It has become increasingly clear that (i) mucosal surfaces are important not only in the transmission but also the pathogenesis of lentiviral infections and (ii) development of the immune system at mucosal surfaces is shaped by interaction with the outside world. Our recent research synthesizes these findings and tests how the status of the mucosal immune system at the time of infection may impact upon the pathogenesis of lentiviral disease.
The development and composition of the mucosal immune system has previously been invoked to explain local damage by opportunistic pathogens, repair of normal damage to the mucosal barrier, and susceptibility to systemic autoimmune conditions. For instance, a 2006 publication in Science demonstrated that microbial colonization of mice triggers production of RegIIIγ, a bactericidal lectin that was later shown to mediate the early protective effects of IL-22 against Citrobacter rodentium, an attaching and effacing bacterial pathogen of mice (Cash et al., Science 313:1126, 2006 and Zheng et al., Nature Medicine 14:282, 2008). More recently, Mazmanian et al. showed that presence of the commensal organism, Bacteroides fragilis, protects mice from experimental colitis induced by Helicobacter hepaticus (Nature 453:620, 2008). Given these examples, we are curious if there might be substantial individual variability in intestinal immune cell populations that would affect the inflammatory stance of the host immune system and the subsequent progress of lentiviral infection. Such variability may also influence response to vaccinations or susceptibility to autoimmune disease.
Principal Investigator - Dennis Hartigan-O'Connor, M.D., Ph.D.
Title: Assistant Professor
Interests: Relationship between variable development of such immune cells and variable control over chronic infectious diseases. Interactions between the normal gut microflora, pathogenic organisms, and immune cells within the intestine.
Research Scientist - Amir Ardeshir, D.V.M., M.P.V.M, Ph.D.
Title: Clinical Veterinarian / Associate Scientist
Interest: Establishment of the gut communities (microbiota) in infancy and its role in programming the immune system.
Postdoctoral Fellow - Steven Laing, D.V.M, Ph.D.
Title: Veterinary Pathologist / Post-doc
Interest: Pathogenesis of inflammatory bowel disease
Postdoctoral Fellow - Gema Mendez Lagares,Ph.D.
Title: Postdoctoral Scholar
Interest: HIV/SIV infection
Graduate Student - Nicole Narayan
Title: Graduate Student, Integrative Genetics and Genomics
Interest: Gut microbiota interactions with the adaptive immune system
Graduate Student - David Merriam
Title: Graduate Student
Interest: Virus-host interactions in mucosal surfaces, Th17 cells and HIV
Undergraduate Student - Connie Chen
Title: Undergraduate, Microbiology
Interest: Immunology and Infectious Diseases
Staff- Ding Lu, M.S.
Title: Lab Manager
Interest: Pathogenesis of SIV, HIV and HCV infection and interactions between viruses and host immune systems
Staff- Justin H. Fontaine
Title: SRA - Immunology Core
Interest: Immunology/Virology/Molecular Biology
Former Staff - Jonathan LJ Liu
Title: Junior Specialist
Ardeshir A*, Narayan NR*, Méndez-Lagares G*, Lu D, Rauch M, Huang Yong, Van Rompay KKA, Lynch SV, Hartigan-O’Connor DJ. (2014) Breast-fed and bottle-fed infant rhesus macaque develop distinct gut microbiotas and immune systems. Sci. Transl. Med. Sept 3; 6:252.
Hartigan-O’Connor DJ, Lin D, Ryan JC, Shvachko VA, Cozen ML, Segal MR, Terrault NA, Lanier LL, Manos MM, McCune JM. (2014) Monocyte activation by interferon α is associated with failure to achieve a sustained virologic response after treatment for hepatitis C virus infection. J Infect Dis. May 15;209(10):1602-12.
Kanthaswamy S, Elfenbein HA, Ardeshir A, Ng J, Hyde D, Smith DG, Lerche N. (2014) Familial aggregation of chronic diarrhea disease (CDD) in rhesus macaques (Macaca mulatta). Am J Primatol. Mar;76(3):262-70.
Estell KE, Dawson DR, Magdesian KG, Swain E, Laing ST, Siso S, Mapes S, Pusterla N. Quantitative Molecular Viral Loads in Seven Horses with Naturally Occurring Equid Herpesvirus-1. (2014) Equine Vet J. In press.
Ramsey JJ, Tran D, Giorgio M, Griffey SM, Koehne A, Laing ST, Taylor SL, Kim K, Cortopassi GA, Lloyd KC, Hagopian K, Tomilov AA, Migliaccio E, Pelicci PG, McDonald RB. (2014) The Influence of Shc Proteins on Life Span in Mice. J Gerontol A Biol Sci Med Sci. In press.
Ardeshir A, Oslund KL, Ventimiglia F, Yee J, Lerche NW, Hyde DM. (2013) Idiopathic microscopic colitis of rhesus macaques: quantitative assessment of colonic mucosa. Anat Rec (Hoboken). Aug;296(8):1169-79
Tanaka T, Lerche NW, Farver TB, Ardeshir A, Kass PH. (2013) Specific-pathogen-free status is associated with lower infant mortality rate in rhesus macaque (Macaca mulatta) colonies at the California National Primate Research Center. J Med Primatol. Aug;42(4):186-91.
