmission+across+cervical+mucosa.++We+demonstrated+that+the+NG+exposure+on+the+cervical+tissue+in+the+organ+culture+model+showed+physical+characteristics+of+NG+infection+and+induced+high+levels+of+inflammatory+cytokines+IL1-%CE%B2+and+TNF-%CE%B1+that+have+been+observed+during+in-vivo+NG+infection+in+the+cervix.+In+elucidating+the+mechanism+of+NG+induced+enhancement+of+HIV-1+transmission%2C+we+demonstrated+that+NG+not+by+itself+but+the+culture+fluids+from+NG+exposed+tissues+(reminiscent+of+cervical+milieu)+increased+HIV-1+transcription+from+the+HIV-+LTR+in+TZM-bl+cells%2C+induced+full+length+HIV-1+from+latently+infected+U1+and+ACH2+cells+and+increased+transmission+of+HIV-1+across+cervical+mucosa.+The+whole+genome+transcriptome+analysis+using+second-generation+sequencing+of+the+micro-dissected+epithelial+layer+of+the+tissues+exposed+to+NG+and+HIV-1+identified+with+high+statistical+significance+differentially+expressed+genes+in+NG+exposed+and+HIV-1+exposed+tissues%2C+and+identified+common+cellular+factors+as+well+as+pathways+involved+in+cell+activation%2C+migration+and+stimulation+expressed+in+the+epithelia.+%0D%0AOut+of+these+only+two+differentially+expressed+genes+that+were+common+between+tissues+exposed+to+both+NG+and+HIV-1+are+CXCL10+and+IL8.+Addition+of+inhibitors+of+CXCL10+and+IL8+suppressed+HIV-1+transmission%2C+while+addition+of+CXCL10+and+IL8+increased+HIV-1+transmission+indicating+that+CXCL10+and+IL8+could+be+involved+in+HIV-1+transmission+across+cervical+epithelia.+IL-1%CE%B2+also+increased+CXCL10+and+IL8+expression+in+cervical+tissues+and+enhanced+HIV-1+transmission+Altogether+these+data+are+consistent+with+a+model+(Figure+42)+for+NG+induced+enhanced+HIV-1+transmission%3A+NG+infection+secretes+IL-1%CE%B2+which+induces+increased+production+of+epithelial+CXCL10+and+IL-8+causing+the+++migration+of+HIV-1+target+cells+CD3%2BT+cells+and+macrophages+towards+intraepithelial+region+that+fuels+HIV-1+replication+in+submucosa+and+consequently+enhances+HIV-1+transmission.%0D%0ATaken+together%2C+our+results+confirm+that+the+risk+of+acquisition+of+HIV-1+infection+in+the+ecto-cervical+region+increases+with+prior+NG+infection.+From+the+public+health+perspective%2C+identification+of+IL-1%CE%B2+and+its+target+cellular+proteins+in+NG+induced+enhanced+HIV-1+transmission+could+be+useful+in+development+of+drugs+that+impair+HIV+transmission.+Further+work+in+nonhuman+primates+or+humanized+mouse+models+could+provide+confirmation+of+the+role+of+CXCL10+and+IL-8+in+HIV+transmission+and+its+modulation+by+NG+secreted+proteins+like+IL-1%CE%B2+in+vivo.&rft.date=2016-09-09&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F28095%2F1%2FAnwesha_Sanyal_PhD_dissert_6_2016.pdf&rft.identifier=++Sanyal%2C+Anwesha++(2016)+Identification+of+cellular+factors+involved+in+Neisseria+gonorrhoea+induced+enhanced+HIV-1+transmission+in+a+cervical+tissue+based+organ+culture+model.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++