England captain Owen Farrell could miss the start of the Six Nations as he faces up to three months out following ankle surgery, Saracens have confirmed.
Farrell's club and country team-mate Jamie George will also be out until the end of January with a knee injury.
Both players were injured during England's win against Australia at Twickenham on Saturday.
England's Six Nations campaign begins against Scotland at Murrayfield on Saturday, 5 February.
Fly-half and centre Farrell, 30, has been given a timeline of between 10 to 12 weeks for his recovery, with hooker George, 31, expected to be sidelined for between eight and 10 weeks.
Following their injuries, both players were immediately withdrawn from England's squad to face South Africa and were replaced by Gloucester's Harry Elrington and Jack Singleton.
Farrell may also be a doubt for England's second round fixture against Italy on Sunday, 13 February but George will not require surgery and may be in contention to make the first squad.
The playmaker was also forced to miss the Test against Tonga after initially testing positive for Covid-19, only for the result to be later confirmed as a false positive.
George fought his way back into England's autumn internationals squad after initially being left out by head coach Eddie Jones and impressed against Tonga and Australia until injury struck.
Saracens have been boosted though by the return to full training of England and British & Irish Lions back Elliot Daly.
The 29-year-old has been out since the end of the Lions' tour to South Africa, following surgery on a stress fracture, but is available again for selection.
However, Italy prop Marco Riccioni has been ruled out for the rest of the season and will have surgery on Wednesday on a ruptured anterior cruciate ligament (ACL) in his right knee.
The 24-year-old sustained the injury playing for his country in their Test defeat by Argentina in Treviso on Saturday.