Natural Transmission of Bat-like Severe Acute Respiratory Syndrome Coronavirus 2 Without Proline-Arginine-Arginine-Alanine Variants in Coronavirus Disease 2019 Patients

Clin Infect Dis. 2021 Jul 15;73(2):e437-e444. doi: 10.1093/cid/ciaa953.


Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains the furin cleavage Proline-Arginine-Arginine-Alanine (PRRA) motif in the S1/S2 region, which enhances viral pathogenicity but is absent in closely related bat and pangolin coronaviruses. Whether bat-like coronaviral variants without PRRA (∆PRRA) can establish natural infections in humans is unknown.

Methods: Here, we developed a duplex digital polymerase chain reaction assay to examine ∆PRRA variants in Vero-E6-propagated isolates, human organoids, experimentally infected hamsters, and coronavirus disease 2019 (COVID-19) patients.

Results: We found that SARS-CoV-2, as currently transmitting in humans, contained a quasispecies of wild-type, ∆PRRA variants and variants that have mutations upstream of the PRRA motif. Moreover, the ∆PRRA variants were readily detected despite being at a low intra-host frequency in transmitted founder viruses in hamsters and in COVID-19 patients, including in acute cases and a family cluster, with a prevalence rate of 52.9%.

Conclusions: Our findings demonstrate that bat-like SARS-CoV-2ΔPRRA not only naturally exists but remains transmissible in COVID-19 patients, which has significant implications regarding the zoonotic origin and natural evolution of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; furin cleavage PRRA motif; transmission; viral variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Animals
  • Arginine
  • COVID-19*
  • Chiroptera*
  • Humans
  • Proline
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / genetics


  • Spike Glycoprotein, Coronavirus
  • Arginine
  • Proline
  • Alanine