 |
 |
 |
 |
 |
 |
 |
Member Information
Karuppiah Muthumani, Ph.D.
Research Assistant Professor, Department of Pathology and Laboratory Medicine
Office Phone: 215-746-8217
Office Fax: 215-573-9436
Email: muthuman@mail.med.upenn.edu
Website(s): http://www.med.upenn.edu/apps/faculty/index.php/g275/p15594
Education:
MS 1989 Madurai Kamaraj University, India
PhD 1996 Madurai Kamaraj University, India
PDF 1998-2002 University of Pennsylvania
Keywords: HIV-1 viral proteins Vpr and Nef, Chikungunya virus (CHIKV), Vaccine, Immune activation
Research and/or Clinical Interests:
Immunopathogenesis of HIV-1 viral proteins, Cellular and viral proteins interactions, Immune activation and viral replication, Vaccine and therapeutic development; Immunopathogenesis of Chikungunya virus
Summary:
Viral Immunopathogenesis
(a) Human Immunodeficiency virus (HIV): We focus on understanding the pathogenic interplay between HIV-1 and immune cells. Direct infection of immune cells by this virus leads to serious immunological and neurological complications that are often associated with disease progression. Our studies explore the molecular biology of the Vpr and Nef gene products including their mechanisms of action, interactions with host cell signaling proteins, modulation of T cell and APC function, regulation of apoptosis, cell cycle arrest, and modulation of NF-kB mediated immune regulation.
(b) Chikungunya Virus (CHIKV): Chikungunya virus (CHIKV) is a single stranded (+) sense RNA virus, which belongs to the genus Alphavirus of the Togaviridae family. It is transmitted to humans through mosquitoes. Human infection with CHIKV leads to the development of arthritic disease. However, the mechanisms behind the pathogenesis of this disease are poorly understood.
CHIKV does not replicate in primary lymphocytes, monocytes, or dendritic cells. However, replication in susceptible cells is cytopathic and associated with the induction of apoptosis. The following questions are being examined: (i) exploring the tropism of CHIKV and its replication characteristics; (ii) investigating the signals that alter host cell functions (ii) identifying the molecular mechanisms that underlie host receptor modifications that facilitate viral entry and (iii) we will focus on three particular highly relevant immune activation cascades, the Toll pathways as well as the p38 signaling pathway and the NF-kB/TNF activation pathway.
Immune activation and viral replication
As several steps of the viral life cycle are dependent upon the host cell cycle progression, modulation of immune activation represents a possible area of therapeutic treatment for HIV infection. In this way, it is proposed that viral replication may be effectively blocked due to incomplete reverse transcription and a lack of proviral DNA integration. Immune pathogenesis itself is suspected to play a major role in immune destruction by the virus. Our focuses include determining the mechanism by which cellular signaling is required for the virus and investigating the role of immune inhibitors in PD-1 regulation and viral replication. Furthermore, immune-related effects of inhibitors treatment are investigated in nonhuman primate models by assessing antigen-specific immune responses against simian immunodeficiency virus (SIV) Gag and Env, and surveying of specific immune markers including CTLA4, PD-1 and HLA-DR, known to be regulated during T cell exhaustion.
Gene therapy & vaccine development
Another major focus of our research is the development of DNA-based vaccines for HIV-1 and CHIKV. Chikungunya fever epidemics are sustained by human-mosquito-human transmission, with the epidemic cycle being similar to those of dengue and urban yellow fever. While the threat of a pandemic continues to engage the public’s attention, the peculiar problems associated with the more immediate and very real seasonal epidemics are also worthy of consideration. Significant advances in DNA vaccine technology have been made over the last several years. Currently, we are constructing novel, consensus-based vaccine constructs expressing patient-derived, virus-specific, CHIKV antigens capable of inducing broad immune responses. Additional efforts include the improvement of antigen expression, processing, and presentation. Insight gained from these studies will hopefully contribute to the development of vaccines and therapeutic treatments to CHIKV-associated disease.
Representative Publications:
Monis, M., Lee, B., Bailer, R.T., Luo, Q., and Montaner L.J. 2001. CCR5 and CXCR4 surface expression associated with X4 and R5 HIV-1 infection yet not replication in Th1 and Th2 cells. AIDS 15:1941-1949.
Muthumani K et al (2008). HIV-1 Nef induces Programmed Death (PD)-1 expression through a p38 MAPK dependent mechanism.J Virol.2008 82(23):11536-44.
Muthumani K et al (2008). Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine 26(40):5128-34.
Shedlock DJ, Hwang D, Choo AY, Chung CW, Muthumani K, Weiner DB. (2008). HIV-1 viral genes and mitochondrial apoptosis. Apoptosis. (9):1088-1099.
Chattergoon MA, Muthumani K et al (2008). DR5 activation of Caspase-8 induces DC maturation and immune enhancement in vivo. Molecular Therapy 16(2):419-426
Muthumani K et al (2006). The HIV-1 Vpr and glucocorticoid receptor complex is a gain of function interaction that prevents the nuclear localization of PARP-1. Nature Cell Biology 8(2): 170-179.
Muthumani K et al (2005). HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood 106(6):2059-2068.
Muthumani K et al (2005). HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro. International Immunology 17(2): 103-116.
Muthumani K. et al (2005). Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism. Cell Death Differentiation 1:962-970.
Muthumani K et al (2005). HIV-1 Viral protein-r (Vpr) protects against lethal superantigen challenge while maintaining homeostatic T cell levels in vivo. Molecular Therapy 12(5): 910-21.
Muthumani K et al (2004). Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor. AIDS 18(5):739-48
Muthumani K et al (2003). Mechanism of HIV-1 Viral protein R (Vpr) induced apoptosis. Biochemistry Biophysics Research Communication 304: 583-592.
Muthumani K et al (2002). HIV-1 Vpr Induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. Journal of Biological Chemistry 227(40): 37820-37831.
