SARS-like WIV1-CoV poised for human emergence

Abstract

Outbreaks from zoonotic sources represent a threat to both human disease as well as the global economy. Despite a wealth of metagenomics studies, methods to leverage these datasets to identify future threats are underdeveloped. In this study, we describe an approach that combines existing metagenomics data with reverse genetics to engineer reagents to evaluate emergence and pathogenic potential of circulating zoonotic viruses. Focusing on the severe acute respiratory syndrome (SARS)-like viruses, the results indicate that the WIV1-coronavirus (CoV) cluster has the ability to directly infect and may undergo limited transmission in human populations. However, in vivo attenuation suggests additional adaptation is required for epidemic disease. Importantly, available SARS monoclonal antibodies offered success in limiting viral infection absent from available vaccine approaches. Together, the data highlight the utility of a platform to identify and prioritize prepandemic strains harbored in animal reservoirs and document the threat posed by WIV1-CoV for emergence in human populations.A lthough previously associated with upper respiratory infections, the emergence of severe acute respiratory coronavirus (SARS-CoV) in [2002][2003], and more recently, Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission leading to virulent pandemic viral infections (1, 2). Whereas prevailing research suggests that SARSCoV emerged from viruses in the Chinese horseshoe bat, identifying a progenitor strain that used human angiotensin converting enzyme 2 (ACE2) had proven elusive (3, 4). However, recent metagenomics studies isolated several SARS-like virus sequences that share ≥90% genome-wide homology and represented the closest sequences to the epidemic strains (5, 6). Importantly, researchers also isolated replication competent virus; WIV1-CoV, part of the Rs3306 cluster, could use ACE2 orthologs and mediated low-level replication in human cells (5). Overall, the evidence indicates that SARS-CoV likely emerged from Chinese horseshoe bats and that similar viruses are still harbored in these populations.The identification of WIV1-CoV and its capacity to use ACE2 orthologs offers a warning for possible reemergence and provides an opportunity to prepare for a future CoV outbreak. To achieve this goal, a new platform is required to translate metagenomics findings; the approach must generate critical diagnostic reagents, define emergence potential of novel strains, and determine efficacy of current therapeutics. Building on this premise, we developed a framework to examine circulating CoVs using reverse genetic systems to construct full-length and chimeric viruses. The results indicate that viruses using WIV1-CoV spike are poised to emerge in human populations due to efficient replication in primary human airway epithelial cell cultures. However, additional adaptation, potentially independent of the spike protein receptor-binding domain, is required for pathogenesis and epidemic disease. Importantly,...

Epigenetic Landscape during Coronavirus Infection

“…More recent studies have shown that SARS-CoV, as well as a large reservoir of SARS-like bat CoV (SL-CoV) have the ability to efficiently utilize the human angiotensin-converting enzyme 2 (ACE2) receptor for docking and entry and replicate efficiently in primary human airway epithelial cells. These data document the presence of a large animal reservoir of prepandemic SARS-like bat CoV that supports the possibility of direct bat-to-human transmission and recurrent outbreaks in the future [5,6,7]. …”

Structural insights into coronavirus entry

“…These viruses are HCoV-NL63 and HCoV-229E (α-CoVs) as well as HCoV-OC43 and HCoV-HKU1 (β-CoVs). Numerous SARS-CoV and MERS-CoV-like viruses currently circulate in bats and dromedaries making outbreaks of highly pathogenic human CoVs a global health threat (Ge et al, 2013;Haagmans et al, 2014;Hu et al, 2017;Menachery et al, 2015Menachery et al, , 2016Sabir et al, 2016).…”

Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes

“…MERS-CoV has infected at least 2100 people with a high mortality rate of 35% since 2012 (http://www.who.int/csr/ don/7-november-2017-mers-saudi-arabia/en/). Because of international travel and climate change, we cannot rule out the possibility of the emergence of additional highly pathogenic CoVs in the near future (Menachery et al, 2015(Menachery et al, , 2016. Thus, the development of antiviral drugs effective against CoVs is urgently needed.…”