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. 2018 Jul 16;8(1):10727.
doi: 10.1038/s41598-018-28900-1.

A spike-modified Middle East respiratory syndrome coronavirus (MERS-CoV) infectious clone elicits mild respiratory disease in infected rhesus macaques

Adam S Cockrell  1 , Joshua C Johnson  2 , Ian N Moore  3 , David X Liu  2 , Kevin W Bock  3 , Madeline G Douglas  4 , Rachel L Graham  4 , Jeffrey Solomon  5 , Lisa Torzewski  2 , Christopher Bartos  2 , Randy Hart  2 , Ralph S Baric  6 , Reed F Johnson  7
Affiliations

A spike-modified Middle East respiratory syndrome coronavirus (MERS-CoV) infectious clone elicits mild respiratory disease in infected rhesus macaques

Adam S Cockrell et al. Sci Rep. .

Abstract

The recurrence of new human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) underscores the need for effective therapeutic countermeasures. Nonhuman primate models are considered the gold standard for preclinical evaluation of therapeutic countermeasures. However, MERS-CoV-induced severe respiratory disease in humans is associated with high viral loads in the lower respiratory tract, which may be difficult to achieve in nonhuman primate models. Considering this limitation, we wanted to ascertain the effectiveness of using a MERS-CoV infectious clone (icMERS-0) previously shown to replicate to higher titers than the wild-type EMC 2012 strain. We observed respiratory disease resulting from exposure to the icMERS-0 strain as measured by CT in rhesus monkeys with concomitant detection of virus antigen by immunohistochemistry. Overall, respiratory disease was mild and transient, resolving by day 30 post-infection. Although pulmonary disease was mild, these results demonstrate for the first time the utility of CT imaging to measure disease elicited by a MERS-CoV infectious clone system in nonhuman primate models.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Temperature and arterial O2 saturation. (a) Study animals did not develop fever or deviate outside of normal macaque temperature ranges. (b) Animals did not exhibit O2 saturation loss outside of normal macaque ranges. Normal ranges are depicted in beige.
Figure 2
Figure 2
Percent change in lung hyperdensity (PCLH). (a) Representative lung field (b) Lung consolidation depicted as the percentage of the volume of hyperdense voxels in the total lung volume for each icMERS virus exposed animal. *Day 5 for NHP6 was omitted due to improper endotracheal tube intubation for the imaging breadth hold. Solid and dotted black lines indicate the baseline mean and 3 SD range of the hyperdense volume from ic-MERS-0 exposed animals included in this study. Dotted red lines indicate the upper and lower method range limits of MERS exposed rhesus monkeys (n = 33).
Figure 3
Figure 3
Pulmonary pathology in rhesus macaques inoculated with MERS-0. (a) Diffuse, mild pulmonary congestion. NHP3 at day 5 of MERS post-inoculation. (b) Multifocal, mild interstitial pneumonia characterized by type II pneumocyte hyperplasia and alveolar edema, fibrin and hemorrhage. NHP6 at day 5 of MERS post-inoculation. HE; (c) Multifocal alveolar emphysema containing small amount of eosinophilic to basophilic fibrillary material. NHP6 at day 5 of MERS post-inoculation. HE. (d) Day 30 H&E of lung demonstrating clearance of proteinaceous material and resolution of mild interstitial pneumonia.
Figure 4
Figure 4
Immunohistochemistry of MERS spike protein in the lung. (a) Rare MERS spike antigen positive pneumocytes (arrows) of NHP6 at day 5 pi. (b) Rare MERS spike antigen positive cells in the submucosal glands (arrow) and lymphoid aggregates (^) of NHP6 at day 5 pi; (c) Many epithelial cells (arrow) of submucosal glands in the bronchi and fewer cells in the BALTs (^) were positive for MERS spike antigen of NHP2 at day 30 pi. (d) Increased numbers of alveolar macrophages that are positive for CD26 and MERS-CoV on day 5 pi. (e) Reduced hyperplasia and fewer CD26+ cells and alveolar macrophages were present on day 30 pi.
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