Impact of Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) on Anti-Viral Immunity to West Nile Virus

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2015-08
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Roe, Kelsey
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[Honolulu] : [University of Hawaii at Manoa], [August 2015]
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West Nile virus (WNV) has emerged as a pathogen of importance in the Western Hemisphere over the past two decades. Its association with severe neurological disease justifies the need to understand mechanisms of immune control in order to promote the development of therapies. One of the earliest steps in controlling WNV infection occurs through the activation of innate immune pathways such as Toll-like receptor-3 (TLR-3), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs). Typically, binding of WNV-derived replication products to these receptors causes activation of downstream signaling resulting in the production of antiviral type I interferon (IFN) and pro-inflammatory cytokines such as TNF-α and IL-1β. The activation of inflammatory pathways is very tightly regulated at multiple steps to promote efficient clearance of the virus without causing tissue damage. In WNV, the mechanisms associated with regulation of inflammation are not completely characterized as yet. To begin to understand how WNV regulates host inflammatory response, we initiated studies to examine the role of triggering receptor expressed on myeloid cells 1 (TREM-1) in antiviral immunity. TREM-1 signaling is linked with the amplification of inflammation. However, other recently characterized roles of TREM-1 such as activation of antigen presenting cells and recruitment of immune cells to the site of infection, suggest that this receptor might be an important player in immunity to WNV. Here, we investigated the effect of virus infection on the expression of TREMs and the role TREM-1 plays during anti-WNV immunity. Our results demonstrated that TREM-1 expression increased in immune cells following flavivirus (WNV, dengue virus and Japanese encephalitis virus) and influenza virus infection, and exposure to Ebola virus glycoprotein. In vivo, TREM-1 and TREM-3 transcripts were significantly up regulated in the peritoneal cells from WNV-infected mice, which correlated with high viremia, while antiinflammatory TREM-2 and TREM-like transcript-1 (TLT-1) expression was reduced. We further document that infiltrating inflammatory monocytes, as well as resident glial cells, contributed to increased TREM-1 in WNV-infected brain. The cellular consequence of TREM-1 activation using an agonist antibody was the amplification of WNV-associated TNF-α and IL-6 production, which was attenuated in the presence of TREM-1 inhibitory peptide. Importantly, significantly higher mortality and viremia in WNV-infected TREM-1/3-/- mice suggested antiviral function of this receptor. TREM-1/3-/- mice exhibited enhanced virus titers in the periphery and brain, and failed to sustain the production of pro-inflammatory cytokines, such as IL-6, in the serum. Although the levels of WNV-specific antibodies were comparable in both groups of mice, TREM-1/3-/- mice had fewer IFN-γ producing CD8 T cells in the WNV-infected spleen following re-stimulation with WNV peptide. Moreover, brains from TREM-1/3-/- mice displayed major hallmarks of neuroinflammation including increased levels of inflammatory cytokines, activation of GFAP and infiltration of leukocytes. Intriguingly, survival of mice following intracranial inoculation of WNV was not significantly different between both groups suggesting that TREM-1/3-dependent immune responses in the periphery contribute to the WNV disease outcome. Collectively, our results support novel roles of TREM-1 as an amplifier of WNVassociated innate immunity and initiation of adaptive immunity to effectively and timely clear the virus from periphery and prevent neuroinvasion. These studies provide novel insights into the complex interactions that occur between inflammatory pathways responding to WNV and may allow for the characterization of similar networks of innate immune regulation in other viruses of global importance. Further, these studies may lead to identification of viral and cellular targets for the development of urgently required immunotherapeutic strategies.
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Ph.D. University of Hawaii at Manoa 2015.
Includes bibliographical references.
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Tropical Medicine & Med Micro
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