Project description:Comparative analysis of Genome wide expression was performed to demonstrate diagnostic potential of expression profiling and to identify host response genes in scrub typhus. The results showed that there is a unique expression pattern in peripheral blood leukocytes of scrub typhus infected patients that could discriminate scrub typhus from the other infections and also provided insight into host transcriptional responses to this paticular infection.
Project description:Comparative analysis of Genome wide expression was performed to demonstrate diagnostic potential of expression profiling and to identify host response genes in scrub typhus. The results showed that there is a unique expression pattern in peripheral blood leukocytes of scrub typhus infected patients that could discriminate scrub typhus from the other infections and also provided insight into host transcriptional responses to this paticular infection. Genome-wide expression in peripheral blood mononuclear cells (PBMCs) from patients with scrub typhus were compared to those from healthy control and from patients with dengue fever, murine typhus or malaria.
Project description:Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of scrub typhus. As O. tsutsugamushi is detected in circulating monocytes during acute phase of scrub typhus, we wondered if this organism was able to infect monocytes. We showed here that O. tsutsugamushi replicated in monocytes from healthy donors. Using human whole genome microarrays, we found that O. tsutsugamushi the expression of genes in which up-regulated and down-modulated genes were equally distributed. , the expression of type I interferon, interferon-stimulated genes and M1-associated genes was significantly up-regulated. Second, O. tsutsugamushi the expression of apoptosis-related genes and induced cell death in monocytes. Live organisms were indispensable to type I interferon response and apoptosis and enhanced the expression of M1 cytokines. These findings were related to the transcriptional changes found in mononuclear cells from patients with scrub typhus. Hence, a microarray study revealed the up-regulation of 613 genes and the down-modulation of 517 genes. Importantly, IFN-related genes were specifically enriched and some features of M1 polarization were observed in patients, as found in O. tsutsugamushi-stimulated cells. Our results provide a comprehensive understanding of scrub typhus pathogenesis in which IFN-mediated activation of monocytes appears as critical.
Project description:Scrub typhus is a life-threatening disease caused by Orientia tsutsugamushi, a bacterium that mainly infects endothelial cells in vitro and in vivo. Evidence suggests that the interaction of O. tsutsugamushi with myeloid cells may play a pivotal role in O. tsutsugamushi infection. We showed here that O. tsutsugamushi intensively replicated within human monocyte-derived macrophages. Bacterial organisms stimulated the expression of a large panel of genes including type I interferon, interferon-stimulated, inflammatory, apoptosis-related genes and induced an M1-type gene response in macrophages. This transcriptional signature was accompanied by functional consequences such as the release of inflammatory cytokines such as Tumor Necrosis Factor and interleukin-gamma. Live O. tsutsugamushi organisms were necessary for type I interferon response and, to a lesser degree, to inflammatory response. As interferon-gamma is known to elicit M1 polarization, we assessed the effect of interferon-gamma on O. tsutsugamushi fate in macrophages. Exogenous interferon-gamma partly inhibited O. tsutsugamushi replication within macrophages. Our results suggest that the inflammatory response induced by O. tsutsugamushi may account for the local and systemic inflammation observed in scrub typhus and that interferon-gamma may be useful as an adjuvant treatment of patients with scrub typhus.
