Human Cervical Epithelial Cells Mediated Host Innate Immunity Against HIV-1 And HSV-2 Infections

Part Ⅰ Poly I:C activates human cervical epithelial cells(HCEs)to produce antiviral factors and inhibits HIV infection of macrophagesSexual transmission is the main route of HIV transmission and female reproductive tract(FRT)is a primary site of HIV invasion.Because there are a large number of HIV target cells in the lamina propria of FRT,including CD4~+T cells,macrophages and dendritic cells,it is of importance to understand the FRT innate immunity against viral infections.As the first layer of cells in the FRT,the human cervical epithelial cells(HCEs)are in directly contact with HIV-containing sperm and/or the free viruses.In addition to playing an important physiological barrier role in the FRT,HCEs are also involved in the innate immunity of FRT.Our and other researchers have shown that HCEs express immunologically functional toll-like receptor 3(TLR3),which recognizes viral double-stranded RNA(ds RNA)and initiates innate immune response to viral infections.In this study,we determined whether Poly I:C,a TLR3 agonist,can activate the TLR3/Interferon(IFN)signaling pathway of HCEs,produce the antiviral factors and inhibit HIV infection of macrophages.Our study shows that the activation of TLR3 in HCEs induces the production of antiviral factors that can be transported to HIV-infected macrophages by exosomes.Key findings:1.HCEs possess a functional TLR3 signaling pathway,activation of which induces IFN regulatory factor 3(IRF3)/IRF7,and type I and type III IFNs.HCEs produce and release IFNs which can bind to the corresponding receptors on the surface of macrophages and exert anti-HIV effects;2.Activation of the TLR3 signaling pathway in HCEs induces the multiple antiviral factors,including the IFN-stimulated genes(ISGs:OAS-1,ISG56,Mx A,Mx2)and the HIV restriction mi RNAs(mi R-28,mi R-29 family,mi R-125b,mi R-150,mi R-382,mi R-223,mi R-20a,and mi R-198).These antiviral factors can be packed in exosomes secreted by HCEs and transported to macrophages,exerting anti-HIV effect in macrophages;3.TLR3-activated HCEs produce the CC chemokines(MIP-1α,MIP-1βand RANTES),which can competitively bind to the HIV co-receptor CCR5 and block HIV entry into macrophages.Part Ⅱ IL-22 inhibits HSV-2 infection of HCEsHerpes simplex virus type 2(HSV-2)is an enveloped double-stranded DNA virus,which belongs to Herpesviridae family.HSV-2 is the main pathogen of genital herpes.Once infected,patients can carry the virus for life and periodically develop genital herpes.Because both HSV-2 and HIV have the ability to infect humans through sexual transmission,co-infection with HIV and HSV-2 is very common.Importantly,studies have shown that HSV-2 infection could increase the risk of HIV transmission.Therefore,the prevention and treatment of genital herpes is very important.At present,there is no effective vaccine against HSV-2.Among the anti-HSV-2 drugs,acyclovir,valaciclovir,and famciclovir are commonly used in clinical practice.These nucleotide analogs could inhibit HSV-2 DNA synthesis and reduce clinical symptoms,but cannot completely eradicate the virus.In addition,these drugs have side effects,and long-term use can lead to the emergence of drug-resistant strains.Therefore,it is necessary to develop more effective drugs.IL-22 belongs to the IL-10 family and is mainly produced by activeted T cells such as Th1,Th17,and Th22.Extracellular secreted IL-22 mainly acts on epithelial cells,endothelial cells,and fibroblasts in tissues.IL-22 binds to the IL-22 receptor complex(IL-22R1 and IL-10R2)on the surface of target cells,and activates the JAK/STAT signaling pathway to initiate the innate immune in the cells.In this study,we determined whether IL-22 activates the innate immunity of HCEs and inhibit HSV-2 infection.Our study shows that IL-22 can effectively inhibit HSV-2 infection of HCEs.Key findings:1.HCEs express IL-22 receptor complexes(IL-22R1 and IL-10R2);2.IL-22 binding to IL-22 R on the surface of HCEs to activate JAK/STAT signaling pathway,which induces the expression of STAT1/3 and ISGs;3.STAT1 plays a key role in IL-22-mediated anti-HSV-2 effect;4.IL-22 can increase the expression of tight junction proteins(ZO-1 and Occludin)in HCEs;5.IL-22 inhibits HSV-2 IE,E and L gene expression in HCEs.