Isolation of MERS-related coronavirus from lesser bamboo bats that uses DPP4 and infects human-DPP4-transgenic mice

Nat Commun. 2021 Jan 11;12(1):216. doi: 10.1038/s41467-020-20458-9.

Abstract

While a number of human coronaviruses are believed to be originated from ancestral viruses in bats, it remains unclear if bat coronaviruses are ready to cause direct bat-to-human transmission. Here, we report the isolation of a MERS-related coronavirus, Tylonycteris-bat-CoV-HKU4, from lesser bamboo bats. Tylonycteris-bat-CoV-HKU4 replicates efficiently in human colorectal adenocarcinoma and hepatocarcinoma cells with cytopathic effects, and can utilize human-dipeptidyl-peptidase-4 and dromedary camel-dipeptidyl-peptidase-4 as the receptors for cell entry. Flow cytometry, co-immunoprecipitation and surface plasmon resonance assays show that Tylonycteris-bat-CoV-HKU4-receptor-binding-domain can bind human-dipeptidyl-peptidase-4, dromedary camel-dipeptidyl-peptidase-4, and Tylonycteris pachypus-dipeptidyl-peptidase-4. Tylonycteris-bat-CoV-HKU4 can infect human-dipeptidyl-peptidase-4-transgenic mice by intranasal inoculation with self-limiting disease. Positive virus and inflammatory changes were detected in lungs and brains of infected mice, associated with suppression of antiviral cytokines and activation of proinflammatory cytokines and chemokines. The results suggest that MERS-related bat coronaviruses may overcome species barrier by utilizing dipeptidyl-peptidase-4 and potentially emerge in humans by direct bat-to-human transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Caco-2 Cells
  • Chiroptera / virology*
  • Coronavirus Infections / immunology
  • Coronavirus Infections / pathology
  • Coronavirus Infections / transmission
  • Coronavirus Infections / virology*
  • Cytokines / metabolism
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / metabolism*
  • HEK293 Cells
  • Host Specificity
  • Humans
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle East Respiratory Syndrome Coronavirus / genetics
  • Middle East Respiratory Syndrome Coronavirus / isolation & purification*

Substances

  • Cytokines
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse