While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10. Author summary Middle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient type I and III interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. Meanwhile, a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes was observed along the whole respiratory mucosa with a rapid clearance of the virus in tissues. Thus, innate immune responses occurring in the nasal mucosa might be key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.
【초록키워드】 viral infection, Cytokine storm, innate immune response, Inflammatory responses, Vaccines, Transcription, Infection, interferon, lung, virus, MERS-CoV, chemokine, antiviral drug, Asymptomatic, humans, Respiratory disease, Asymptomatic carriers, understanding, Mild, IFN, respiratory tract, Adaptive immune response, disease, expression, interferon response, nasal mucosa, ISGs, ISG, NF-κB, CCL3, leukocytes, infiltration, Infectious virus, Middle East, Type III IFN, mucosa, clinical manifestation, leukocyte, immune response gene, Simultaneous, Regulation, tissue damage, tissues, CCL2, virus clearance, type I, transcriptional regulation, syndrome, high mortality, upregulation, pro-inflammatory cytokine, etiological agent, Concomitant, respiratory syndrome coronavirus, anti-inflammatory effect, MERS-CoV infection, IL10, reservoir, clearance, lethal disease, while, driving, triggering, anti-inflammatory cytokine, Host, effective, post inoculation, stimulated, contribute, correlated, transcribed, elicited, immunological pathway, interferons (IFNs, pro-inflammatory gene, provoke, 【제목키워드】 Inflammation, nasal, IFN, MERS-CoV infection, epithelia, feature, produced, Type,