Theresa L. Chang
- ADJUNCT ASSISTANT PROFESSOR Medicine, Infectious Diseases
Ph.D., New York University
Aaron Diamond AIDS Research Center, Rockefeller University
- Dr. Theresa Chang has been working on the molecular basis of virus-host interactions since she was a Ph.D student in Dr. Alice's Huang's Laboratory at NYU where she demonstrated the differential regulation of Vesicular Stomatitis Virus RNA transcription and replication by viral NS protein via cellular phosphatase. During her postdoctoral trainings at Yale University with Joan Steitz and Xin-Yuan Fu, she discovered that IL-4 blocked tumor cell proliferation through STAT1 activation. In Dr. John Moore’s laboratory, Dr. Chang demonstrated that that CD8 antiviral factors, found in long-term HIV-infected nonprogressors, inhibited HIV infection through STAT1 signaling pathway. Meanwhile, she discovered that RANTES, a ligand for CCR5 receptor, enhanced HIV infection by activation of MAP kinase through interaction with glycosaminoglycan. As a scientist at Osel, Inc. and a visiting scholar at Stanford University, she developed a co-culture system for bacteria and mammalian cells to demonstrate anti-HIV activity of a primary isolate of lactobacilli, commensal bacteria in the vaginal mucosa, engineered to express CD4. As a faulty at MSSM, she demonstrated the dual role of human alpha-defensin-1 (HNP for human neutrophil peptide) in anti-HIV immunity by acting on the virion and target cell. Similar to its anti-HIV effect on the target cell, HNP-1 inhibits influenza viral infection through suppression of PKC signaling pathway. Recently, my laboratory discovered human defensins 5 and 6 (HD5 and HD6), highly abundant in the gut and crucial for the control of bacteria pathogens, were induced in response to gonococcal (GC) infection in vitro and in the genital mucosa, resulting in an increase in HIV infectivity. We also found that GC infection enhanced HIV infection of resting CD4+ T cells through TLR2 activation.
Role of Defensins and TLR's in Viral Transmission and Pathogenesis
Our current studies focus on the role of defensins and TLRs in viral transmission and pathogenesis. Our hypothesis is that the innate response serves a double-edged sword in viral transmission in the settings of sexually transmitted infections (STIs). Innate effectors such as HNPs, the most antimicrobial peptides in neutrophils, inhibit HIV and influenza virus by interfering with cell signaling pathway(s). In contrast, human defensin 5 (HD5) and HD6, induced in cervicovaginal epithelial cells and the genital mucosa in response to STIs, significantly promote HIV infectivity. STIs such as Chlamydia and GC activate TLR2 and TLR4. We have recently demonstrated that GC enhances HIV infection of resting CD4+ T cells through TLR2 activation and that GC-mediated HIV enhancement is achieved via multiple mechanisms. Currently, we are investigating how innate immunity such as defensins and TLR activation influences viral infection and microbiota in the mucosa and how pathogens alter innate immunity and subsequently affect the result of viral infection. A proteomics and genomics approach followed by systems biology analysis will be taken. We will attempt to examine the role of innate immunity in STI-mediated enhancement of HIV transmission in vivo. Other current research projects include understanding the role of HNPs in host defense during chronic viral infection, dissecting the molecular mechanisms of HIV co-receptor switch in human peritoneal macrophages, and establishing a novel in vitro culture to study HIV-HCV co-infection in primary peritoneal macrophages from cirrhotic patients.
Ding J, Teleshova N, Rapista A, Jarvis GA, Klotman ME, Chang TL. Neisseria gonorrhoeae enhance HIV infection in primary resting CD4 + T cells through TLR 2 activation. J. Immunol 2010; 184: 2814-2824.
Chang TL, Klepper A, Ding J, Garber J, Rapista A, Mosoian A, Hubner W, Guterrez J, Walewski J, Abergel J, Schiano T, Branch A. Human peritoneal macrophages from ascitic fluid can be infected by a broad range of human immunodeficiency virus -tye 1 isolates.. J. AIDS 2010; 53: 292-302.
Chang TL, Ding J, Chou YY. Defensins in viral infection. J. Innate Immunity 2009; 1: 413-420.
Chang TL, Klotman ME, Rapista A, Teleshova A, Micsenyi A, Jarvis GA, Lu W, Porter E. Neisseria gonorrhoeae-induced human defensins 5 and 6 increase HIV infectivity: Role in enhanced transmission. J. Immunol 2008; 180: 6176-6185.
Chang TL, Teleshova N, Profy AT, Klotman ME. Inhibitory effect of PRO2000, a candidate microbicide, on dendritic cells-mediated HIV transfer. Antimicrob Agents Chemother 2008; 52: 1751-1758.
Chang T, Salvatore M, Garcia-Sastre A, Ruchala P, Lehrer RI, Klotman ME. Alpha-deensin inhibits influenza virus replication by cell-mediated mechanism(s).. J. Infectious Diseases 2007; 196(6): 835-846.
Chang TL, Klotman ME. Defensins in antiviral immunity. Nature Rev Immunol 2006; 6: 447-456.
Chang T, Vargas, Jr. J, Delportillo A, Klotman ME. Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. J. Clin Invest 2005; 115: 765-773.
Chang TL, Chang CC, Simpson DA, Xu Q, Martin PK, Lagenaur LA, Schoolnik FK, Ho DD, Hillier SL, Holodniy M, Lewicki JA, Lee PP. Inhinbitioin of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two- domain CD4. PNAS 2003; 100(6): 11672-11677.
Klotman ME, Chang TL, Mosoian A, Pine R, Moore JP. Soluble factor(s) secreted from CD8+T lymphocytes inhibits human immunodeficiency virus replication through STAT1 activiation. J. Virol 2002; 76: 569-581.
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Dr.Chang is not currently required to report Industry relationships.
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