Donald H. Rubin, M.D.

Faculty Appointments
Professor of Medicine Professor of Pathology, Microbiology and Immunology
M.D., Medicine, Cornell University Medical College, New York, New YorkB.A., Sociology, Stony Brook University, Stony Brook, New York
Office Address
1310 24th Avenue South
Nashville, TN 37212
Research Description
Research has focused on understanding cellular and molecular aspects of viral infection in the GI tract and liver using reovirus. This work has led to the development of an exciting technology to sort out cellular genes that participate in cellular infection. Gene-trap retroviruses are used to select cells that are resistant to lytic reovirus infection. One hundred twenty cell lines have been established with a reovirus resistant phenotype and the genes disrupted are being characterized. Of the 120 genes disrupted, 20 of the genes are known. Many of these known genes are part of the endocytic pathway and 50% have been associated with virus infections. This work has been expanded to include the study of cellular genes involved in Trypanosoma cruzi infection. In addition, the laboratory is currently pursuing studies to elucidate the mechanisms of generating effective mucosal immunity. Recent studies have found that there is an oligoclonal response of the host to reovirus and that mucosal CD8+ that express the aa homodimer do not signal via NfkB.
Research Keywords
Molecular Genetics of the Pathogen-Host Interaction, Mechanism of Mucosal Immunity
LaFrance ME, Farrow MA, Chandrasekaran R, Sheng J, Rubin DH, Lacy DB. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2015 Jun 6/2/2015; 112(22): 7073-8. PMID: 26038560, PMCID: PMC4460460, PII: 1500791112, DOI: 10.1073/pnas.1500791112, ISSN: 1091-6490.

Murray JL, Sheng J, Rubin DH. A role for H/ACA and C/D small nucleolar RNAs in viral replication. Mol. Biotechnol. 2014 May; 56(5): 429-37. PMID: 24477674, DOI: 10.1007/s12033-013-9730-0, ISSN: 1559-0305.

Endsley MA, Somasunderam AD, Li G, Oezguen N, Thiviyanathan V, Murray JL, Rubin DH, Hodge TW, O'Brien WA, Lewis B, Ferguson MR. Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain. Virology [print-electronic]. 2014 Apr; 454-455: 60-6. PMID: 24725932, PMCID: PMC4018752, PII: S0042-6822(14)00050-6, DOI: 10.1016/j.virol.2014.02.006, ISSN: 1096-0341.

Radin JN, González-Rivera C, Frick-Cheng AE, Sheng J, Gaddy JA, Rubin DH, Algood HM, McClain MS, Cover TL. Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect. Immun [print-electronic]. 2014 Jan; 82(1): 423-32. PMID: 24191302, PMCID: PMC3911829, PII: IAI.00827-13, DOI: 10.1128/IAI.00827-13, ISSN: 1098-5522.

Dziuba N, Ferguson MR, O'Brien WA, Sanchez A, Prussia AJ, McDonald NJ, Friedrich BM, Li G, Shaw MW, Sheng J, Hodge TW, Rubin DH, Murray JL. Identification of cellular proteins required for replication of human immunodeficiency virus type 1. AIDS Res. Hum. Retroviruses [print-electronic]. 2012 Oct; 28(10): 1329-39. PMID: 22404213, PMCID: PMC3448097, DOI: 10.1089/AID.2011.0358, ISSN: 1931-8405.

Fennessey CM, Sheng J, Rubin DH, McClain MS. Oligomerization of Clostridium perfringens epsilon toxin is dependent upon caveolins 1 and 2. PLoS ONE [print-electronic]. 2012; 7(10): e46866. PMID: 23056496, PMCID: PMC3462777, PII: PONE-D-12-17436, DOI: 10.1371/journal.pone.0046866, ISSN: 1932-6203.

Murray JL, McDonald NJ, Sheng J, Shaw MW, Hodge TW, Rubin DH, O'Brien WA, Smee DF. Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis. Antivir. Chem. Chemother. 2012; 22(5): 205-15. PMID: 22374988, DOI: 10.3851/IMP2080, ISSN: 2040-2066.

Ivie SE, Fennessey CM, Sheng J, Rubin DH, McClain MS. Gene-trap mutagenesis identifies mammalian genes contributing to intoxication by Clostridium perfringens e-toxin. PLoS ONE. 2011; 6(3): e17787. PMID: 21412435, PMCID: PMC3055893, DOI: 10.1371/journal.pone.0017787, ISSN: 1932-6203.

