Innate immune response in neuronopathic forms of Gaucher disease confers resistance against viral-induced encephalitis
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RESEARCH
Innate immune response in neuronopathic forms of Gaucher disease confers resistance against viral‑induced encephalitis Sharon Melamed1†, Roy Avraham1†, Deborah E. Rothbard2, Noam Erez1, Tomer Israely1, Ziv Klausner3, Anthony H. Futerman2, Nir Paran1 and Einat B. Vitner1*
Abstract Both monogenic diseases and viral infections can manifest in a broad spectrum of clinical phenotypes that range from asymptomatic to lethal, suggesting that other factors modulate disease severity. Here, we examine the interplay between the genetic neuronopathic Gaucher’s disease (nGD), and neuroinvasive Sindbis virus (SVNI) infection. Infection of nGD mice with SVNI had no influence on nGD severity. However, nGD mice were more resistant to SVNI infection. Significantly different inflammatory responses were seen in nGD brains when compared with SVNI brains: the inflammatory response in the nGD brains consisted of reactive astrocytes and microglia with no infiltrating macrophages, but the inflammatory response in the brains of SVNI-infected mice was characterized by infiltration of macrophages and altered activation of microglia and astrocytes. We suggest that the innate immune response activated in nGD confers resistance against viral infection of the CNS. Keywords: Gaucher’s disease, Alphaviruses, Sindbis virus, Encephalitis, Glucosylceramide, Brain inflammation, Astrocytosis, Microgliosis
Introduction Brain inflammation is a common characteristic of many disorders of the central nervous system (CNS). Irrespective of whether a disease is genetic or infectious in origin, activation of the brain’s immune response is normally present [66]. The CNS resident immune system is comprised mainly of innate immune cells, with microglia and astrocytes the key components. However, under certain pathological conditions, peripheral innate and adaptive immune cells, including monocytes, neutrophils, T cells *Correspondence: [email protected] † Sharon Melamed and Roy Avraham have contributed equally to the work 1 Department of Infectious Diseases, Israel Institute for Biological Research, P.O. Box 19, 7410001 Ness‑Ziona, Israel Full list of author information is available at the end of the article
and B cells, can enter the CNS [69]. The inflammatory response can be chronic or acute, and the outcome of the activation may be beneficial, deleterious, or neutral. Infection of the CNS is a major global healthcare concern, and is associated with high morbidity and mortality [38, 71]. Neuroinfectious diseases may be associated with acute changes in mental and motor function, followed by chronic neurological dysfunction which can persist long after recovery from the infectious event. In neuroinfectious diseases, the innate immune response is critical for limiting pathogen invasion of the CNS and essential to mediate host resistance. However, if the response fails to eliminate the aggressor, inflammation may lead to progressive disease and ultimately death. Persistent activation of the immune response in the CNS has been implicated as
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