MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) presents an emerging threat to public health worldwide by causing severe respiratory disease in humans with high virulence and case fatality rate (about 35%) since 2012. Little is known about the pathogenesis and innate antiviral response in primary human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) upon MERS-CoV infection. In this study, we assessed MERS-CoV replication as well as induction of inflammatory cytokines and chemokines in MDMs and immature and mature MDDCs. Immature MDDCs and MDMs were permissive for MERS-CoV infection, while mature MDDCs were not, with stimulation of proinflammatory cytokine and chemokine upregulation in MDMs, but not in MDDCs. To further evaluate the antiviral activity of well-defined drugs in primary antigen presenting cells (APCs), three compounds (chloroquine, chlorpromazine and toremifine), each with broad-spectrum antiviral activity in immortalized cell lines, were evaluated in MDMs and MDDCs to determine their antiviral effect on MERS-CoV infection. While chloroquine was not active in these primary cells, chlorpromazine showed strong anti-MERS-CoV activity, but it was associated with high cytotoxicity narrowing the potential window for drug utilization. Unlike in established cells, toremifene had marginal activity when tested in antigen presenting cells, with high apparent cytotoxicity, also limiting its potential as a therapeutic option. These results demonstrate the value of testing drugs in primary cells, in addition to established cell lines, before initiating preclinical or clinical studies for MERS treatment and the importance of carefully assessing cytotoxicity in drug screen assays. Furthermore, these studies also highlight the role of APCs in stimulating a robust protective immune response to MERS-CoV infection.

A Systematic Review of therapeutic agents for the treatment of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

“…Toremifene, Chlorpromazine, and Chloroquine were evaluated using Vero cells, human monocyte-derived macrophages (MDMs) and immature dendritic cells (MDDCs) [41]. These drugs were transferred to cells 1 h prior to infection with MERS-CoV.…”

“…Toremifene reduced virus by 1-1.5 log10 at a dose more than 20 μM. Chlorpromazine reduced MERS-CoV by 2 log10 and had a narrow therapeutic window and a high toxicity [41]. Chloroquine, Chloropromazine, and loperamide were tested on Huh7 cells [43].…”

The risk factors associated with MERS-CoV patient fatality: A global survey

“…Coronaviruses are single-stranded positive-sense RNA viruses (Zumla et al 2015), with human pathogenic strains resulting in a common cold to a severe acute respiratory syndrome (Castaño-Rodriguez et al 2018). MERS-CoV, an emerging zoonotic virus (Alamoudi et al 2018;Cong et al 2018) is pathogenic in human, resulting in shortness of breath, cough, fever, diarrhea, and frequently pneumonia (Cong et al 2018;Sherbini et al 2017). The exact animal origin of MERS-CoV is not fully understood, but the transmission pattern and the evidence from virologic studies suggest that it may have originated in bats and was transmitted to camels sometime in the distant past (Hu et al 2015, Wang et al 2014.…”

MERS coronavirus outbreak: Implications for emerging viral infections

“…This was accompanied by initial steps of viral infection and replication, evidenced by increased N protein RNA in infected cells, but not by productive replication or viral amplification . Recent studies suggested that while mature MDDCs did not seem to be permissive to MERS-CoV infection, immature MDDCs were permissive but, unlike with macrophages, infection in vitro did not result in up-regulation of proinflammatory cytokine and chemokine production (Cong et al, 2018). As dendritic cells enter peripheral tissues and carry antigens to lymphoid tissues, it has been suggested that they may contribute to MERS-CoV dissemination by acting as vehicles, possibly explaining the isolation of MERS-CoV from specimens other than respiratory tract samples such as blood, stool, and urine from MERS-CoV infected patients Guery et al, 2013).…”