Many inflammatory processes directly impact the function of the central nervous system (CNS) and give rise to human diseases. For example, acute infection of the CNS can induce a variety of disease states such as meningitis and encephalitis. Meningitis occurs when microbes infect the lining of the brain, whereas encephalitis is usually caused by infection of the brain itself. Epidemiological studies estimate 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 than one year of age can result in mild to moderate neurological disability by the age of 5. At 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 microbes have the capacity to infect and injure the CNS, it is important to uncover potential routes to pathogenesis. One of our main interests is to mechanistically define the impact of acute infections on the CNS and establish treatments to ameliorate adverse symptoms associated with these infections. We study viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus), parasitic (plasmodium berghei), and fungal (cryptococcus neoformans) infections to identify the similarities and differences in how the immune system responds to these different challenges. We also study sterile inflammatory responses (i.e., traumatic brain injury) to provide insights into how CNS immune cells respond to damage in the absence of an infectious agent. To advance our understanding of neural-immune interactions during CNS inflammatory diseases, we utilize a contemporary approach referred to as intravital two-photon laser scanning microscopy (TPLSM), which allows us to watch immune cells operate in the living brain in real time. This is accomplished by using fluorescently tagged immune cells and pathogens. By using fluorescent tags, the position of the pathogen can be studied in relation to innate (e.g. microglia, monocytes, macrophages, neutrophils, dendritic cells) and adaptive (e.g. microbe-specific CD8 T cells, CD4 T cells, B cells) immune cells as a disease develops. We can also administer therapeutic compounds into the viewing window and watch how this influences the inflammatory process in real time. This powerful approach allows us to evaluate the efficacy of potential therapeutics at the site of disease. Using the LCMV model of viral meningitis, we have recently demonstrated by TPLSM that virus-specific cytotoxic lymphocytes (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. Virus-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 by releasing of cytotoxic effector molecules;rather, they can also contribute to CNS disease by recruiting pathogenic innate immune cells. Based on our studies of other models of infection, breakdown of CNS vasculature by innate immune cells appears to be a general inflammatory reaction, and we are in the process of identifying the molecular mediators that cause this to occur. Another novel finding that emerged from our TPLSM studies pertains to division programming of T cells. 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. 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, CTL 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 TPLSM 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. 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 diseases following 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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