Cell Biology & Molecular Genetics Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/2750
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Item CHARACTERIZING THE INHIBITION OF INNATE IMMUNE SIGNALING BY MYCOBACTERIUM TUBERCULOSIS(2017) Ahlbrand, Sarah; Briken, Volker; Molecular and Cell Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Numerous cytokines are induced as a consequence of infection by Mycobacterium tuberculosis (Mtb), an intracellular pathogen that is responsible for millions of deaths each year. These cytokines play varied roles in eliciting and regulating the innate and adaptive immune responses against Mtb and often determine disease outcome. The pro-inflammatory cytokine interleukin 1β (IL-1β) is required for Mtb maintenance and clearance, as mice lacking the ability to produce IL-1β succumb very quickly to infection compared to infected wildtype mice. In contrast, interferon β (IFNβ) is largely thought to be detrimental to the host during Mtb infection based on collective studies in patients and mouse models. Both IL-1β and IFNβ are induced during Mtb infection, but here we demonstrate that Mtb has also evolved mechanisms to reduce their production and/or signaling. Previously, we’ve shown that Mtb can inhibit IL-1β production induced by the Absent in Melanoma 2 (AIM2) inflammasome. These findings were expanded upon by investigating the mechanisms by which Mtb inhibits AIM2 activation. A gain-of-function screen was also utilized in the non-pathogenic mycobacterial species Msmeg to identify Mtb genomic regions contributing to this phenomenon. In addition, we demonstrate that Mtb inhibits IFNβ signaling by inhibiting IFNβ-induced JAK1 and Tyk2 phosphorylation, leading to changes in the host type I interferon transcriptional profile. These studies provide insight into two previously undescribed mechanisms Mtb utilizes to manipulate the host immune response.Item Characterization of the West Nile virus pathogen associated molecular patterns(2013) German, Jennifer; Fredericksen, Brenda L; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The recent emergence of West Nile virus (WNV) in the western hemisphere has been marked by an increase in severe neurological disease. The factors that contribute to this increase in pathogenicity are poorly understood, however, there is evidence that the host antiviral response plays a significant role in controlling WNV mediated disease. The innate antiviral response is mediated by a variety of pathogen recognition receptors, including RIG-I. Here, we analyzed the RIG-I mediated antiviral response to WNV infection. We identified multiple regions of the pathogenic WNV-NY genome and antigenome that act as pathogen associated molecular patterns (PAMPs) capable of stimulating the RIG-I response. Additionally, preliminary examination of the related, non-pathogenic WNV-MAD78 genome has revealed stimulatory regions that differ from those found in the WNV-NY genome. One of PAMP region, the 5'UTR, was analyzed further to elucidate the secondary structural elements present in the RNA, which may be contributing to the antiviral response. Similar, equally stimulatory structures were found in the 5'UTR of both the WNV-NY strain WNV-MAD78, indicating similar structures may be recognized for RIG-I activation. We also examined the role of DDX3, a DExD/H box helicase similar to RIG-I, in WNV infection. DDX3 appeared to co-localize with WNV protein and DDX3 expression was reduced at late points in infection, but DDX3 overexpression had no effect on viral replication or protein expression. Therefore, the exact role that DDX3 plays during the course of WNV infection remains unresolved. Taken together, our data suggests a specific structural requirement to activate the RIG-I mediated antiviral response.