Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection

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 immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs 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, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, 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 here 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 noncytolytic viral control.

Noncanonical Transmission of a Measles Virus Vaccine Strain from Neurons to Astrocytes

“…In published experiments that are a prelude to these studies, we found that measles virus RNA was detectable in brain tissues of infected NSE-hCD46 transgenic mice months to years after inoculation ( 16 ). Moreover, upon immunosuppression, MV reproduction rebounded, suggesting long-term maintenance of replication-competent viral genomes.…”

“…At 30 days postinoculation (dpi), NSE-hCD46 + /RAG2 KO mice were sacrificed, followed by perfusion, brain sectioning, and immunofluorescence (IF) staining for MV nucleoprotein (MV-N), combined with brain cell markers. In parallel, NSE-hCD46 + mice infected for 90 dpi were irradiated lethally and reconstituted with RAG2 KO bone marrow, as previously published ( 16 ); this procedure results in MV reactivation from dormancy. At 14 days post-bone marrow reconstitution (105 dpi), mice were euthanized, followed by IF staining of brain sections.…”

“…Our lab established the first of these transgenic mice, in which the hCD46 vaccine strain receptor was restricted to neurons using a neuron-specific promoter, neuron-specific enolase (NSE) ( 15 ). This well-established model mimics the neuropathology observed in humans caused by the wild-type virus ( 15 – 19 ). For example, our recent study showed that MV reproduction in the brain is kept in check by CNS-resident memory T cells.…”

“…As we show in this report, this state of viral “dormancy,” in which MV replicates to low levels in the absence of overt disease, surprisingly occurs in both neuronal and nonneuronal cells. When the host is immunosuppressed, sentinel immune cells leave the CNS, and virus reproduction and spread resume, resulting in neuropathogenic outcomes ( 16 , 20 , 21 ).…”

Mechanisms of viral persistence in the brain and therapeutic approaches

“…Additionally, measles may persist in the brain without causing disease [81,82] further suggesting that mutations do not wholly account for persistence but do contribute to pathology. Additional evidence for this hypothesis comes from murine models, in which immune suppression after resolution of infection resulted in re-emergence of viral pathogens with distinct disease phenotypes [41].…”