Project description:A number of inhibitors of chemokine CCL2 and its receptor CCR2 are in development and may find application for treating a range of inflammatory conditions, including autoimmune and viral arthritides. Herein we sought to determine the effect of CCR2 deficiency on arthritis caused by an arthritogenic alphavirus, Chikungunya virus. Chikungunya virus (LR2006-OPY1) was injected subcutaneously into the hind foot of either CCR2 knockout or wild-type control mice (n=4-6). At day 0 and d7 post infection, RNA from the feet was harvested, the RNA was pooled (4-6 feet per time point per mouse strain) and gene expression analysis was performed using Mouse Gene ST arrays (Affymetrix).
Project description:A number of inhibitors of chemokine CCL2 and its receptor CCR2 are in development and may find application for treating a range of inflammatory conditions, including autoimmune and viral arthritides. Herein we sought to determine the effect of CCR2 deficiency on arthritis caused by an arthritogenic alphavirus, Chikungunya virus.
Project description:Although oral antibiotics can predispose to joint inflammation, this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus arthritis to investigate the gut commensals, metabolites, and host mechanisms that promote musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya virus (CHIKV) infection. This phenotype was associated with loss of short chain fatty acids (SCFA) and greater intestinal permeability, and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and pro-inflammatory cytokines. Administration of exogenous SCFA or colonization of mice with bacterial species that generate SCFA mitigated CHIKV-induced joint inflammation. Single cell RNA sequencing revealed that gut-derived SCFA restrain the inflammatory phenotype of synovial CD4+ T cells and limit activation of monocytes and osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
Project description:In this study, we aim to identify common host genes involved in pathogenesis of different Chikungunya virus strains as an attempt to recognize probable antiviral targets. We have compared the host gene regulation after infection of monkey kidney cell line (Vero) with two different wild type CHIKV strains i.e. S 27 (human, ECSA), and DRDE-06 (human, ECSA). Vero cells were mock infected or infected with two Chikungunya virus strains (S 27 and DRDE-06) and harvested at 8hpi and 18hpi. The total RNA was extracted and microarray was done using Agilent protocol.
Project description:The emerging alphavirus chikungunya virus (CHIKV) has infected millions of people. However, the factors modulating disease outcome remain poorly understood. We show that depletion of the gut microbiota in oral antibiotic-treated or germ-free mice leads to greater CHIKV infection and spread within one day of virus inoculation. Perturbation of the gut microbiota alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single commensal bacterial species, Clostridium scindens, or its derived metabolite, the bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, commensal gut bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects virus dissemination and potentially, epidemic spread
Project description:The emerging alphavirus chikungunya virus (CHIKV) has infected millions of people. However, the factors modulating disease outcome remain poorly understood. We show that depletion of the gut microbiota in oral antibiotic-treated or germ-free mice leads to greater CHIKV infection and spread within one day of virus inoculation. Perturbation of the gut microbiota alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single commensal bacterial species, Clostridium scindens, or its derived metabolite, the bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, commensal gut bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects virus dissemination and potentially, epidemic spread 3 biological replicates were processed per time point and group
