Phylogenetic and experimental reconstruction of zoonotic transmission of human coronaviruses

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Coronaviruses have received considerable attention since the emergence of SARS-CoV in China 2002/2003. SARS-CoV infection in people exemplified that coronaviruses can cross the species barrier from an animal reservoir to humans and cause severe and lethal disease in humans. Theemergence of MERS-CoV in 2012 showed that zoonotic transmission of coronaviruses is not a rare event. Both viruses have close relatives in bats, and moreover, intermediate hosts, such asracoon dogs, civet cats (SARS-CoV) and dromedary camels (MERS-CoV) have been proposed to facilitate zoonotic transmission. The discovery that dromedary camels harbour MERS-CoV and may act as a bridge reservoir between bats and humans provides an important paradigm for the ecology of viral emergence. Interestingly, the human coronavirus 229E (HCoV-229E; causing common cold in humans), appears to have a similar history of zoonotic transmission, since close relatives were detected in bats as well as in camelid species (alpacas and dromedary camels). While MERS-CoV has a very recent history of zoonotic transmission and differences between viruses isolated from humans and camels are rather small, camel-229E-like-CoV and HCoV-229E have already diverged considerably.The aim of the proposed project is to identify and characterize critical species barriers of CoV zoonotic transmission by using the HCoV-229E system as a model. We will analyse species barriers at the virus entry step (spike-receptor interaction) and during intracellular replication. Importantly, our studies involve bat- camel- and human 229E viruses and primary airway epithelial cultures of their authentic hosts, allowing us to mimic cross-species infection of the upper airways. Specifically, we will focus on:(a) host determinants of cross species transmission, namely innate immune responses (type I interferon system), and we will assess if non-coding RNAs (long non-coding RNA and micro-RNAs) may constitute a critical species barrier, and(b) virus determinants of cross species transmission by following virus adaptation to a new host, and identification of genomic regions/viral domains that are most volatile during adaptation. Relevance: Bats have been shown to harbour a wide variety of diverse CoV species, including close relatives of human coronaviruses (HCoV-229E, SARS-CoV, MERS-CoV). Therefore it is important to define critical virus-host interactions that impact on cross-species transmission. The availability of several full-length bat-229E-like-CoV genome sequences, the discovery of a camel-229E-like-CoV, and the availability of primary epithelial target cells from the authentic hosts offers an unprecedented opportunity to study critical species barriers for the zoonotic transmission of CoVs. This information is extremely valuable to assess the risk of possible future zoonotic transmissions and provide a conceptional framework for efficacious antiviral intervention.