Major Areas of Research
- Examine interactions between the immune and nervous systems in regulating viral pathogenesis in the central nervous system (CNS)
- Determine the mechanism by which innate immune responses in neurons induce neuronal apoptosis and the role of SARM1 in this process
- Identify the mediators of blood-brain barrier breakdown during La Crosse virus infection
- Examine the role of adaptive immune responses in La Crosse virus and Zika virus pathogenesis
- Examine the differences in neuropathogenesis between different members of the California serogroup of orthobunyaviruses
- Identify potential therapeutic pathways to limit virus-mediated damage in the CNS
A number of human viruses have the potential to infect the central nervous system and cause serious encephalitic disease or death. Virus-induced neuronal death can occur either through direct infection of neurons or via indirect mechanisms such as recruitment of inflammatory cells that cause pathological damage. The Neuroimmunology Section studies multiple encephalitic viruses to gain a better insight into the interactions between the immune response to virus infection and the development of neurological disease. A major goal of our laboratory is to elucidate the major pathways that mediate neuropathogenesis so that rationally designed therapeutics may be developed to intervene in the disease process. This includes examining the factors that mediate virus entry into the CNS, the recruitment of inflammatory cells to the brain, and the influence of these cells on CNS damage, as well as direct damage of neurons by virus infection.
One of the viruses under study is La Crosse virus (LACV), a mosquito-transmitted virus belonging to the California serogroup of orthobunyaviruses, which is a leading cause of pediatric viral encephalitis in the United States. Our studies have demonstrated that the innate immune response in neurons contributes to virus-mediated neuronal apoptosis. We have identified one of the main mediators of this damage, a toll-like receptor (TLR)-associated protein named SARM1 (Mukherjee et al., Immunity 2013). Induction of SARM1 in neurons affects mitochondrial localization/damage leading to neuronal death (Mukherjee, Winkler, Taylor et al. J Immunology 2015). Current studies are investigating the specific mechanisms by which SARM1 influences mitochondrial damage.
The ability of LACV to gain access to the CNS to infect neurons is a critical step in the development of neurological disease. We recently demonstrated that LACV infection results in vascular leakage of brain capillaries in localized regions of the brain, which allows the virus to gain access to the CNS and infect neurons (Winkler et al., Acta Neuropathologica 2015). Analysis of brain capillary endothelial cells (BCECs) in these regions showed changes in Rho-GTPases as well as actin and cytoskeleton proteins that are normally associated with BBB breakdown. Further studies are focused on examining the factors that mediate the responses in these BCECs.
Adaptive immune responses, including activated T cells and the production of neutralizing antibodies (NAbs) can also have an important role in regulating virus entry into the CNS, as well as mediating damage within the brain. Analysis of the adaptive immune response to LACV infection showed that although T cells and B cells were not essential for virus-induced neurological damage, they were important in preventing LACV from gaining access to the CNS in resistant adult mice (Winkler et al., J Neuroinflammation 2017). In similar studies using Zika virus, an emerging encephalitic arbovirus in North America, we also found that T cells and B cells played an important role in preventing Zika virus from gaining access to both the brain and the testes in a mouse model (Winkler, Myers et al.. J Immunology 2017). Furthermore, we found that these responses were suppressed in pregnant female mice. Future studies are focused on examining how these responses influence vertical and sexual transmission of this virus.
In addition to LACV, other members of the California serogroup of orthobunyaviruses including Jamestown Canyon virus, Tahyna virus, and Snowshoe hare virus have also been shown to cause neurological disease in humans; however, how these viruses compare in their pathogenesis remains unknown. We are studying the differences in neuropathogenesis of these viruses and identifying the determinants that contribute to neuronal damage. We also collaborated with Olivia Steele-Mortimore (Salmonella Host-Cell Interactions Section) and Corrie Detweiler, (University of Colorado, Boulder) to develop a mouse model of Salmonella meningitis (Bauler, Starr, Nagy et al. A. J. Pathol. 2017) to study the influence of immune responses in mediating bacterial meningitis.
Karin Peterson received her Ph.D. in microbiology and immunology in 1998 from the University of Missouri Medical School, where she studied autoimmunity and the activation of self-reactive T cells. She then went to Rocky Mountain Laboratories (RML) in 1998 as a postdoctoral fellow in the Laboratory of Persistent Viral Diseases and applied her skills in immunology toward understanding the mechanisms that control the immune response to retrovirus infection. During this time, she became interested in the immune responses to virus infections in the central nervous system (CNS). In 2004, Dr. Peterson accepted a position as an assistant professor at Louisiana State University School of Veterinary Medicine, where she furthered her studies on viral pathogenesis in the CNS and also taught classes in immunology and virology. In 2008, she returned to RML as a tenure-track investigator to study the innate immune responses in the CNS and their role in viral pathogenesis. She was tenured in 2016 and became a senior investigator and chief of the Neuroimmunology Section.
Lab members of the NeuroImmunology Section. From left to right: Tyson Woods, Stephen Johnson, Saurav Rout, Rahul Basu, Clayton Winkler, Durbadal Ojha, Paul Policastro, Alyssa Evans and Karin Peterson
Winkler CW, Woods TA, Robertson SJ, McNally KL, Carmody AB, Best SM, Peterson KE. Cutting edge: CCR2 is not required for Ly6Chi monocyte egress from the bone marrow but is necessary for migration within the brain in La Crosse birus encephalitis. J Immunol. 2018 Jan 15;200(2):471-476.
Winkler CW, Woods TA, Rosenke R, Scott DP, Best SM, Peterson KE. Sexual and vertical transmission of Zika virus in anti-interferon receptor-treated Rag1-deficient mice. Sci Rep. 2017 Aug 3;7(1):7176.
Winkler CW, Myers LM, Woods TA, Messer RJ, Carmody AB, McNally KL, Scott DP, Hasenkrug KJ, Best SM, Peterson KE. Adaptive immune responses to Zika virus are important for controlling virus infection and preventing infection in brain and testes. J Immunol. 2017 May 1;198(9):3526-3535.
Winkler CW, Race B, Phillips K, Peterson KE. Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion. Acta Neuropathol. 2015 Aug;130(2):233-45.
Mukherjee P, Winkler CW, Taylor KG, Woods TA, Nair V, Khan BA, Peterson KE. SARM1, not MyD88, mediates TLR7/TLR9-induced apoptosis in neurons. J Immunol. 2015 Nov 15;195(10):4913-21.
Mukherjee P, Woods TA, Moore RA, Peterson KE. Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death. Immunity. 2013 Apr 18;38(4):705-16.