Activation of the Innate Signaling Molecule MAVS by Bunyavirus Infection Upregulates the Adaptor Protein SARM1, Leading to Neuronal Death

Mukherjee, Piyali; Woods, Tyson A.; Moore, Roger A.; Peterson, Karin E.

doi:10.1016/j.immuni.2013.02.013

Cited by 118 publications

(110 citation statements)

References 49 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…3D). This is similar to a lack of an effect of Mavs deficiency on young mice (30). Thus, Unc93b1 and Mavs are essential for protection in adults but do not substantially alter neurological disease in young mice.…”

Section: Irf3supporting

confidence: 61%

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Taylor

Woods

Winkler

et al. 2014

J Virol

View full text Add to dashboard Cite

La Crosse virus (LACV) is the major cause of pediatric viral encephalitis in the United States; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. Our current studies in a mouse model of LACV infection indicated that differences in myeloid dendritic cell (mDC) responses between weanling and adult mice accounted for susceptibility to LACV-induced neurological disease. We found that type I interferon (IFN) responses were significantly stronger in adult than in weanling mice. Production of these IFNs required both endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs). Surprisingly, IFN expression was not dependent on plasmacytoid DCs (pDCs) but rather was dependent on mDCs, which were found in greater number and induced stronger IFN responses in adults than in weanlings. Inhibition of these IFN responses in adults resulted in susceptibility to LACV-induced neurological disease, whereas postinfection treatment with type I IFN provided protection in young mice. These studies provide a definitive mechanism for age-related susceptibility to LACV encephalitis, where mDCs in young mice are insufficiently activated to control peripheral virus replication, thereby allowing virus to persist and eventually cause central nervous system (CNS) disease. IMPORTANCE La Crosse virus (LACV) is the primary cause of pediatric viral encephalitis in the UnitedStates. Although the virus infects both adults and children, over 80% of the reported neurological disease cases are in children. To understand why LACV causes neurological disease primarily in young animals, we used a mouse model where weanling mice, but not adult mice, develop neurological disease following virus infection. We found that an early immune response cell type, myeloid dendritic cells, was critical for protection in adult animals and that these cells were reduced in young animals. Activation of these cells during virus infection or after treatment with type I interferon in young animals provided protection from LACV. Thus, this study demonstrates a reason for susceptibility to LACV infection in young animals and shows that early therapeutic treatment in young animals can prevent neurological disease.

show abstract

Section: Irf3supporting

confidence: 61%

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Taylor

Woods

Winkler

et al. 2014

J Virol

View full text Add to dashboard Cite

show abstract

“…1), while mice receiving PBMCs or splenocytes did not. Immunohistochemical analysis of clinical animals confirmed virus-infected neurons in these mice [29] (data not shown). Flow cytometric, qRT-PCR and immunohistochemical analysis of PBMCs and splenocytes revealed no viral antigen or RNA in these cells [44] (data not shown) confirming they are non-infectious.…”

Section: Lacv Infectivity Is Contained In Plasmamentioning

confidence: 73%

“…While LACV infection rarely causes neurological disease in adults [40], it is the leading cause of pediatric viral encephalitis in the United States [14,15]. LACV neuroinvasion in humans and animal models results in the infection, dysfunction and death of neurons [3,27,29,33]. Virus-induced brain pathology can lead to severe neurological disease with symptoms such as seizures, coma and paralysis [27].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion

et al. 2015

View full text Add to dashboard Cite

Viral neuroinvasion is a critical step in the pathogenesis of viral encephalitis. Multiple mechanisms of neuroinvasion have been identified, but their relative contribution to central nervous system (CNS) infection remains unclear for many viruses. In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowing leakage of virus-sized particles into the brain. Analysis of OB capillaries demonstrated specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas such as the cortex where leakage did not occur. Collectively, these findings indicate that LACV neuroinvasion occurs through hematogenous spread in specific brain regions where capillaries are prone to virus-induced activation such as the OB. Capillaries in these areas may be "hot spots" that are more susceptible to neuroinvasion not only for LACV, but other neurovirulent viruses as well.

show abstract

“…A second mechanism of neuronal apoptosis involves RIG-Ilike receptor (RLR) signaling. While RLR-induced activation of MAVS exhibits antiviral activity [191], it can cause neuronal death by triggering sterile alpha and TIR motif-containing 1 (SARM1) protein [192]. In this regard, mice lacking SARM-1 appeared to be more resistant to LACV-mediated neuronal damage than wild-type mice, despite having similar viral loads in their brain [192].…”

Section: Neuropathogenesis Of Arbovirusesmentioning

confidence: 99%

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

View full text Add to dashboard Cite

Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus-and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause.

show abstract

Activation of the Innate Signaling Molecule MAVS by Bunyavirus Infection Upregulates the Adaptor Protein SARM1, Leading to Neuronal Death

Cited by 118 publications

References 49 publications

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

Contact Info

Product

Resources

About