Ling Wang, PhD

Faculty | Research/Scholarly Activities | Fellowship | ETSU Health: Infectious Disease Care

Associate Professor | Infectious, Inflammatory and Immunologic Disease

Graduate: Wuhan University, China, PhD, Molecular Biology, 2002; BS, 1995, Genetics
Postdoc: UNC at Chapel Hill, 2002-2007, Tumor Virology & Immunology
Research Associate: UNC at Chapel Hill, 2007-2009, Tumor Virology & Immunology
Research Scientist: University of Miami Sylvester Comprehensive Cancer Center, 2010-2014

RESEARCH INTERESTS

Chronic Viral Infection, Inflammation and Immunity, and Oncogenesis

Her research interests include host innate immune deregulation and chronic viral pathogenesis, with the focus on HIV-related, KSHV- and EBV-triggered oncogenic signaling pathways that play essential roles in angiogenesis and immune evasion in cell culture and mouse models. KSHV and EBV are close in the herpesvirus family, and both are carcinogens that cause malignancies in the setting of HIV coinfection. In recent years, I have also been conducting similar research on HIV and HCV using clinical samples. Elucidation of the mechanisms underlying the interaction of persistent viral infections with host innate immune system would advance our understanding of virus-associated chronic diseases including cancers, which account for 20% of all cancers worldwide.

1. The role of KSHV K1 in oncogenesis. KSHV is a gammaherpesvirus which is associated with KS, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). It is also associated with HIV. I have worked on KSHV K1 from 2003 to 2009. I have found that K1 signaling may contribute to KSHV-associated pathogenesis through a paracrine mechanism by promoting the secretion of VEGF and MMP-9 into the surrounding matrix. In the next project, I have found that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. Further, I have found that KSHV infection of endothelial cells modulates cell signaling pathways and induces cell survival and angiogenesis, and thereby contributes to KSHV-induced pathogenesis.

2. Interaction between host innate immune system and EBV in oncogenesis. Nucleic acids derived from pathogens or from certain cellular conditions represent a large category of Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which are recognized by different cellular pathogen recognition receptors (PRRs) and trigger production of type I interferons (IFN-I) and pro-inflammatory cytokines, by specifically binding to intracellular Toll-like receptors or cytosolic receptors. These cytosolic receptors, which are not related to TLRs and we call them “Toll-free” receptors, include the RNA-sensing RIG-I like receptors (RLRs), and the DNA-sensing HIN200 family and cGAS, amongst others. Viruses, exemplified by EBV, have evolved myriad strategies to evoke both host cellular and viral factors to evade IFN-I-mediated innate immune responses, to facilitate their infection, replication, and establishment of latency. We have published a series of papers on the interaction between EBV and IRF7/4-mediated innate immune responses in EBV latency. We are now moving forward to the cGAS-STING pathway, which seems to be a crucial IFN-mediated innate immune pathway in oncogenesis.

3. Immune evasion in chronic HIV/HCV infection. Immune exhaustion and senescence, and chronic inflammation, are exhibited in both HCV and HIV-infected patients. I am interested in the underlying mechanisms, including immunocyte responses and their negative regulation by MDSC and miRNAs.

Representative Publications

1.Wang L, Howell M, Sparks-Wallace A, Hawkins C, Nicksic C, Kohne C, Moorman J, Yao Z, Ning S. p62-mediated Selective Autophagy Endows Virus-transformed Cells with Insusceptibility to DNA Damage under Oxidative Stress. PLoS Pathogens. 2019. 15(4): e1007541. PMID: 31017975

2. Lam Nhat Nguyen, Juan Zhao, Dechao Cao, Xindi Dang, Ling Wang, Jianqi Lian, Ying Zhang, Zhansheng Jia, Xiao Y. Wu, Zheng Morrison, Qian Xie, Yingjie Ji, Zheng Zhang, Mohamed El Gazzar, Shunbin Ning, Jonathan P. Moorman, and Zhi Q. Yao. Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection. Cell Death and Diseases. 2018. 9:900 DOI 10.1038/s41419-018-0897-y.

