Origin and evolution of pathogenic coronaviruses!

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhea syndrome coronavirus (SADS-CoV) to pigs.

INTRODUCTION

Coronaviruses cause respiratory and intestinal infections in animals and humans¹. They were not considered to be highly pathogenic to humans until the outbreak of severe acute respiratory syndrome (SARS) in 2002 and 2003 in Guangdong province, China, as the coronaviruses that circulated before that time in humans mostly caused mild infections in immunocompetent people. Ten years after SARS, another highly pathogenic coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in Middle Eastern countries. SARS coronavirus (SARS-CoV) uses angiotensin-converting enzyme 2 (ACE2) as a receptor and primarily infects ciliated bronchial epithelial cells and type II pneumocytes, whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4; also known as CD26) as a receptor and infects unciliated bronchial epithelial cells and type II pneumocytes. SARS-CoV and MERS-CoV were transmitted directly to humans from market civets (see More Chinese push to end wildlife markets) and dromedary camels, respectively, and both viruses are thought to have originated in bats.

Extensive studies of these two important coronaviruses have not only led to a better understanding of coronavirus biology but have also been driving coronavirus discovery in bats globally. In this review, we focus on the origin and evolution of SARS-CoV and MERS-CoV. Specifically, we emphasize the ecological distribution, genetic diversity, interspecies transmission and potential for pathogenesis of SARS-related coronaviruses (SARSr-CoVs) and MERS-related coronaviruses (MERSr-CoVs) found in bats, as this information can help prepare countermeasures against future spillover and pathogenic infections in humans with novel coronaviruses.

CORONAVIRUS DIVERSITY

Coronaviruses are members of the subfamily Coronavirinae in the family Coronaviridae and the order Nidovirales (International Committee on Taxonomy of Viruses). This subfamily consists of four genera — Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus — on the basis of their phylogenetic relationships and genomic structures (Fig. 1). The alphacoronaviruses and betacoronaviruses infect only mammals. The gammacoronaviruses and deltacoronaviruses infect birds, but some of them can also infect mammals. Alphacoronaviruses and betacoronaviruses usually cause respiratory illness in humans and gastroenteritis in animals. The two highly pathogenic viruses, SARS-CoV and MERS-CoV, cause severe respiratory syndrome in humans, and the other four human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43 and HKU1) induce only mild upper respiratory diseases in immunocompetent hosts, although some of them can cause severe infections in infants, young children and elderly individuals. Alphacoronaviruses and betacoronaviruses can pose a heavy disease burden on livestock; these viruses include porcine transmissible gastroenteritis virus, porcine enteric diarrhea virus (PEDV) and the recently emerged swine acute diarrhea syndrome coronavirus (SADS-CoV)³⁴. On the basis of current sequence databases, all human coronaviruses have animal origins: SARS-CoV, MERS-CoV, HCoV-NL63 and HCoV-229E are considered to have originated in bats; HCoV-OC43 and HKU1 likely originated from rodents. Domestic animals may have important roles as intermediate hosts that enable virus transmission from natural hosts to humans. In addition, domestic animals themselves can suffer disease caused by bat-borne or closely related coronaviruses: genomic sequences highly similar to PEDV were detected in bats, and SADS-CoV is a recent spillover from bats to pigs (Fig. 2). Currently, 7 of 11 ICTV-assigned Alphacoronavirus species and 4 of 9 Betacoronavirus species were identified only in bats (Fig. 3). 

Thus, bats are likely the major natural reservoirs of alphacoronaviruses and betacoronaviruses.