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West Nile virus (WNV) typically leads to asymptomatic infection but can cause severe neuroinvasive disease or death, particularly in the elderly. Innate NK cells play a critical role in antiviral defenses, yet their role in human WNV infection is poorly defined. Here we demonstrate that NK cells mount a robust, polyfunctional response to WNV characterized by cytolytic activity, cytokine and chemokine secretion. This is associated with downregulation of activating NK cell receptors and upregulation of NK cell activating ligands for NKG2D. The NK cell response did not differ between young and old WNV-naïve subjects, but a history of symptomatic infection is associated with more IFN-γ producing NK cell subsets and a significant decline in a specific NK cell subset. This NK repertoire skewing could either contribute to or follow heightened immune pathogenesis from WNV infection, and suggests that NK cells could play an important role in WNV infection in humans.

The genus Flavivirus contains many mosquito-borne human pathogens of global epidemiological importance such as dengue virus, West Nile virus, and Zika virus, which has recently emerged at epidemic levels. Infections with these viruses result in divergent clinical outcomes ranging from asymptomatic to fatal. Myriad factors influence infection severity including exposure, immune status and pathogen/host genetics. Furthermore, pre-existing infection may skew immune pathways or divert immune resources. We profiled immune cells from dengue virus-infected individuals by multiparameter mass cytometry (CyTOF) to define functional status. Elevations in IFNβ were noted in acute patients across the majority of cell types and were statistically elevated in 31 of 36 cell subsets. We quantified response to in vitro (re)infection with dengue or Zika viruses and detected a striking pattern of upregulation of responses to Zika infection by innate cell types which was not noted in response to dengue virus. Significance was discovered by statistical analysis as well as a neural network-based clustering approach which identified unusual cell subsets overlooked by conventional manual gating. Of public health importance, patient cells showed significant enrichment of innate cell responses to Zika virus indicating an intact and robust anti-Zika response despite the concurrent dengue infection. Author summary: Mosquitoes carry many globally important human pathogens including a family of related viruses: dengue virus, West Nile virus, Yellow Fever virus, and recently of critical significance, Zika virus. The Zika virus epidemic emerged very rapidly in the susceptible South American population and in many cases immune responses were unable to control the infection. Immune history is a key element of susceptibility or resistance to severe disease. We examined whether pre-existing infection would skew or divert immune resources and might play a role in the severity of Zika infection in the Americas. Using samples from dengue patients and healthy controls from India, we tested functional responses to Zika virus in the context of pre-existing dengue infection. We quantified frequency and functional status of 36 individual cell subsets in depth using advanced profiling techniques and a novel deep learning algorithm. We showed an intact response to new infection with Zika virus which was enriched for early innate immune pathways and robust even during existing dengue infection. Thus, our study suggests that concurrent dengue infection would not be expected to impair immune responses to new infection with Zika virus. [ABSTRACT FROM AUTHOR]