Friedrich BM, Murray JL, Li G, Sheng J, Hodge TW, Rubin DH, O'Brien WA, Ferguson MR. A functional role for ADAM10 in human immunodeficiency virus type-1 replication. Retrovirology. 2011; 8: 32. PMID: 21569301, PMCID: PMC3118345, PII: 1742-4690-8-32, DOI: 10.1186/1742-4690-8-32, ISSN: 1742-4690.

Rubin DH, Ruley HE. Cellular genetics of host susceptibility and resistance to virus infection. Crit. Rev. Eukaryot. Gene Expr. 2006; 16(2): 155-70. PMID: 16749895, PII: 2d39b24c5067c643,5d0eb34878582d1d, ISSN: 1045-4403.

Murray JL, Mavrakis M, McDonald NJ, Yilla M, Sheng J, Bellini WJ, Zhao L, Le Doux JM, Shaw MW, Luo CC, Lippincott-Schwartz J, Sanchez A, Rubin DH, Hodge TW. Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus. J. Virol. 2005 Sep; 79(18): 11742-51. PMID: 16140752, PMCID: PMC1212642, PII: 79/18/11742, DOI: 10.1128/JVI.79.18.11742-11751.2005, ISSN: 0022-538X.

Organ EL, Sheng J, Ruley HE, Rubin DH. Discovery of mammalian genes that participate in virus infection. BMC Cell Biol. 2004 Nov 11/2/2004; 5(1): 41. PMID: 15522117, PMCID: PMC534806, PII: 1471-2121-5-41, DOI: 10.1186/1471-2121-5-41, ISSN: 1471-2121.

Sheng J, Organ EL, Hao C, Wells KS, Ruley HE, Rubin DH. Mutations in the IGF-II pathway that confer resistance to lytic reovirus infection. BMC Cell Biol. 2004 Aug 8/27/2004; 5: 32. PMID: 15333144, PMCID: PMC517494, PII: 1471-2121-5-32, DOI: 10.1186/1471-2121-5-32, ISSN: 1471-2121.

Organ EL, Nalbantyan CD, Nanney LB, Woodward SC, Sheng J, Dubois RN, Price J, Sutcliffe M, Coffey RJ, Rubin DH. Effects of transforming growth factor-alpha (TGF-alpha) in vitro and in vivo on reovirus replication. DNA Cell Biol. 2004 Jul; 23(7): 430-41. PMID: 15294092, DOI: 10.1089/1044549041474751, ISSN: 1044-5498.

Chen D, Rubin DH. Mucosal T cell response to reovirus. Immunol. Res. 2001; 23(2-3): 229-34. PMID: 11444387, PII: IR:23:2-3:229, DOI: 10.1385/IR:23:2-3:229, ISSN: 0257-277X.

Saragovi HU, Rebai N, Di Guglielmo GM, Macleod R, Sheng J, Rubin DH, Greene MI. A G1 cell cycle arrest induced by ligands of the reovirus type 3 receptor is secondary to inactivation of p21ras and mitogen-activated protein kinase. DNA Cell Biol. 1999 Oct; 18(10): 763-70. PMID: 10541435, DOI: 10.1089/104454999314908, ISSN: 1044-5498.

Mora AL, Chen D, Boothby M, Rubin DH. Lineage-specific differences among CD8+ T cells in their dependence of NF-kappa B/Rel signaling. Eur. J. Immunol. 1999 Sep; 29(9): 2968-80. PMID: 10508271, PII: 10.1002/(SICI)1521-4141(199909)29:09<2968::AID-IMMU2968>3.0.CO;2-X, DOI: 10.1002/(SICI)1521-4141(199909)29:09<2968::AID-IMMU2968>3.0.CO;2-X, ISSN: 0014-2980.

Major AS, Rubin DH, Cuff CF. Mucosal immunity to reovirus infection. Curr. Top. Microbiol. Immunol. 1998; 233(Pt 2): 163-77. PMID: 9599937, ISSN: 0070-217X.

Chen D, Lee F, Cebra JJ, Rubin DH. Predominant T-cell receptor Vbeta usage of intraepithelial lymphocytes during the immune response to enteric reovirus infection. J. Virol. 1997 May; 71(5): 3431-6. PMID: 9094613, PMCID: PMC191488, ISSN: 0022-538X.

