Investigating the outcome of MERS-CoV infection in human peripheral blood mononuclear cells.

Dr Chu, Hin   (Principal Investigator (PI))

Professor Yuen Kwok Yung   (Co-Investigator)

12

2014-12-01

48048

Investigating the outcome of MERS-CoV infection in human peripheral blood mononuclear cells.

B cell, MERS-CoV, monocyte, PBMC, SARS-CoV, T cell

Virology,Microbiology

201409176024

Small Project Funding

2014

Completed

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) is the causative agent of the Middle East Respiratory Syndrome (MERS), which was first reported in 2012 and has since been causing sporadic infections in the human population. As of October 16th, 2014, 877 laboratory-confirmed cases of human infection with MERS-CoV have been reported to WHO, including at least 317 deaths. MERS-infected patients initiate with respiratory symptoms with high fever and may progress into multi-organ failure. Despite sharing similar clinical manifestations, the mortality rate of MERS (~35%) is dramatically higher than that of SARS (9.6%). The mechanism of such difference remains largely unknown. We have previously investigated the susceptibility of human primary monocyte-derived macrophages (MDMs) and monocyte-derived dendritic cells (Mo-DCs) to MERS-CoV and SARS-CoV infection. Importantly, our studies revealed that although MDMs and Mo-DCs were susceptible to infection by both viruses, the outcomes of infection by the two viruses were distinctly different. Specifically, while MERS-CoV productively replicated in MDMs and Mo-DCs, leading to a 2-to-4 log increase in viral genome expression, SARS-CoV-infection in MDMs and Mo-DCs were largely abortive. At the same time, MERS-CoV infection induced significantly higher levels of pro-inflammatory cytokines and chemokines in comparison to SARS-CoV-infected MDMs and Mo-DCs. Overall, our studies on MERS-CoV-infection in MDMs and Mo-DCs suggested that the productive replication of MERS-CoV in these cells types, accompanied by the elevated pro-inflammatory cytokine and chemokine, may contribute to the high mortality observed in MERS-CoV-infected patients. The broad spectrum of clinical features, the detection of extrapulmonary MERS-CoV, and the multi-organ involvement in MERS-CoV-infected patients suggested that this virus might have evolved strategies to evade the immune system and disseminate systematically by infecting the cells circulating the bloodstream. T cells, B cells, monocytes and NK cells are the major components of PBMC and play principal roles in host defence against pathogens. Ironically, these cell types are frequently targeted in viral infections. For instance, HIV targets CD4+ T cells and hijacks them as centers of replication as well as vehicles of dissemination. In this regard, it is of imminent importance to elucidate the role of the above-mentioned cells in MERS-CoV infections. Lymphopenia along with other haematological change are frequently reported in MERS-CoV-infected patients. Previous studies have suggested lymphopenia to be associated with severe infections, including infections caused by Bacillus anthracis, Yersinia pestis, and the Ebola virus. We will seek to investigate the mechanism and cause of lymphopenia in MERS-CoV-infected patients in the proposed study. Overall, to further our understanding in the interplay between MERS-CoV and the immune system, we plan to extend our study and investigate the interaction between MERS-CoV and other key components of the immune system, including T cells, B cells, monocytes and NK cells.