| Abstract: | In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 × 106 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission.In June of 2012, a novel betacoronavirus, associated with severe respiratory disease in humans emerged in the Middle East (1, 2), which is closely related to betacoronaviruses circulating in bats (3, 4). The first isolate of Middle East respiratory coronavirus (MERS-CoV) (5), HCoV-EMC/2012, was obtained from a patient with a fatal pneumonia and acute renal failure. To date, 107 additional human cases have been identified, of which 49 were fatal (6). Aside from cases in Saudi Arabia, Qatar, Jordan, and the United Arab Emirates, imported cases have been identified in the United Kingdom, Germany, France, Tunisia, and Italy (6). Although no information is available on the source or route of primary transmission of MERS-CoV, human-to-human transmission has been recorded (7–9). Clinical data on human cases of MERS-CoV infection are currently sparse, but it appears that this virus mainly causes severe lower respiratory tract disease, occasionally accompanied by renal disease. The severity of disease distinguishes MERS-CoV from other coronaviruses circulating in the human population, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, which are generally associated with upper respiratory tract infections. Instead, MERS-CoV appears to be more similar to the severe respiratory disease caused by severe acute respiratory syndrome (SARS)-CoV.In vitro studies have shown that MERS-CoV replicates efficiently in nonciliated cells in the primary human airway epithelium (10), and in ex vivo human lung cultures MERS-CoV replicated in bronchial, bronchiolar, and alveolar epithelial cells (11), in line with the observed respiratory disease in humans. The recently defined receptor for MERS-CoV, dipeptidylpeptidase 4 (DPP4), is generally expressed in endothelial and epithelial cells and has been shown to be present on cultured human nonciliated bronchiolar epithelium cells (12), providing further information on the respiratory tropism of MERS-CoV.Animal models that recapitulate human disease are essential for understanding pathologic processes involved in disease progression. Moreover, these models are instrumental for the development of prophylactic and therapeutic countermeasures. We have previously shown that rhesus macaques inoculated with a high dose of MERS-CoV isolate HCoV-EMC/2012 developed a respiratory disease reminiscent of that observed in humans (13). To increase our understanding of the pathogenesis of MERS-CoV in the absence of clinical and pathological data from human patients, we present herein a more detailed analysis of the extent of virus replication, the histopathological changes in the respiratory tract and changes in systemic (peripheral blood mononuclear cell, PBMC) and local (lung tissue) gene expression of MERS-CoV–infected rhesus macaques. |