Taterka J, Cebra JJ, Rubin DH. Characterization of cytotoxic cells from reovirus-infected SCID mice: activated cells express natural killer- and lymphokine-activated killer-like activity but fail to clear infection. J. Virol. 1995 Jun; 69(6): 3910-4. PMID: 7745745, PMCID: PMC189116, ISSN: 0022-538X.

Cuff CF, Rubin DH, Cebra JJ. Development, function, and trafficking of mucosal leukocytes in immunodeficient mice. Adv. Exp. Med. Biol. 1995; 371B: 719-24. PMID: 7502884, ISSN: 0065-2598.

Taterka J, Sutcliffe M, Rubin DH. Selective reovirus infection of murine hepatocarcinoma cells during cell division. A model of viral liver infection. J. Clin. Invest. 1994 Jul; 94(1): 353-60. PMID: 8040276, PMCID: PMC296316, DOI: 10.1172/JCI117329, ISSN: 0021-9738.

Hooper DC, Rubin DH, Cebra JJ. Spontaneous proliferation of Peyer's patch cells in vitro. Int. Immunol. 1994 Jun; 6(6): 873-80. PMID: 8086375, ISSN: 0953-8178.

Cuff CF, Cebra CK, Rubin DH, Cebra JJ. Developmental relationship between cytotoxic alpha/beta T cell receptor-positive intraepithelial lymphocytes and Peyer's patch lymphocytes. Eur. J. Immunol. 1993 Jun; 23(6): 1333-9. PMID: 8388798, DOI: 10.1002/eji.1830230622, ISSN: 0014-2980.

Rubin DH, Wetzel JD, Williams WV, Cohen JA, Dworkin C, Dermody TS. Binding of type 3 reovirus by a domain of the sigma 1 protein important for hemagglutination leads to infection of murine erythroleukemia cells. J. Clin. Invest. 1992 Dec; 90(6): 2536-42. PMID: 1281838, PMCID: PMC443412, DOI: 10.1172/JCI116147, ISSN: 0021-9738.

Taterka JA, Cuff CF, Rubin DH. Viral gastrointestinal infections. Gastroenterol. Clin. North Am. 1992 Jun; 21(2): 303-30. PMID: 1324891, ISSN: 0889-8553.

Rubin DH, Weiner DB, Dworkin C, Greene MI, Maul GG, Williams WV. Receptor utilization by reovirus type 3: distinct binding sites on thymoma and fibroblast cell lines result in differential compartmentalization of virions. Microb. Pathog. 1992 May; 12(5): 351-65. PMID: 1501574, PII: 0882-4010(92)90098-9, ISSN: 0882-4010.

Williams WV, Weiner DB, Borofsky MA, Rubin DH, Yui K, Greene MI. Modulation of T cell responses with MHC-derived peptides. Immunol. Res. 1992; 11(1): 11-23. PMID: 1602179, ISSN: 0257-277X.

Williams WV, Kieber-Emmons T, Weiner DB, Rubin DH, Greene MI. Contact residues and predicted structure of the reovirus type 3-receptor interaction. J. Biol. Chem. 1991 May 5/15/1991; 266(14): 9241-50. PMID: 1709165, ISSN: 0021-9258.

Cebra JJ, Cuff CF, Rubin DH. Relationship between alpha/beta T cell receptor/CD8+ precursors for cytotoxic T lymphocytes in the murine Peyer's patches and the intraepithelial compartment probed by oral infection with reovirus. Immunol. Res. 1991; 10(3-4): 321-3. PMID: 1659604, ISSN: 0257-277X.

Cuff CF, Cebra CK, Lavi E, Molowitz EH, Rubin DH, Cebra JJ. Protection of neonatal mice from fatal reovirus infection by immune serum and gut derived lymphocytes. Adv. Exp. Med. Biol. 1991; 310: 307-15. PMID: 1667070, ISSN: 0065-2598.

Piccoli DA, Witzleben CL, Guico CJ, Morrison A, Rubin DH. Synergism between hepatic injuries and a nonhepatotropic reovirus in mice. Enhanced hepatic infection and death. J. Clin. Invest. 1990 Oct; 86(4): 1038-45. PMID: 2170443, PMCID: PMC296830, DOI: 10.1172/JCI114806, ISSN: 0021-9738.

