George Kruis has been ruled out England's remaining November fixtures as head coach Eddie Jones named his squad to face Japan this weekend.
Lock Kruis limped out of Saturday's defeat to New Zealand with a calf injury and is expected to be out of action up to eight weeks, according to Jones.
The Saracens forward is likely to be replaced in the starting line-up by Courtney Lawes, who made his return from a back injury from the bench against the All Blacks, with Bath's Charlie Ewels another who could profit from his absence.
Kruis is also in line to miss the final autumn international against Australia on Nov. 24 as injuries continue to bite for the Red Rose. Fellow Saracens duo Mako and Billy Vuniola remain on the sidelines, while Wasps' Joe Launchbury is another high-profile absentee as Jones shapes his squad ahead of next summer's Rugby World Cup in Japan.
"George has got a calf injury. It's highly unlikely he'll be available again for a few weeks - anywhere from four to eight weeks," Jones said.
"It's a calf strain. He did it during the game. It's disappointing because he'd been out injured for a while and was just coming back into form.
"We'll certainly miss him, but it opens the door for Courtney Lawes or Charlie Ewels to come in. It's testing the depth of the squad."
Midfield duo Manu Tuilagi and Alex Lozowski, however, are back in the squad having missed the New Zealand match because of injury and suspension respectively.
Saracens utility man Lozowski is expected to compete with current incumbent Henry Slade for a starting berth at outside centre, but Jones has urged caution with the returning Tuilagi.
"Manu came in and did some training on Monday but again we'll be overcautious with him," Jones told Sky Sports. "He's about 99 per cent but there's that last one per cent of top speed that he hasn't got yet. We'll just keep monitoring him.
Asked whether the powerful Leicester centre was in line for his first England appearance in four years, the England head coach added: "Probably not, but we'll wait and see."
Prop Nick Shonert, lock Elliott Stooke and wing Joe Cokanasiga could all make their England debuts after being included in Jones' 30-man squad, while Worcester youngster Ted Hill is named as an apprentice. There was again no place for Mike Brown, with Elliot Daly favoured at full-back.
England face Japan at Twickenham on Saturday as Eddie Jones comes up against the team he coached from 2012 to 2015.
Full Squad:
Backs (14): Ashton, Cokanasiga, Care, Daly, Farrell, Ford, Lozowski, May, Nowell, Slade, Te'o, Tuilagi, Wigglesworth, Youngs
Forwards (16): Ewels, George, Hartley, Hepburn, Hill*, Itoje, Lawes, Mercer, Moon, Schonert, Shields, Sinckler, Stooke, Underhill, Williams, Wilson
*Apprentice player