Lemoy MJ, Westworth DR, Ardeshir A, Tarara RP. (2013) Reference intervals for preprandial and postprandial serum bile acid in adult rhesus macaques (Macaca mulatta). J Am Assoc Lab Anim Sci. Jul;52(4):444-7.
Méndez-Lagares G*, Romero-Sánchez MC*, Ruiz-Mateos E, Genebat M, Ferrando-Martínez S, Muñoz-Fernández MA, Pacheco YM, Leal M. (2013) Long-Term Suppressive Combined Antiretroviral Treatment Does Not Normalize the Serum Level of Soluble CD14. J Infect Dis. Apr 15;207:1221.
G. Sasseville, J. L. Mankowski, A. Baldessari, C. Harbison, S. Laing, S. Kaliyaperumal, K. Mätz-Rensing, A. D. Miller, L. D. Schmidt, J. Kaplan-Kees, E. J. Dick, Jr, J. R. Reader, D. Liu, L. K. Crawford, J. H. Lane, S. M. Corner, I. D. Pardo, M. G. Evans, R. Murnane, and K. A. Terio. (2013) Meeting Report: Emerging Respiratory Viral Infections and Nonhuman Primate Case Reports. Veterinary Pathology. Nov;50(6):1145-53.
Laing ST, Sammak R, Lemoy MJ, Tarara R. (2013) Metastatic hepatocellular carcinoma in a juvenile Rhesus macaque (Macaca mulatta). Comparative Medicine. Oct; 63(5): 448-453.
Miller CN, Hartigan-O’Connor DJ, Lee MS, Laidlaw G, Cornelissen IP, Matloubian M, Coughlin SR, McDonald DM, McCune JM. (2013) IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. Int Immunol. Aug;25(8):471-83.
Laing ST, Weber ES, Yabsley MJ, Shock BC, Grosset C, Petritz OA, Barr B, Reilly CM, Lowenstine LJ. (2013) Fatal hepatic tetratrichomoniasis in a juvenile Waldrapp Ibis (Geronticus eremita). Journal of Veterinary Diagnostic Investigation. Mar; 25(2): 277-81.
Broadhurst MJ, Ardeshir A, Kanwar B, Mirpuri J, Gundra UM, Leung JM, Wiens KE, Vujkovic-Cvijin I, Kim CC, Yarovinsky F, Lerche NW, McCune JM, Loke P. (2012) Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon. PLoS Pathog. Nov;8(11):e1003000.
Briz V, García D, Méndez-Lagares G, Ruiz-Mateos E, de Mulder M, Moreno-Pérez D, Navarro ML, León JA, de José MI, Ramos JT, Mellado MJ, González-Tomé MI, Leal M and Muñoz-Fernández MA. (2012) High prevalence of X4/DM-tropic variants in children and adolescents infected with HIV-1 by vertical transmission. Pediatr Infect Dis J. Oct;31:1048.
Díaz L*, Méndez-Lagares G*, Correa-Rocha R, Pacheco YM, Ferrando-Martínez S, Ruiz-Mateos E, Del Mar Del Pozo-Balado M, León JA, Gurbindo MD, de José MI, Leal M, Muñoz-Fernández MA. (2012) Detectable viral load aggravates immunosenescence features of CD8 T-cell subsets in vertically HIV-infected children. J Acquir Immune Defic Syndr. Aug 15;60:447.
Méndez-Lagares G*, Díaz L*, Correa R, León JA, Ferrando-Martínez S, Ruiz-Mateos E, Pozo-Balado MM, Gurbindo MD, de José MI, Muñoz-Fernández MA, Leal M and Pacheco YM. (2012) Specific patterns of CD4-associated immunosenescence in vertically HIV-infected subjects. Clin Microbiol Infect. Jun;19:558.
Hartigan-O’Connor DJ, Abel K, Van Rompay KK, Kanwar B, McCune JM. (2012) SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment. Sci Transl Med. May 30;4(136):136ra69
Méndez-Lagares G, Pozo-Balado MM, Genebat M, García-Pergañeda A, Leal M and Pacheco YM. (2012) Severe immune dysregulation affects CD4+CD25hiFoxP3+ Regulatory T-cells in HIV-infected patients with low-level CD4 T-cell repopulation despite suppressive HAART. J Infect Dis. May 15;205:1501.
Méndez-Lagares G, García-Pergañeda A, Pozo-Balado MM, Genebat M, Ruiz-Mateos E, García-García M, Muñoz-Fernández MA, Pacheco YM and Leal M. (2012) Differential alterations of the CD4 and CD8 T-cell subsets in HIV-infected patients on highly active antiretroviral therapy with low CD4 T-cell restoration. J Antimicrob Chemother. May;67:1228.
Pulido I, Machmach K, Romero-Sánchez MC, Genebat M, Méndez-Lagares G, Ruiz-Mateos E, Leal M. (2012) T-cell changes after a short-term exposure to maraviroc in HIV-infected patients are related to antiviral activity. J Infect. Apr;64:417.
Laing ST, Ivens A, Butler V, Ravikumar SP, Laing R, Woods DJ, Gilleard JS. (2012) The transcriptional response of Caenorhabditis elegans to ivermectin exposure reveals novel genes involved in the response to reduced food intake. PLoS One. Feb 14;7(2):e31367.
*Authors contributed equally to this work.