Rubin DH, Morrison AH, Witzleben CL, Guico CJ, Piccoli DA. Site of reovirus replication in liver is determined by the type of hepatocellular insult. J. Virol. 1990 Sep; 64(9): 4593-7. PMID: 2166834, PMCID: PMC247936, ISSN: 0022-538X.

London SD, Cebra-Thomas JA, Rubin DH, Cebra JJ. CD8 lymphocyte subpopulations in Peyer's patches induced by reovirus serotype 1 infection. J. Immunol. 1990 Apr 4/15/1990; 144(8): 3187-94. PMID: 2157763, ISSN: 0022-1767.

George A, Kost SI, Witzleben CL, Cebra JJ, Rubin DH. Reovirus-induced liver disease in severe combined immunodeficient (SCID) mice. A model for the study of viral infection, pathogenesis, and clearance. J. Exp. Med. 1990 Mar 3/1/1990; 171(3): 929-34. PMID: 2155280, PMCID: PMC2187778, ISSN: 0022-1007.

Cuff CF, Lavi E, Cebra CK, Cebra JJ, Rubin DH. Passive immunity to fatal reovirus serotype 3-induced meningoencephalitis mediated by both secretory and transplacental factors in neonatal mice. J. Virol. 1990 Mar; 64(3): 1256-63. PMID: 2154608, PMCID: PMC249241, ISSN: 0022-538X.

Rubin DH, Bauman LJ, Lauby JL. The relationship between knowledge and reported behavior in childhood asthma. J Dev Behav Pediatr. 1989 Dec; 10(6): 307-12. PMID: 2689468, ISSN: 0196-206X.

Weisenthal RW, Sinclair SH, Frank I, Rubin DH. Long-term outpatient treatment of CMV retinitis with ganciclovir in AIDS patients. Br J Ophthalmol. 1989 Dec; 73(12): 996-1001. PMID: 2558708, PMCID: PMC1041953, ISSN: 0007-1161.

Williams WV, London SD, Weiner DB, Wadsworth S, Berzofsky JA, Robey F, Rubin DH, Greene MI. Immune response to a molecularly defined internal image idiotope. J. Immunol. 1989 Jun 6/15/1989; 142(12): 4392-400. PMID: 2786032, ISSN: 0022-1767.

London SD, Cebra JJ, Rubin DH. Intraepithelial lymphocytes contain virus-specific, MHC-restricted cytotoxic cell precursors after gut mucosal immunization with reovirus serotype 1/Lang. Reg Immunol. 1989 Mar; 2(2): 98-102. PMID: 2577122, ISSN: 0896-0623.

Cebra JJ, Cebra-Thomas JA, Cuff CF, George A, Kost SI, London SD, Rubin DH. Reoviruses as probes of the gut mucosal T cell population. Immunol. Invest. 1989 Jan; 18(1-4): 545-58. PMID: 2543626, ISSN: 0882-0139.

London SD, Cebra JJ, Rubin DH. The reovirus-specific cytotoxic T cell response is not restricted to serotypically unique epitopes associated with the virus hemagglutinin. Microb. Pathog. 1989 Jan; 6(1): 43-50. PMID: 2471913, PII: 0882-4010(89)90006-5, ISSN: 0882-4010.

Williams WV, Guy HR, Rubin DH, Robey F, Myers JN, Kieber-Emmons T, Weiner DB, Greene MI. Sequences of the cell-attachment sites of reovirus type 3 and its anti-idiotypic/antireceptor antibody: modeling of their three-dimensional structures. Proc. Natl. Acad. Sci. U.S.A. 1988 Sep; 85(17): 6488-92. PMID: 2457914, PMCID: PMC281998, ISSN: 0027-8424.

Weiner DB, Girard K, Williams WV, McPhillips T, Rubin DH. Reovirus type 1 and type 3 differ in their binding to isolated intestinal epithelial cells. Microb. Pathog. 1988 Jul; 5(1): 29-40. PMID: 3072462, PII: 0882-4010(88)90078-2, ISSN: 0882-4010.

Kaljot KT, Shaw RD, Rubin DH, Greenberg HB. Infectious rotavirus enters cells by direct cell membrane penetration, not by endocytosis. J. Virol. 1988 Apr; 62(4): 1136-44. PMID: 2831376, PMCID: PMC253121, ISSN: 0022-538X.

