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Alan Sariol

Mentor: Stanley Perlman, MD, PhD

Year Entered Into Program: 2015

Terminal Degree(s) Received: PhD 2021

Research Description

Role of microglia in MHV-induced demyelination

The proposed research project involves the use of a drug, PLX5622, that is currently in clinical trials for use in rheumatoid arthritis. The drug is a specific inhibitor of the kinase activity of CSF-1 receptor, a receptor expressed on macrophages and microglia that regulates survival and proliferation of these cells. Previous research has shown that
dietary treatment with PLX5622 eliminates more than 95% of microglia, a cell that acts as the resident macrophage of the central nervous system.

Mouse hepatitis virus (MHV) is a murine coronavirus that causes a variety of disease in susceptible rodents. JHMV is neurotropic strain of mouse hepatitis virus that, when neuroattenuated, causes chronic, immune-mediated demyelinating encephalomyelitis. This inflammatory demyelination allows it to be used as a murine model of multiple
sclerosis.

Microglia and incoming peripheral macrophages both act as effectors in clearing JHMV, however little is known about the differences between these cells due to difficulty differentiating them in an infected mouse. Previous work by the Ransohoff lab has shown that microglia and macrophages have differential roles in the experimental autoimmune
encephalomyelitis (EAE) model of multiple sclerosis. Dietary treatment with PLX5622 allows depletion of microglia in the brain without depleting infiltrating macrophages, allowing study of the specific role of microglia in the chronic inflammatory response to JHMV infection.

Earlier work on the project performed during my rotation in the lab showed that depleting microglia prior to infection results in more severe acute encephalitis and a complete loss of survival. Current and future work will focus on depletion of microglia with PLX5622 at later time points in relation to the infection.

Awards

  • Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2016-present
  • AAI Young Investigator Award – Autumn Immunology Conference 2016

Publications

  1. Vickers MA, Sariol A, Leon J, Ehlers A, Locher AV, Dubay KA, Collins L, Voss D, Odle AE, Holida M, Merrill AE, Perlman S, Knudson CM. Exponential increase in neutralizing and spike specific antibodies following vaccination of COVID-19 convalescent plasma donors. Transfusion. 2021 Apr 8. doi: 10.1111/trf.16401. Epub ahead of print. PMID: 33829513.
  2. Sariol, A., and Perlman, S.: Lessons for COVID-19 Immunity from Other Coronavirus Infections. Immunity 53(2):248-263, 2020.  PMCID: PMC7359787.
  3. Sariol, A., Mackin, S., Allred, M.G., Ma, C., Zhou, Y., Zhang, Q., Zou, X., Abrahante, J.E., Meyerholz, D.K., Perlman, S.:  Microglia Depletion Exacerbates Demyelination and Impairs Remyelination in a Neurotropic Coronavirus Infection. Proceedings of the National Academy of Sciences 117(39):24464-24474, 2020.  PMCID:  PMC7533697
  4. Zheng, Jian, Z., Sariol, A., Meyerholz, D., Zhang, Q., Abrahante Lloréns, J.E., Narumiya, S., and Perlman, S.: Prostaglandin D2 Signaling in Dendritic Cells Is Critical for the Development of EAE.” Journal of Autoimmunity, 114:102508, 2020.  PMCID: PMC7332282
  5. Borbón, Tiffany Y., Breanna M. Scorza, Gwendolyn M. Clay, Fellipe Lima Nobre de Queiroz, Alan J. Sariol, Jayden L. Bowen, Yani Chen, et al. “Coinfection with Leishmania Major and Staphylococcus Aureus Enhances the Pathologic Responses to Both Microbes through a Pathway Involving IL-17A.” PLoS Neglected Tropical Diseases 13(5):e0007247, 2019.  PMCID: PMC6527190
  6. Wheeler, D. L., Sariol, A., Meyerholz, D. K. & Perlman, S. Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest 128:931-943, 2018.  PMCID: PMC5824854

Research