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Signal transducers and activators of transcription (STAT) 1 is critical for cellular responses to type I interferons (IFN-Is), with the capacity to determine the outcome of viral infection. We previously showed that while wildtype (WT) mice develop mild disease and survive infection with lymphocytic choriomeningitis virus (LCMV), LCMV infection of STAT1-deficient mice results in a lethal wasting disease that is dependent on IFN-I and CD4+ cells. IFN-Is are considered to act as a bridge between innate and adaptive immunity. Here, we determined the relative contribution of STAT1 on innate and adaptive immunity during LCMV infection. We show that STAT1 deficiency results in a biphasic disease following LCMV infection. The initial, innate immunity-driven phase of disease was characterized by rapid weight loss, thrombocytopenia, systemic cytokine and chemokine responses and leukocyte infiltration of infected organs. In the absence of an adaptive immune response, this first phase of disease largely resolved resulting in survival of the infected host. However, in the presence of adaptive immunity, the disease progressed into a second phase with continued cytokine and chemokine production, persistent leukocyte extravasation into infected tissues and ultimately, host death. Overall, our findings demonstrate the key contribution of STAT1 in modulating innate and adaptive immunity during type I interferon-mediated lethal virus infection., Author summary The mammalian immune system is divided into innate and adaptive immunity. In response to harmful agents, innate immunity acts first, followed by late-acting, specialized, adaptive immunity. Type I interferons (IFN-Is) are important means of communication between innate and adaptive immunity. IFN-Is mediate their effects via a number of signaling molecules, principally including signal transducers and activators of transcription 1 (STAT1). The importance of STAT1 to the immune response is evident from our previous finding that mice deficient in STAT1 develop a lethal, host immunity-mediated disease following infection with the otherwise harmless lymphocytic choriomeningitis virus (LCMV). In the present study, we characterized the role of STAT1 in protecting against harmful host immune responses against LCMV. We report that STAT1 plays a significant role in lessening both the early, inflammatory responses of innate immunity and the sustained, destructive actions of adaptive immunity. These findings exemplify the extent of STAT1’s role as a key immune response modulating factor.

Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, responsible for varicella upon primary infection and herpes zoster following reactivation from latency. To establish lifelong infection, VZV employs strategies to evade and manipulate the immune system to its advantage in disseminating virus. As innate lymphocytes, natural killer (NK) cells are part of the early immune response to infection, and have been implicated in controlling VZV infection in patients. Understanding of how VZV directly interacts with NK cells, however, has not been investigated in detail. In this study, we provide the first evidence that VZV is capable of infecting human NK cells from peripheral blood in vitro. VZV infection of NK cells is productive, supporting the full kinetic cascade of viral gene expression and producing new infectious virus which was transmitted to epithelial cells in culture. We determined by flow cytometry that NK cell infection with VZV was not only preferential for the mature CD56dim NK cell subset, but also drove acquisition of the terminally-differentiated maturity marker CD57. Interpretation of high dimensional flow cytometry data with tSNE analysis revealed that culture of NK cells with VZV also induced a potent loss of expression of the low-affinity IgG Fc receptor CD16 on the cell surface. Notably, VZV infection of NK cells upregulated surface expression of chemokine receptors associated with trafficking to the skin –a crucial site in VZV disease where highly infectious lesions develop. We demonstrate that VZV actively manipulates the NK cell phenotype through productive infection, and propose a potential role for NK cells in VZV pathogenesis., Author summary Varicella zoster virus (VZV) is a pervasive pathogen, causing chickenpox during primary infection and shingles when the virus reactivates from latency. VZV is therefore a lifelong infection for humans, warranting investigation of how this virus interacts with the immune system. One of the first immune cells to respond to viral infection are natural killer (NK) cells, yet little is known about how VZV interacts with NK cells. We demonstrate for the first time that VZV infects human blood NK cells and can use them to pass on infection to other cells in culture. Furthermore, VZV displays a predilection for infecting mature NK cells, and amplifies expression of receptors that would promote trafficking to the skin– the site of highly infectious lesions during chickenpox and shingles. Our findings suggest a role for NK cells in VZV disease and enhances our understanding of how lifelong infections interact with the human immune system.