Areas of Interest
MOLECULAR PATHOGENESIS OF ENCEPHALITIC VIRUS INFECTIONS
My laboratory is investigating the molecular genetics of virus-host cell interactions in viruses that cause encephalitis. Our long-term studies have been on mouse adenovirus type 1 (MAV-1). Human adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries. Also, adenovirus infections are a serious complication of pediatric bone marrow transplants. MAV-1 affords us the opportunity to address adenovirus-host interactions in the natural host as well as in cell culture. By understanding how viral and cellular gene functions are regulated during infection, we can gain insight into disease processes.
MAV-1 causes encephalitis, due to breakdown of the blood-brain barrier (BBB). MAV-1 causes acute and persistent viral infections in susceptible mice via infection of cells of the monocyte/macrophage lineage and endothelial cells. Current experiments are directed at understanding the molecular mechanisms by which the virus disrupts the BBB to cause disease in the central nervous system (CNS). Using virus and mouse mutants, we are also investigating how the virus elicits the innate immune response, for example, whether through Toll-like receptors or the inflammasome.
A major cellular response to the stresses is the activation of eIF2a kinases through one of four mammalian protein kinases. The most well-known of these kinases responding to viral infection is PKR. Viruses have many ways to overcome the antiviral effects of PKR. We have found that MAV-1 depletes PKR from infected cells, an unprecedented mechanism for a DNA-containing virus. Another eIF2a kinase that is less well studied in virus infections in GCN2. Using mice genetically mutant in GCN2, we have found that GCN2 is antiviral for MAV-1 infections, particularly in macrophages. We are currently investigating the interactions between MAV-1 and PKR and GCN2.
We are also studying virus-host interactions by investigating the contributions of host genetics to adenovirus disease. We identified inbred strains of mice that are far more susceptible to MAV-1 disease than other strains. We are assessing the biological differences in MAV-1 encephalitis in susceptible and resistant strains. Through positional cloning experiments, we identified at least two quantitative trait loci (QTLs) for susceptibility to MAV-1. The major QTL, on mouse Chromosome 15, encompasses the Ly6 complex, and we are using further genetic and immunological approaches to identify the specific Ly6 gene(s) responsible. We anticipate that identifying the genes associated with these QTLs will identify new mechanisms in virus-host interactions.
We have a collaborative project with Brazilian scientists to characterize the neuropathogenesis of arboviruses (arthropod-vectored viruses) dengue (DENV) and Oropouche virus (OROV) using mouse models. The CNS clinical signs caused by DENV are now recognized as more extensive than previously appreciated. These include encephalitis, meningitis, myelitis, encephalopathy, disseminated acute encephalomyelitis, neuromyelitis, optical neuritis, and Guillain-Barré syndrome. OROV is second only to DENV in causing febrile illnesses in Brazil. OROV infection can be quite debilitating, although the virus does not cause death. We are investigating a form of OROV infection that causes aseptic meningitis with severe neurological clinical signs in approximately 5% of patients seeking medical care.
Singh, P.K., I. Khatri, A. Jha, C.D. Pretto, K.R. Spindler, V. Arumugaswami, S. Giri, A. Kumar, and M.K. Bhasin. 2018. Determination of system level alterations in host transcriptome due to Zika virus (ZIKV) infection in retinal pigment epithelium. Sci. Rep. 8:11209. PMCID: PMC6060127
Ashley, S.L.*, C.D. Pretto*, M.T. Stier, P. Kadiyala, L. Castro-Jorge, T.-H. Hsu, R. Doherty, K.E. Carnahan, M.G. Castro, P.R. Lowenstein, and K.R. Spindler. 2017. Matrix metalloproteinase activity in infections by an encephalitic virus, mouse adenovirus type 1. J. Virol. 91: e01412-16. PubMed ID: 34307280 *These authors contributed equally. Featured in J. Virol. Spotlight, March 2017 vol. 91 no. 6, https://jvi.asm.org/content/91/6/e00101-17.full
Castro-Jorge, L.A., C.D. Pretto, A.B. Smith, O. Foreman, K.E. Carnahan, and K.R. Spindler. 2017. A protective role for IL-1 signaling during mouse adenovirus type 1-induced encephalitis. J. Virol. 91: e02106-16. PubMed ID: 27903802
Tirumuru, N., C.D. Pretto, L.A. Castro Jorge, K.R. Spindler. 2016. Mouse adenovirus type 1 early region 1A effects on the blood-brain barrier. mSphere 1:e00079-16. PubMed ID: 27303733
Gounder, A.P., N.D. Myers, P.M. Treuting, B.A. Bromme, S.S. Wilson, M.E. Wiens, W. Lu, A.J. Ouellette, K.R. Spindler, W.C. Parks, and J.G. Smith. 2016. Defensins potentiate a neutralizing antibody response to enteric viral infection. PLoS Pathog. 12: e1005474. PubMed Central ID: PMC4774934
Hsu, T.-H., and K.R. Spindler. 2012. Identifying host factors that regulate viral infection. PLoS Pathog. 8:e1002772.
Hsu, T.-H., I.W. Althaus, O. Foreman, and K.R. Spindler. 2012. Contribution of a single host genetic locus to mouse adenovirus type 1 infection and encephalitis. mBio 3:e00131-12.
Spindler, K.R., and T.-H. Hsu. 2012. Viral disruption of the blood-brain barrier. Trends Microbiol. 20:282-290.
Stier, M.T., and K.R. Spindler. 2012. Polymorphisms in Ly6 genes in Msq1 encoding susceptibility to mouse adenovirus type 1. Mamm. Genome 23: 250-258.
Ashley, S.L., S.M. Ameres, S.R. Gerrard, O. Foreman, K.A. Eaton, J.B. Weinberg, K.R. Spindler. 2011. Host genetic variation in susceptibility to Punta Toro virus. Virus Res. 157:71-75.
Spindler, K.R., A.R. Welton, E.S. Lim, S. Duvvuru, I.W. Althaus, J.E. Imperiale, A.I. Daoud, and E.J. Chesler. 2010. The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed LY6 family. J. Immunol. 184:3055-3062.
Gralinski, L.E., S.L. Ashley, S.D. Dixon, and K.R. Spindler. 2009. Mouse adenovirus type 1-induced breakdown of the blood-brain barrier. J. Virol. 83:9398-9410.
Ashley, S.L.*, A.R. Welton*, K.M. Harwood, N. Van Rooijen, and K.R. Spindler. 2009. Mouse adenovirus type 1 infection of macrophages. Virology 390:307-314. *These authors contributed equally.
Robinson, M., B. Li, Y. Ge, D. Ko, S. Yendluri, T. Harding, M. VanRoey, K.R. Spindler, and K. Jooss. 2009. A novel immune-competent murine tumor model for the evaluation of conditionally replication-competent (oncolytic) murine adenoviral vectors. J. Virol. 83:3450-3462.
Raman, S., T.-H. Hsu, S.L. Ashley, and K.R. Spindler. 2009. Integrin and heparan sulfate usage as receptors for mouse adenovirus type 1. J. Virol. 83:2831-2838.
Welton, A.R.*, L.E. Gralinski*, and K.R. Spindler. 2008. Mouse adenovirus infection of natural killer cell-deficient mice. Virology 373:163-170. *These authors contributed equally.
Welton, A.R., E.J. Chesler, C. Sturkie, A.U. Jackson, G.N. Hirsch, and K.R. Spindler. 2005. Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1. J. Virol. 79:11517-11522.