3. Lin Wang, Dechao Cao, Ling Wang, Juan Zhao, Lam Nguyen, Xindi Dang, Yingjie Ji, Xiao Wu, Zheng Morrison, Qian Xie, Mohamed Elgazzar, Shunbin Ning, and Jonathan moorman, Zhi Q. Yao. HCV-associated exosomes promote myeloid-derived suppressor cell expansion via inhibiting miR-124 to regulate T follicular cell differentiation and function. Cell Discovery. 2018. In press

4. Zhao J, Dang X, Zhang P, Nguyan L, Cao D, Wang L, Wu X, Morrison Z, Zhang Y, Jia Z, Xie Q, Wang L, Ning S, El Gazzar M, Moorman J, Yao Z. Insufficiency of DNA repair enzyme ATM promotes naïve CD4 T cell loss in chronic hepatitis C virus infection. Cell Discovery. 2018. 4(16): doi:10.1038/s41421-018-0015-4

5. Wang L, Howell M, McPeak B, Riggs K, Kohne C, Yohanon J.-U., Foxler DE, Sharp TV, Moorman JP, Yao ZQ, Ning S. LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death. Oncotarget. 2018. 9(5):6282-6297. PMID: 29464072. DOI: doi.org/10.18632/oncotarget.23676.

6. Ning S. Wang L*. Identification of PP1 as the First Phosphatase for IRF7. Journal of Cell Signaling. 2017. 2: 146. Full-text PDF.

7. Zhou J, Yang X, Ning S, Wang L, Wang K, Zhang Y, Yuan F, Li F, Zhuo D, Tang L, Zhuo D. Identification of KANSARL as the First Cancer Predisposition Fusion Gene Specific to the Population of European Ancestry Origin. Oncotarget. 2017. 8:50594-50607 PMCID: PMC5584173 (Highlighted at RNA-Seq blog).

8. Wang L, Wang Y, Zhao J, Ren J, Hall KH, Moorman JP, Yao ZQ, Ning S*. LUBAC modulates LMP1 activation of NFκB and IRF7. Journal of Virology. 2017. 91(4): e1138-16. PMID: 27903798

9. Wang L, Ren J, Li G, Moorman JP, Yao ZQ, Ning S. LMP1 Signaling Pathway Activates IRF4 in Latent EBV Infection and A Positive Circuit between PI3K and Src Is Required. Oncogene. 2017. 36(16):2265-2274. PMID: 27819673

10. Ren JP, Wang L, Zhao J, Wang L, Ning S, El Gazzar M, Moorman JP, Yao ZQ. Decline of miR-124 in myeloid cells promotes regulatory T-cell development in hepatitis C virus infection. Immunology. 2017. 150(2):213-220. PMID: 27753084

11. Wang L, Zhao J, Ren J, Hall KH, Moorman JP, Yao ZQ, Ning S*. Protein Phosphatase 1 abrogates IRF7-mediated type I IFN response in antiviral immunity. European Journal of Immunology. 2016. 46(10):2409-2419. PMID: 27469204

12. Wang L, Zhao J, Ren JP, Wu XY, Morrison ZD, Elgazzar MA, Ning S, Moorman JP, Yao ZQ. Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AIDS. 2016. 30(10):1521-1531. PMID: 26959508.

13. Ning S, Wang L*. Inactivation of type I IFN Jak-STAT pathway in EBV latency. J. Can. Biol. Treat. 2016. 3: 009. Full Text

14. Zhou Y, Li GY, Ren JP, Wang L, Zhao J, Ning S, Zhang Y, Lian JQ, Huang CX, Jia ZS, Moorman JP, Yao ZQ. Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via ΔNp63-miR-181a-Sirt1 pathway. 2016. 100(5):1201-1211. PMID: 27354409

15. Ren J, Ying R, Cheng Y, Wang L, Elgazzar M, Li G, Ning S, Moorman J, Yao Z. HCV-induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T cell development. 2016. J Viral Hepat. 23(10):755-766. PMID: 27004559.

