Investigation on the role of human primary macrophages and dendritic cells in the pathogenesis of emerging viral pathogens

Abstract

In the past decade, there have been several global outbreaks of emerging and reemerging zoonotic viral diseases. Since late 2019, the Coronavirus Disease 2019 (COVID-19) pandemic has resulted in over 145 million confirmed cases with more than 3 million deaths globally. A novel human pathogenic coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the causative agent of COVID-19. Although various vaccines and repurposed antiviral drugs have been approved for emergency use, the pandemic remains a substantial public health threat. Zika virus (ZIKV), another emerging viral pathogen, is a mosquito-borne flavivirus. Since 2015, ZIKV has rapidly spread to over 87 countries and remains a potential risk of future epidemics. To date, there is no effective vaccines or antiviral treatment for ZIKV. Macrophages and dendritic cells are key antigen-presenting cells and play pivotal roles in the pathogenesis of virus infection. They are the front line of defense against viral infection acting as mediators of innate and adaptive immunity. On the other hand, they can also be targeted by invading viruses and serve as reservoirs for virus replication and dissemination. Prior to our studies, the roles of these sentinel cell types in the pathogenesis of SARS-CoV-2 and ZIKV, and the related underlying mechanisms remained unclear. In addition, SARS-CoV-2 was reported to be highly sensitive to type-I and -III IFN. However, the effects of type-II IFN on SARS-CoV-2 infection remained elusive. In our studies, we investigated the basic characteristics of SARS-CoV-2 and ZIKV in human primary monocyte-derived macrophages (MDMs) and dendritic cells (moDCs). Both MDMs and moDCs were permissive to SARS-CoV-2 infection but did not support productive virus replication. Importantly, SARS-CoV-2 infection did not upregulate any IFN response in both cell types, but triggered a significant high level of pro-inflammatory cytokine/chemokine expression in MDMs but not in moDCs. We further demonstrated that these attenuated host responses in moDCs were associated with viral antagonism of STAT1 phosphorylation. We next evaluated the effects of type-II IFN on SARS-CoV-2 infection. Our results demonstrated that type-II IFN potently inhibited SARS-CoV-2 infection in human lung epithelial cells and ex vivo human lung tissues. Mechanistically, the antiviral response of type-II IFN to SARS-CoV-2 was due to the IDO1-mediated signaling pathway. In contrast to SARS-CoV-2, ZIKV replication was largely restricted in MDMs but not in moDCs. The results illustrated that ZIKV infection in MDMs did not efficiently suppress type-I IFN-mediated antiviral responses and failed to inhibit STAT1 and STAT2 phosphorylation. Moreover, depletion of STAT2 but not STAT1 in MDMs significantly rescued ZIKV and yellow fever virus (YFV) replication, suggesting the importance of STAT2 in antiviral response. We further delineate the underlying mechanisms to explore the host determine factors involved in ZIKV replication. In this direction, we identified TMPRSS13 as a novel host dependency factor for efficient ZIKV replication by RNA-Seq and siRNA screening using ZIKV-infected MDMs and moDCs samples. Taken together, our studies advance the knowledge of SARS-CoV-2 and ZIKV pathogenesis and provide insights into developing therapeutic strategies against emerging virus infection.