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. Recent experiments have been 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 have also investigated 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. The virus does this by degrading PKR by a proteasomal mechanism. 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 especially interested in the viral genes involved in PKR degradation and in cell-specific interactions of MAV-1 infected cells with host GCN2.
Goffin, E., J. Javau, E. Destexhe, C.D. Pretto, K.R. Spindler, B. Machiels and L. Gillet. 2019. Oral vaccination with replication-competent adenovirus in mice reveals the dissemination of the viral vector beyond the gastrointestinal tract. J. Virol. doi:10.1128/JVI.00237-19.
Goodman, D.E., C.D. Pretto, T.A. Krepostman, K.E. Carnahan, K.R. Spindler. 2019. Enhanced replication of mouse adenovirus type 1 following virus-induced degradation of protein kinase R (PKR). mBio 10e00668-19.
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.