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Miller KD, Matullo CM, Milora KA, Williams RM, O'Regan KJ, Rall GF
Immune-mediated control of a dormant neurotropic RNA virus infection
J Virol (2019) In process.
Abstract
Genomic material from many neurotropic RNA viruses (e.g., measles virus (MV), West Nile virus (WNV), Sindbis virus (SV), rabies virus (RV), and influenza A virus (IAV)) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here, we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV, and moreover, that immune suppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occur after experimental depletion of cells of the adaptive immune response, and is associated with a loss of T resident memory (Trm) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term infected mice display severe gait and motor problems, as compared to the wasting and lethal disease that occurs during acute infection of immunodeficient hosts. These results illuminate the potential consequences of non-cytolytic, immune-mediated viral control in the CNS, and demonstrate that, what were once considered "resolved" RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection.IMPORTANCE Viral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented in this manuscript provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of non-cytolytic viral control.
Note
Publication Date: 2019-09-03.
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Last updated on Wednesday, September 04, 2019