Respiratory viral infections are commonly associated with acute respiratory illness in COPD patients, and the use of RT-PCR assays significantly increases the ability to diagnose these infections.

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Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states of the United States and is now the leading cause of epidemic encephalitis in North America. As a member of the family Flaviviridae, WNV is part of a group of clinically important human pathogens, including dengue virus and Japanese encephalitis virus. The members of this family of positive-sense, single-stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt a significant amount of cellular factors to translate their genomes effectively. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. mTOR is a serine/threonine kinase that acts as a central cellular censor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection and that pharmacologic inhibition of mTOR (KU0063794) significantly reduced WNV growth. We used an inducible Raptor and Rictor knockout mouse embryonic fibroblast (MEF) system to further define the role of mTOR complexes 1 and 2 in WNV growth and viral protein synthesis. Following inducible genetic knockout of the major mTOR cofactors raptor (TOR complex 1 [TORC1]) and rictor (TORC2), we now show that TORC1 supports flavivirus protein synthesis via cap-dependent protein synthesis pathways and supports subsequent WNV growth. IMPORTANCE Since its introduction in New York West Nile virus (WNV) is an enveloped, single-stranded, positive-sense RNA virus in the genus Flavivirus, which includes multiple clinically important viral species such as dengue virus, yellow fever virus, and Japanese encephalitis virus. Since the first North American outbreak in New York City, NY, in 1999 (1), WNV has spread across the continent to become the leading cause of epidemic encephalitis (2). To date, there have been more than 37,000 confirmed cases of WNV disease, 16,000 cases of neuroinvasive disease, and 1,500 fatalities (www.cdc.gov/westnile). Currently, there is no licensed human vaccine or pharmacologic therapy for WNV. Owing to difficulties in predicting the location and timing of WNV outbreaks, insufficient enrollment of WNV-infected patients has complicated human clinical trial design for candidate vaccines and therapeutic interventions. A better understanding of the molecular pathogenesis of flaviviruses and the mechanisms behind how they successfully compete with host messages for access to translational components may reveal broad-spectrum antiflaviviral targets that can be evaluated and licensed for treatment of acute flaviviral infections.Due to the high mutation rates of RNA viral genomes and their subsequent ability to rapidly generate escape mutations, we ...

Purpose of Review Arbovirus (arthropod-borne virus) infections are increasingly important causes of neurologic disease in the United States through both endemic transmission and travel-associated infections. This article reviews the major arbovirus infections that can cause neurologic disease likely to be encountered in the United States. Recent Findings West Nile virus continues to be an important cause of epidemic encephalitis, while emerging arbovirus infections such as dengue and chikungunya have rapidly expanded their geographic distribution. As emerging arboviruses expand in new geographic regions, neurologic abnormalities are reported in new patient populations. Summary Emerging arbovirus infections are increasingly important causes of neurologic disease throughout the world and in the United States. While no US Food and Drug Administration (FDA)–approved therapy is yet available for these infections, prompt recognition and diagnosis from the consulting neurologist will ensure appropriate supportive care for the patient.

Severe SARS-CoV-2 infection is associated with strong inflammation and autoantibody production against diverse self-antigens, suggesting a system-wide defect in B cell tolerance. BND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset. We asked whether SARS-CoV-2–associated inflammation impairs BND cell peripheral tolerance. To address this, PBMCs and plasma were collected from healthy controls, individuals immunized against SARS-CoV-2, or subjects with convalescent or severe SARS-CoV-2 infection. We demonstrate that BND cells from severely infected individuals are significantly activated, display reduced inhibitory receptor expression, and restored BCR signaling, indicative of a breach in anergy during viral infection, supported by increased levels of autoreactive antibodies. The phenotypic and functional BND cell alterations significantly correlate with increased inflammation in severe SARS-CoV-2 infection. Thus, autoreactive BND cells are released from peripheral tolerance with SARS-CoV-2 infection, likely as a consequence of robust systemic inflammation.

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Double negative (DN) B cells (CD27-IgD-) comprise a heterogenous population of DN1, DN2, and the recently described DN3 and DN4 subsets. In autoimmune disease, DN2 cells are reported to be precursors to autoreactive antibody secreting cells and expansion of DN2 cells is linked to elevated interferon levels. Severe SARS-CoV-2 infection is characterized by elevated systemic levels of pro-inflammatory cytokines and serum autoantibodies and expansion of the DN2 subset in severe SARS-CoV-2 infection has been reported. However, the activation status, functional capacity and contribution to virally-induced autoantibody production by DN subsets is not established. Here, we validate the finding that severe SARS-CoV-2 infection is associated with a reduction in the frequency of DN1 cells coinciding with an increase in the frequency of DN2 and DN3 cells. We further demonstrate that with severe viral infection DN subsets are at a heightened level of activation, display changes in immunoglobulin class isotype frequency and have functional BCR signaling. Increases in overall systemic inflammation (CRP), as well as specific pro-inflammatory cytokines (TNFα, IL-6, IFNγ, IL-1β), significantly correlate with the skewing of DN1, DN2 and DN3 subsets during severe SARS-CoV-2 infection. Importantly, the reduction in DN1 cell frequency and expansion of the DN3 population during severe infection significantly correlates with increased levels of serum autoantibodies. Thus, systemic inflammation during SARS-CoV-2 infection drives changes in Double Negative subset frequency, likely impacting their contribution to generation of autoreactive antibodies.