A Mouse Model for Betacoronavirus Subgroup 2c Using a Bat Coronavirus Strain HKU5 Variant

Agnihothram, Sudhakar; Yount, Boyd L.; Donaldson, Eric F.; Huynh, Jeremy; Menachery, Vineet D.; Gralinski, Lisa E.; Graham, Rachel L.; Becker, Michelle M.; Tomar, Sakshi; Scobey, Trevor D.; Osswald, Heather L.; Whitmore, Alan; Gopal, Robin; Ghosh, Arun K.; Mesecar, Andrew; Zambon, Maria; Heise, Mark; Denison, Mark R.; Baric, Ralph S.

More recently, another ␤-CoV, called Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in the Middle East in April of 2012, causing pneumonia and ARDS, as well as renal failure in some patients (7, 8) . To date, MERS-CoV has spread to eight countries and has been implicated in 182 cases and 79 reported deaths, with mortality rates approaching 43%, especially in elderly patients (9) . MERS-CoV shares a close phylogenetic relationship with the Pipistrellus bat coronavirus (BtCoV) strain HKU5 and Tylonycteris BtCoV strain HKU4; all three viruses are classified in ␤-CoV subgroup 2c (see Fig. S1A in the supplemental material) (7, 10) . Bats can serve as reservoirs for circulating swarms of zoonotic viruses, and some are readily positioned to directly cross the species barrier and infect human populations (3, 4) . SARS-CoV is believed to have originated from closely related bat predecessor strains similar to BtCoV HKU3, although the exact precursor virus has not been identified (3, 4, 11) . While the zoonotic source of MERS-CoV remains unknown, recent reports identified the presence of ␤-CoVs with close amino acid similarity to MERS-CoV in Nycteris and Pipistrellus bat species (12, 13) . Another study described the close similarity of MERS-CoV to Bt-CoV HKU5; both of these homologous viruses share high degrees of amino acid sequence similarity across important replicase protein targets, such as the 3C-like protease (3CLpro; also known as nonstructural protein 5 [nsp5]) (82%), polymerase (92%), and proofreading exonuclease (91%), as well as the nucleocapsid (N) protein (68%) (7, 10) . A recent finding suggests that most of these proteins coevolve within subgroups of CoVs, making them attractive targets to test in models of closely related subgroups (14) .