The overall goal is to identify the cellular mechanism of fatal respiratory insufficiency in arboviral encephalitides. Respiratory insufficiency is a serius outcome of arboviral encephalitis, and more specifically West Nile neurological disease, and can result in a poor prognosis. We have used rodent models to establish that neurological deficits cause the respiratory distress and are the primary pathophysiological mechanism of death for West Nile virus (WNV) and other viral encephalitides. These findings represent a breakthrough on how these viruses cause respiratory failure and death, but the cellular mechanism(s) causing these pathological responses are unknown, and are the subject of this application. The hypothesis to be tested is that the chemokine CXCR4/CXCL12 axis delays early entry of viral specific T lymphocytes into the parenchyma of the ventrolateral medulla (VLM) containing respiratory-control neurons. Additionally, we hypothesize that this delay results in higher virus load, and elevated inhibitory somatostatin (SST) neuropeptide or its receptor that contribute to lethal respiratory failure. This hypothesis is based on three recent findings. 1) Our finding that neurological respiratory insufficiency is a primary pathophysiologica mechanism of death in rodents infected with WNV and other arboviruses, which might be relevant to fatal viral encephalitides of human patients. 2) Remarkably, WNV envelope-immunostained neurons are tightly co-localized (96%) with SST-stained neurons in the VLM, which implies that WNV and/or inflammation are inducing SST. Specifically within the pre-B?tzinger complex, an area critical for respiratory rhythmogenesis, there are many neurons heavily stained for SST. This may be biologically significant in WN neurological disease, because SST in the VLM is a potent negative regulator of breathing. Evidence that SST neuropeptide plays a role in the generation and control of respiration is based on profound negative respiratory effects caused by exogenously administered SST to the VLM, and a restoration of respiratory function by administration of antagonists to SST receptors. 3) CXCR4/CXCL12 axis delays entry of WNV-specific T lymphocytes from the perivascular spaces into the parenchyma of non-specified areas of the brain. Unfortunately, cytopathic neurotropic viruses, such as WNV, require penetration of viral specific CD8+ T cells into the parenchyma for clearance of the virus. This delay results in an increased viral load leading to increased inflammatory responses and decreased survival of WNV-infected mice. Consequently, the effect of delayed entry of protective T cells specifically in the VLM may aberrantly increase the SST inhibitory peptide under immune-pathological conditions and contribute to arboviral-induced respiratory failure.
The specific aims designed to test the hypothesis are:
Aim 1. Determine if delayed entry of WNV- specific T cells via the CXCR4/CXCL12 axis contributes to fatal respiratory insufficiency by increasing SST, and inflammatory cells specifically in the parenchyma of the VLM. We will accomplish this by quantifying inflammatory cells and SST in the VLM of WNV-infected mice with respiratory insufficiency, as compared to WNV-infected mice without respiratory insufficiency. Additionally, an antagonist of CXCR4 will be evaluated for its ability to mitigate these pathological events in the VLM.
Aim 2. Determine if increased expression of SST or its receptor(s) is involved with WNV-induced respiratory insufficiency. This will be accomplished by determining if an antagonist to the SST receptor stereotaxically injected into the VLM can mitigate the effects of the virus to suppress respiratory functions.

Public Health Relevance

The purpose of this project is to investigate the cellular mechanism of fatal respiratory insufficiency in arboviral encephalitis, inasmuch as neurological respiratory failure may be a common pathophysiological mechanism of death for these diseases. The ultimate goal is to better manage and treat viral encephalitis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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Utah State University
Veterinary Sciences
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United States
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Siddharthan, Venkatraman; Van Wettere, Arnaud J; Li, Rong et al. (2017) Zika virus infection of adult and fetal STAT2 knock-out hamsters. Virology 507:89-95
Zukor, Katherine; Wang, Hong; Hurst, Brett L et al. (2017) Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters. J Neurovirol 23:186-204