16. Ren, J; Zhao, J; Griffin, J ; Wang, L; Wu, X; Morrison, Z; Li, G; El Gazzar, M; Ning, S; Moorman, J; Yao, Z. Hepatitis C virus-induced myeloid-derived suppressor cells regulate T cell differentiation and function via the STAT3 pathway. Immunology. 2016. 148: 377-386. PMID: 27149428

17. Yuan F, Dutta T, Wang L, Song L, Gu L, Qian L, Benitez A, Ning S, Malhotra A, Deutscher MP, Zhang Y. Human DNA exonuclease TREX1 is also an exoribonuclease that acts on single-stranded RNA. J. Biol. Chem. 2015. 290(21):13344-53 PMID: 25855793.

18. Wang L, Yao Z, Jonathan M, Xu Y, Ning S. Gene expression profiling identifies IRF4-associated molecular signatures in hematological malignancies. PLoS One. 2014. 9(9):e106788. PMID: 25207815 19. Gretchen L. Bentz, Anjali Bheda-Malge, Ling Wang, Julia Shackelford, Blossom Damania, Joseph S. Pagano. KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation. 2014. Virology. 448: 293-302. PMID: 24314660

20. Wang L, Ning S. IRF4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells *. Journal of Virology. 2013. 87(17): 9672-9679. PMID: 23804646 * Chosen for “Spotlight “ by the editors

21. Roy D, Sin SH, Lucas A, Venkataramanan R, Wang L, Eason A, Chavakula V, Hilton IB, Tamburro KM, Damania B, Dittmer DP. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Research. 2013. 73(7): 2235-2246. PMID: 23382046

22. Gregory SM, Wang L, West JA, Dittmer DP, Damania B. Latent Kaposi's sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines. Journal of Virology. 2012. 86(7): 3916-3923. PMID: 22278234

23. Wang L, Toomey NL, Diaz LA, Walker G, Ramos JC, Barber GN, Ning S. Oncogenic IRFs provide a survival advantage for EBV- or HTLV1- transformed cells through induction of BIC expression. Journal of Virology. 2011. 85(16): 8328-8337. PMID: 21680528

24. Guilluy C, Zhang Z, Bhende PM, Sharek L, Wang L, Burridge K, Damania B. Latent KSHV Infection Increases the Vascular Permeability of Human Endothelial Cells. Blood. 2011. 118(9): 5344-5354. PMID: 21881052

25. Gonzalez CM, Wang L. and Damania B. KSHV encodes a deubiquitinating enzyme. Journal of Virology. 2009. 83(19):10224-10233. PMID: 19640989

26. O'Hara AJ., Wang L, Dezube B, Harrington WJ Jr, Damania B, Dittmer DP. Tumor suppressor micro RNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood. 2009. 113(23):5938-5941. PMID: 19252139

27. O'Hara AJ, Chugh P, Wang L, Netto E, Luz E, Harrington WJ, Dezube B, Damania B, Dittmer DP. Pre-Micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. Plos Pathogens. 2009. 5(4):1-14. PMID: 19381257

28. Wang L, Damania B. KSHV confers a survival advantage to endothelial cells. Cancer Research. 2008. 68(12): 4640-4648. PMID: 18559509. (Highlighted in Nature Reviews Cancer, 2008, 8: 569)

29. Nun TK, Kroll DJ, Oberlies NH, Soejarto DD, Case RJ, Piskaut P, Matainaho T, Hilscher C, Wang L, Dittmer DP, Gao SJ, Damania B. Development of a fluorescence-based assay to screen antiviral drugs against Kaposi’s sarcoma-associated herpesvirus. Molecular Cancer Therapeutics. 2007. 6(8): 2361-2370. PMID: 17699731

30. Sin SH, Roy D, Wang L, Staudt MR, Fakhari, FD, Patel DD, Henry D, Harrington WJ Jr, Damania B, Dittmer DP. Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood. 2007. 109 (5): 2165-2173. PMID: 17082322

31. Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B. Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. Cancer Research. 2006. 66(7):3658-3666. PMID: 16585191

