Acute viral infection of the central nervous system can induce a variety of disease states. A disease state of particular interest to our group stems from the ability of viruses to induce meningitis (or inflammation of the lining of the brain). It is estimated that viral meningitis is induced with a peak monthly incidence of 1 in 100,000 persons, particularly in temperate climates. The disease is associated with symptoms that include fever, headache, stiffness of the neck, and seizures. Enteroviruses are the most common cause of viral meningitis, accounting for approximately 75-90% of the cases. Other meningitis-inducing viruses in humans include herpesviruses, human immunodeficiency virus-1, arbovirus, mumps virus, and lymphocytic choroimeningitis virus (LCMV). While complications associated with enterovirus-induced meningitis (the most common viral meningitis) in adults are rare, and are often seen in the immunocompromised, studies have shown that infection of children less that one year of age can result in mild to moderate neurological disability by the age of 5. On the other end of the spectrum, herpesviruses induce an array of CNS disorders that include encephalitis, myelitis, and meningitis, and these disorders have a very high mortality rate if left untreated. Because so many viruses have the capacity to infect and injure the CNS, it is important to uncover potential routes to pathogenesis. One of the main interests of our laboratory is to mechanistically define the impact of acute viral infections on the CNS and establish treatments to ameliorate adverse symptoms. The virus we study primarily in the laboratory is LCMV, which is a noncytopathic RNA virus that infects both mice and humans. Intracerebral inoculation of immunocompetent mice with LCMV induces a fatal choriomeningitis (the disease for which LCMV is named). The virus alone causes no disease;rather, infiltrating immune cells are absolutely required for convulsive seizures and fatalities. The LCMV model therefore provides an ideal scenario to study how immune cells mediate neurological dysfunction following engagement within the infected meninges. To advance our understanding of these interactions, we study meningitis in real time using intravital two photon microscopy (TPM). Over the past year, we have developed a collection of recombinant LCM viruses that express different fluorescent proteins (teal, green, yellow, orange, cherry, etc). This enables us to visualize the position and distribution of LCMV infected cells in the meninges. We also monitor innate (microglia, monocytes, macrophages, neutrophils, dendritic cells) and adaptive (anti-viral CD8 T cells, CD4 T cells, B cells) immune cells using fluorescent protein reporter mice. Collectively, we can monitor the dynamics and interactions of all relevant immune populations during LCMV induced meningitis. LCMV meningitis is mediated by anti-viral cytotoxic lymphocytes (CTL), and over the past year we have continued with studies designed to elucidate how these cells cause disease. We demonstrated previously that CTL drive acute onset seizures during meningitis by massively recruiting myelomonocytic cells (monocytes and neutrophils), which damage meningeal blood vessels and compromise the blood-cerebral spinal fluid (CSF) barrier. LCMV-specific CTL participate in myelomonocytic cell recruitment by directly producing chemokines (CCL3, 4, and 5) that attract them. These data revised our thinking about viral meningitis by demonstrating that CTL do not always cause pathogenesis directly through the release of cytotoxic effector mechanism. They can also contribute to CNS disease by recruiting pathogenic innate immune cells. Another novel finding that emerged from our TPM studies of LCMV specific CTL pertains to their division program. Starting from a simple dynamic observation of virus-specific CTL undergoing mitosis in the LCMV infected meninges, we developed a new conceptual understanding of the T cell division programming. Over the past year, we elucidated a novel mechanism that gives the immune system the ability to respond more appropriately to a viral infection, and infected tissues the ability to control CTL numbers locally. The traditional view of T cell proliferation is that it is a hardwired program instituted primarily in secondary lymphoid tissues by dendritic cells. This program is quite slow, often requiring up to 24 hrs before the first round of division is observed. Even at the peak of an anti-viral response, T cell division is estimated to require 6-8 hrs, and during this time, virus continues to replicate unchecked. Interestingly, during LCMV meningitis, we depart lymphoid tissues and migrate through the blood while still in cell cycle. In fact, up to one third of anti-viral CTL in the blood remained in active stages of cell cycle. Using TPM we demonstrated that upon arrival at a site infection (meninges), CTL can engage antigen presenting cells (APCs) and undergo mitosis within just 15 minutes. We further demonstrated that the CTL division program is not hardwired, but can be influenced by APCs at the site of infection. Interactions with local APCs and cognate peptide-MHC I can advance CTL through stages of cell cycle. These data support the novel concept that the CTL division program is cumulative and results from the summation of signals accumulated systemically following viral infection. We postulate that this general mechanism enables infected tissues to more readily fine tune the adaptive immune response by applying proliferative brakes to thwart unwanted immunopathology or by facilitating cell cycle progression to outcompete increasing viral replication. This finding is especially important in light of recent studies demonstrating that inhibitory ligand blockade (e.g., anti-PD-1 and anti-IL-10) improves clearance of a persistent viral infection in part by modulating T cell numbers. These treatments also foster immunopathology and may do so locally. Overall, our study is the first to highlight that CTL migrate while still in cell cycle, that CTL division programming is cumulative and can be modified at the site of viral infection by interactions with APCs, and that the CNS meninges is a site permissive to CTL division. We are now in the process of devising strategies to modulate CTL division programming as a therapy to mitigate CNS disease following viral infection.

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Russo, Matthew V; Latour, Lawrence L; McGavern, Dorian B (2018) Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury. Nat Immunol 19:442-452
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