Systems biology of the host response to severe infection

This thesis provided more insight into the host response to severe infection by using systems-based approaches. We focused on RNA expression profiling to characterize biological mechanisms that may be used to decipher the dominant features of sepsis pathophysiology. The leukocyte transcriptomes of healthy subjects with experimentally induced endotoxemia was evaluated to identify transcriptional signatures and pertaining biological pathways that showed a dependency on LPS dose. We also evaluated leukocyte transcriptomes of patients with intra-abdominal sepsis having blood culture positive E. coli infections to provide clinical relevance to the LPS dependent transcriptional signature. We identified differentially abundant circulatory small non coding RNA in community-acquired pneumonia patients as compared to healthy subjects, and delineated micro RNAs that putatively target specific cellular pathways. We also identified and characterized circular (circ)RNAs expression in specific immune cell-types of patients with sepsis due to community-acquired pneumonia relative to healthy subjects and ascertain robustness of our findings we also determined circRNA in an independent cohort of healthy volunteers in the context of immune cell specific in vitro validation assays. The high-throughput RNA-sequencing data in human monocytes obtained from sepsis patients was used to identify the induced antisense long non coding RNA JHMD1D-AS1. We used RNA knockdown and over-expression experiments in human monocytes or a pro-monocytic cell line to investigate the function of JHMD1D-AS1 in the regulation of the cellular inflammatory response. The other part of the thesis explored CSF inflammatory mediator profiles and underlying genetic mechanisms driving the severity and outcome of pneumococcal meningitis patients.