Abstract
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.
Highlights
Middle East respiratory syndrome (MERS) is a disease caused by a zoonotic Coronavirus (MERS-CoV) that emerged in 2012 in the Kingdom of Saudi Arabia [1] raising a toll of 2,562 confirmed human cases in 27 countries, with 881 deaths until the November 2020 [2]
The severity of MERS lesions in humans has been attributed to aberrant innate and adaptive immune responses based essentially on data obtained from macrophages isolated from healthy donors or infected patients, as well as dosage of cytokines/chemokines from bronchoalveolar lavages
Some MERS-CoV African strains isolated from dromedary camels, as opposed to the Arabian human isolated EMC/2012 strain, can induce higher levels of IFNβ, IFNλ1, IFN stimulated genes (ISGs) and proinflammatory cytokines mRNA in Calu-3 cells after 48 h of infection [23]
Summary
Middle East respiratory syndrome (MERS) is a disease caused by a zoonotic Coronavirus (MERS-CoV) that emerged in 2012 in the Kingdom of Saudi Arabia [1] raising a toll of 2,562 confirmed human cases in 27 countries, with 881 deaths until the November 2020 [2]. The severity of MERS lesions in humans has been attributed to aberrant innate and adaptive immune responses based essentially on data obtained from macrophages isolated from healthy donors or infected patients, as well as dosage of cytokines/chemokines from bronchoalveolar lavages. The outcome of these studies reveals an overproduction of proinflammatory cytokines/chemokines due to the activation of C-type lectin receptors, RIG-I like receptors (RLRs) and an impaired production of type I interferons (IFN) [16,17,18,19]. It is postulated that when the viral burden is high and the mucosal fitness is broken, type I IFNs take over, leading to enhanced immune responses provoking uncontrolled pro-inflammatory responses [32]
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