Cebra JJ, Cebra ER, Cebra-Thomas JA, George A, Lebman DA, London SD, Rubin DH, Schweitzer PA. Specific and nonspecific perturbations of B- and T-cell subsets in Peyer's patches. Monogr Allergy. 1988; 24: 173-80. PMID: 3129647, ISSN: 0077-0760.

Rubin DH, Costello T, Witzleben CL, Greene MI. Transport of infectious reovirus into bile: class II major histocompatibility antigen-bearing cells determine reovirus transport. J. Virol. 1987 Oct; 61(10): 3222-6. PMID: 3476756, PMCID: PMC255901, ISSN: 0022-538X.

Rubin DH. Reovirus serotype 1 binds to the basolateral membrane of intestinal epithelial cells. Microb. Pathog. 1987 Sep; 3(3): 215-9. PMID: 3504220, PII: 0882-4010(87)90098-2, ISSN: 0882-4010.

London SD, Rubin DH, Cebra JJ. Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches. J. Exp. Med. 1987 Mar 3/1/1987; 165(3): 830-47. PMID: 2950199, PMCID: PMC2188298, ISSN: 0022-1007.

London SD, Rubin DH, Cebra JJ. Murine Peyer's patches are capable of generating a cytotoxic T cell (CTL) response to nominal antigens. Adv. Exp. Med. Biol. 1987; 216A: 267-78. PMID: 2891243, ISSN: 0065-2598.

Rubin DH, Eaton MA, Costello T. Reovirus type 1 is secreted into the bile. J. Virol. 1986 Nov; 60(2): 726-8. PMID: 3022004, PMCID: PMC288947, ISSN: 0022-538X.

Rubin DH, Eaton MA, Anderson AO. Reovirus infection in adult mice: the virus hemagglutinin determines the site of intestinal disease. Microb. Pathog. 1986 Feb; 1(1): 79-87. PMID: 2854595, PII: 0882-4010(86)90034-3, ISSN: 0882-4010.

Rubin DH, Kornstein MJ, Anderson AO. Reovirus serotype 1 intestinal infection: a novel replicative cycle with ileal disease. J. Virol. 1985 Feb; 53(2): 391-8. PMID: 2982027, PMCID: PMC254649, ISSN: 0022-538X.

Anderson AO, MacDonald TT, Rubin DH. Effect of orally administered avridine on enteric antigen uptake and mucosal immunity. Int. J. Immunother. 1985; 1: 107-15.

Twist EM, Kolonich K, Rubin DH. Propagation of rotaviruses in the presence of chicken serum. J. Gen. Virol. 1984 Jul; 65 ( Pt 7): 1207-10. PMID: 6086811, DOI: 10.1099/0022-1317-65-7-1207, ISSN: 0022-1317.

Abramczuk J, Vorbrodt A, Rubin DH, Fields BN, Koprowski H. Interactions of preimplantation mouse embryos with reovirus serotypes 1 and 3. Infect. Immun. 1983 Oct; 42(1): 301-7. PMID: 6311748, PMCID: PMC264558, ISSN: 0019-9567.

Offit PA, Rubin DH. Viral diseases: infections of the gastrointestinal tract. Compr Ther. 1982 Aug; 8(8): 21-6. PMID: 6290133, ISSN: 0098-8243.

Hrdy DB, Rubin DH, Fields BN. Molecular basis of reovirus neurovirulence: role of the M2 gene in avirulence. Proc. Natl. Acad. Sci. U.S.A. 1982 Feb; 79(4): 1298-302. PMID: 6951176, PMCID: PMC345950, ISSN: 0027-8424.

Rubin D, Weiner HL, Fields BN, Greene MI. Immunologic tolerance after oral administration of reovirus: requirement for two viral gene products for tolerance induction. J. Immunol. 1981 Oct; 127(4): 1697-701. PMID: 6974200, ISSN: 0022-1767.

Wolf JL, Rubin DH, Finberg R, Kauffman RS, Sharpe AH, Trier JS, Fields BN. Intestinal M cells: a pathway for entry of reovirus into the host. Science. 1981 Apr 4/24/1981; 212(4493): 471-2. PMID: 6259737, ISSN: 0036-8075.

Rubin DH, Fields BN. Molecular basis of reovirus virulence. Role of the M2 gene. J. Exp. Med. 1980 Oct 10/1/1980; 152(4): 853-68. PMID: 7420022, PMCID: PMC2185979, ISSN: 0022-1007.