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Ranjit Ray, Ph.D.

Professor
Infectious Diseases

Research Interests

My research activities for many years have focused on RNA viruses; specially on the molecular mechanisms of virus-host interactions, pathogenesis, and vaccine development. For the last several years, I have primarily focused on hepatitis C virus (HCV) related areas. Some of the highlights are listed below:

1. Immunomodulation by HCV: Innate immune function is an important arm of the protective immune response. We have shown that HCV-induced autophagy impairs the innate immune response. CD55 limits complement activation on the host cell surface by accelerating the decay of C3 convertases. We have shown that HCV core protein enhances cell surface expression of CD55 in hepatocytes and CD55 associates with purified HCC V particles, which may limit complement-mediated damage to infected cells and released virus. Natural killer (NK) cells and the complement system play critical roles in the first line of defense against pathogens. HCV subverts the ability of NK cells to positively mediate complement protein expression.

We have shown that cells endogenously expressing HCV proteins perturb HLA-DR cell surface expression. A deficiency in expression of HLA-DR molecules was associated with the negative regulation of CIITA, GAS, and the HLA-DR promoters at the transcriptional level, induction of interleukin-10 (IL-10) in monocyte derived DCs, and inhibition of DC-mediated antigen-specific T-cell activation. Interestingly, in our Phase I clinical trial with candidate subunit vaccine, IL-10 secretion by PBMCs, but not IL-12, was noted. Thus, the mechanisms of selective functional impairment of antigen presenting cells in response to HCV antigens remain to be identified.

2. Mechanisms of liver disease progression by hepatitis C virus (HCV): HCV often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used several experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these observations at the molecular level should aid in developing strategies for effective therapies against HCV mediated liver disease progression.

3. HCV vaccine development effort: Hepatitis C virus (HCV) infection is a major health problem. Direct acting antivirals (DAA) are an advancement for HCV treatment. However, HCV eradication does not eliminate the risk of HCC development, especially when the patients have more advanced fibrosis, indicating the necessity for developing HCC prevention therapies to improve patient prognosis. DAAs are unlikely to help in the development of a protective immune response to prevent reinfection. Thus, a prophylactic vaccine inducing both T- and B- cell responses is important and highly relevant to public health. We conducted a Phase I clinical trial in human

volunteers for safety and immunogenicity of recombinant HCV E1 and E2 glycoproteins at the Saint Louis University Vaccine and Treatment Evaluation Unit. Immunogenicity of the recombinant E1/E2 purified proteins was modest, only ~25% vaccine sera displayed a detectable virus neutralizing activity and antibody response did not correlate with the dose of the immunogen. Vaccinated individuals failed to exhibit a dose dependent immune response, and did not induce IL-12 expression. IL-12; in concert with antigen presenting cells, amplifies the induction of CD4+ T-helper cells, and directs cell mediated immune response. We need to identify the underlying mechanisms for this impairment of a strong protective immune response and resolve by selecting appropriate antigens for a candidate vaccine.

4. Respiratory virus (PIV/RSV) vaccine development: Human parainfluenza viruses (PIV) and respiratory syncytial virus (RSV) are leading causes of viral lower respiratory tract illness in children and in high-risk adult populations. Extensive research helped us in understanding the important viral components, their immunogenicity, and developing genetically engineered live attenuated candidate vaccines. Several of which are already being evaluated in preclinical and clinical trials, and should hasten the development of vaccines against these important respiratory pathogens. I have completed several important observations on vaccine development efforts, especially against PIV and RSV.

5. Understanding Ebola virus (EBOV) mediated pathogenesis and inhibitors of viral infection: Ebola is a rare and deadly disease caused by infection with a strain of Ebola virus. The 2014 Ebola epidemic is the largest in history, affecting multiple countries in West Africa. Ebola is spread through direct contact with blood and body fluids of a person already showing symptoms of Ebola. I have made significant observations on the pathological consequence of EBOV glycoprotein on endothelial cells. I also participated in identifying a novel series of benzodiazepine compounds as potential inhibitors of filoviral infection.

6. Recent research activity on Zika virus: We have uncovered potential mechanisms by which Zika virus induces human neural stem cell (hNSC) damage at an early developmental stage.

Publications and Media Placements

Selected Publications 

Sandip K. Bose, Keith Meyer, Adrian M. Di Bisceglie, Ratna B. Ray, and Ranjit Ray. 2012. Hepatitis C virus induces epithelial mesenchymal transition in primary human hepatocytes. J. Virol. 86:13621-13628.

Budhaditya Mazumdar, Hangeun Kim, Keith Meyer, Sandip K. Bose, Adrian M. Di Bisceglie, Ratna B. Ray, Michael S. Diamond, John P. Atkinson, Ranjit Ray. 2013. Hepatitis C virus infection upregulates CD55 expression on hepatocyte surface and promotes association with virus particles. J. Virol. 87, 7902-7910. PMCID: PMC3700207

Young-Chan Kwon, Hangeun Kim, Keith Meyer, Adrian M. Di Bisceglie, and Ranjit Ray. 2016. Distinct CD55 isoform synthesis and inhibition of complement dependent cytolysis by hepatitis C virus. J Immunol 197(4), 1127-36. PMID: 27357152.

Reina Sasaki, Pradip Devhare, Robert Steele, Ranjit Ray, and Ratna B. Ray. 2017. Hepatitis C virus induced CCL5 secretion from macrophages activates hepatic stellate cells. Hepatology. 66, 746-757 PMCID: PMC28318046

Reina Sasaki, Pradip Devhare, Ratna B. Ray, Ranjit Ray. 2017. Hepatitis C virus induced tumor initiating cancer stem-like cells activate stromal fibroblasts in xenograft tumor model. Hepatology, 66:1766-1778.

Pradip Devhare, Keith Meyer, Robert Steele, Ratna B. Ray, and Ranjit Ray. 2017. Zika virus infection dysregulates human neural stem cell growth and inhibits differentiation into neuroprogenitor cells. Cell Death & Disease, 8, e3106; doi:10.1038/cddis.2018.517. PMCID: PMC5682681

Y-C Kwon, Keith Meyer, Guangyong Peng, Soumya Chatterjee, Daniel F Hoft, and Ranjit Ray. 2019. Hepatitis C virus E2 envelope glycoprotein induces immunoregulatory phenotype in macrophages. Hepatology (in press). Feb 14. doi: 10.1002/hep.29843. [Epub ahead of print] PMID:29443378.

Complete list of published work in my bibliography (138 publications)