32. Hong GK, Kumar P, Wang L, Damania B, Gulley ML, Delecluse HJ, Polverini PJ, Kenney SC. Epstein-Barr Virus Lytic Infection Is Required for Efficient Production of the Angiogenesis Factor Vascular Endothelial Growth Factor in Lymphoblastoid Cell Lines. Journal of Virology. 2005. 79(22):13984-13992. PMID: 16254334

33. Wang L, Wakisaka N, Tomlinson CC, DeWire SM, Krall S, Pagano J, Damania B. The Kaposi’s Sarcoma-Associated Herpesvirus (KSHV/HHV8) K1 Protein Induces Expression of Angiogenic and Invasion Factors. Cancer Research. 2004. 64(8): 2774-2781. PMID: 15087393

34. Ning S, Wang L*. The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers. Current Cancer Drug Targets. 2018. DOI: 10.2174/1568009618666181016164920. * Corresponding author

35. Ling Wang, Shunbin Ning. "Toll-free" pathways for production of type I interferons. AIMS Allergy and Immunology. 2017. 1(3): 143-163. PMID: 29202128 Free full text PDF

36. Ling Wang, Shunbin Ning. Viral and Cellular MicroRNAs in Regulation of EBV Latency and Oncogenesis. Herpersviridae. 2017. Chapter 3, 1-41. Avid Sciences. German. Free full text PDF

37. Ling Wang, Guangyu Li, Zhi Q. Yao, Jonathan Moorman, Shunbin Ning. MicroRNA regulation of viral immunity, latency, and carcinogenesis of selected tumor viruses and HIV. Reviews in Medical Virology. 2015. 25: 320-341. Aug 10. doi: 10.1002/rmv.1850. [Epub ahead of print]. PMID: 26258805

38. Wang L*, Zhao J, Schank M, Khanal S, Dang X, Cao D, Nguyen LNT, Zhang Y, Wu XY, Adkins JL, Brueggeman J, Zhang J, Ning S, El Gazzar M, Moorman JP, Yao ZQ*: Identification of virus-specific B-cell epitopes by convalescent plasma from COVID-19 patients. Molecular Immunology 2022, 152:215-223. https://doi.org/10.1016/j.molimm.2022.10.016. PMID: 36379129. * Corresponding authors

39. Wang L, Hensley CR, Howell ME, Ning S: Bioinformatics-Driven Identification of p62 as A Crucial Oncogene in Liver Cancer. Front Oncol 2022, 12:923009.10.3389/fonc.2022.923009 PMID: 35814476

40. Wang L, Lu Z, Zhao J, Schank M, Cao D, Dang X, Nguyen LN, Nguyen LNT, Khanal S, Zhang J, Wu XY, El Gazzar M, Ning S, Moorman JP, Yao ZQ: Selective oxidative stress induces dual damage to telomeres and mitochondria in human T cells. Aging Cell 2021, 20(12):e13513. PMID: 34752684

41. Wang L, Howell MEA, Sparks-Wallace A, Zhao J, Hensley CR, Nicksic CA, Horne SR, Mohr KB, Moorman JP, Yao, ZQ, Ning S. The Ubiquitin Sensor and Adaptor Protein p62 Mediates Signal Transduction of a Viral Oncogenic Pathway. mBio. 2021. 12(5):e0109721. PMID: 34488443

42. Wang L, Sparks-Wallace A, Casteel JL, Howell MEA, Ning S: Algorithm-Based Meta-Analysis Reveals the Mechanistic Interaction of the Tumor Suppressor LIMD1 With Non-Small-Cell Lung Carcinoma. Frontiers in Oncology 2021, 11(1031).10.3389/fonc.2021.632638 PMID: 33869018

43. Wang L, Zhao J, Nguyan LNT, Adkins JL, Schank M, Khanal S, Nguyen LN, Dang X, Cao D, Thakuri BKC, Lu Z, Zhang J, Zhang Y, Wu XY, Gazzar ME, Ning S, Moorman JP, Yao ZQ: Blockade of SARS-CoV-2 spike protein mediated cell-cell fusion using COVID-19 convalescent plasma. Scientific Reports 2021. 11: 5558. PMID: 33692386

Complete List of Relevant Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47809215/?sort=date&direction=descending