Evolution of ACE2 and SARS-CoV-2 Interplay Across 247 Vertebrates

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause the most serious pandemics of Coronavirus Disease 2019 (COVID-19), which threatens human health and public safety. SARS-CoV-2 spike (S) protein uses angiotensin-converting enzyme 2 (ACE2) as recognized receptor for its entry into host cell that contributes to the infection of SARS-CoV-2 to hosts. Using computational modeling approach, this study resolved the evolutionary pattern of bonding affinity of ACE2 in 247 jawed vertebrates to the spike (S) protein of SARS-CoV-2. First, high-or-low binding affinity phenotype divergence of ACE2 to the S protein of SARS-CoV-2 has appeared in two ancient species of jawed vertebrates, Scyliorhinus torazame (low-affinity, Chondrichthyes) and Latimeria chalumnae (high-affinity, Coelacanthimorpha). Second, multiple independent affinity divergence events recur in fishes, amphibians-reptiles, birds, and mammals. Third, high affinity phenotypes go up in mammals, possibly implying the rapid expansion of mammals might accelerate the evolution of coronaviruses. Fourth, we found natural mutations at eight amino acid sites of ACE2 can determine most of phenotype divergences of bonding affinity in 247 vertebrates and resolved their related structural basis. Moreover, we also identified high-affinity or low-affinity-associated concomitant mutation group.The group linked to extremely high affinity may provide novel potentials for the development of human recombinant soluble ACE2 (hrsACE2) in treating patients with COVID-19 or for constructing genetically modified SARS-CoV-2 infection models promoting vaccines studies. These findings would offer potential benefits for the treatment and prevention of SARS-CoV-2.

Temporal dynamics of human respiratory and gut microbiomes during the course of COVID-19 in adults

SARS-CoV-2 infects multiple organs including the respiratory tract and gut. Whether regional microbiomes are disturbed significantly to affect the disease progression of COVID-19 is largely unknown. To address this question, we performed cross-sectional and longitudinal analyses of throat and anal swabs from 35 COVID-19 adults and 15 controls by 16S rRNA gene sequencing. The results allowed a partitioning of patients into 3-4 categories (I-IV) with distinct microbial community types in both sites. Lower-diversity community types often appeared in the early phase of COVID-19, and synchronous fast restoration of both the respiratory and gut microbiomes from early dysbiosis towards late near-normal was observed in 6/8 mild COVID-19 adult patients despite they had a relatively slow clinical recovery. The synchronous shift of the community types was associated with significantly positive bacterial interactions between the respiratory tract and gut, possibly along the airway-gut axis. These findings reveal previously unknown interactions between respiratory and gut microbiomes, and suggest that modulations of regional microbiota might help to improve the recovery from COVID-19 in adult patients.

Progressive worsening of the respiratory and gut microbiome in children during the first two months of COVID-19

Children are less susceptible to COVID-19 and manifests lower morbidity and mortality after infection, for which a multitude of mechanisms may be proposed. Whether the normal development of gut-airway microbiome is affected by COVID-19 has not been evaluated. We demonstrate that COVID-19 alters the respiratory and gut microbiome of children. Alteration of the microbiome was divergent between the respiratory tract and gut, albeit the dysbiosis was dominated by genus Pseudomonas and sustained for up to 25-58 days in different individuals. The respiratory microbiome distortion persisted in 7/8 children for at least 19-24 days after discharge from the hospital. The gut microbiota showed early dysbiosis towards later restoration in some children, but not others. Disturbed development of both gut and respiratory microbiomes, and prolonged respiratory dysbiosis in children imply possible long-term complications after clinical recovery from COVID-19, such as predisposition to an increased health risk in the post-COVID-19 era.

Pangolin homology associated with 2019-nCoV

To explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.