England captain Owen Farrell will miss the 2022 Six Nations after suffering a new ankle injury, head coach Eddie Jones confirmed.
The 30-year-old required surgery after damaging his right ankle during training with club side Saracens, who confirmed on Wednesday he will be sidelined for eight to 10 weeks.
Farrell has not played since another ankle injury sustained during the November Test victory over Australia at Twickenham.
The news is a significant blow to Jones' plans, with Farrell having been earmarked to play at number 12 and act as a guide for inexperienced fly-half Marcus Smith.
"Owen has had his operation, so he'll be out of the Six Nations," Jones said.
"[It is a] massive blow for him personally, but it's a chance for people to step up. It's an opportunity for other people to fill those leadership roles and an opportunity for other players to play for that number 12 jumper.
"In today's rugby, it's rare that you have all your best players on the field. We're used to it.
"Last night we had to leave the hotel because of a fire outside, so the boys are adaptable. They know how to get along with things and there's an opportunity there to build a little more leadership depth."
George Ford had already been recalled to the squad following injuries to Farrell and Jonny May, who has a knee problem.
England's preparations for the clash in Glasgow were further disrupted by a positive COVID-19 test for Joe Marler, while Courtney Lawes – among the favourites to deputise for Farrell as captain – has been sitting out training because of head injury protocols.
The team were also evacuated from their hotel in Brighton after a suspected electrical fire nearby.
England begin their campaign against Scotland at Murrayfield on February 5 before facing Italy in Rome a week later.
Italy-England fixture has become a classic – Mancini
Roberto Mancini believes Italy's rivalry with England has become a "classic" as they prepare to do battle in their opening Euro 2024 qualifier on Thursday.
The Azzurri won the last European Championship by beating Gareth Southgate's side on penalties in the final at Wembley in 2021.
Italy and the Three Lions then played out a goalless draw in the Nations League last June, before Giacomo Raspadori secured a 1-0 victory for Mancini's men in their last meeting three months later.
England will get another chance to gain a measure of revenge in a Group C clash at Stadio Diego Armando Maradona this week and Mancini is expecting an almighty challenge in Naples.
He said: "For me, it's become a classic. England and Italy seem to meet a lot, a bit like Italy and Germany in the past.
"For a long time now they've become a fantastic team, full of talented players, with strength and technique. It'll be a tough game just like all the others have been.
"They have more choice than us for many reasons, but in Naples we want to play a good match, play well and start these qualifiers well."
Italy failed to qualify for the World Cup in Qatar last year and head coach Mancini says they are in a rebuilding process.
"Unfortunately there was the difficult interlude of the World Cup, but apart from a few games, the team has always done well," Mancini continued.
"We arrived twice in the Nations League finals [they face Spain in a semi-final in June], this means that there is value [in the team]. We have to rebuild something important because to win there must be solid foundations. There have been some good things in the Nations League."
Mancini expects his players to do Gianluca Vialli – who was Italy's head of delegation when they won the rearranged Euro 2020 two years ago – proud after he died at the age of 58 in January.
He added: "I've already talked about it with the boys, it will be important for us to remember him, as if he were here with us. He had his space and it's not easy for us, we have to try to do well for him."
Rashford and Pope withdraw from England squad as Forster earns recall
Marcus Rashford and Nick Pope have withdrawn from England's squad for their Euro 2024 qualifiers against Italy and Ukraine after sustaining injuries.
As confirmed by Chelsea head coach Graham Potter last week, Mason Mount has also pulled out through injury.
Pope reported an injury following Newcastle United's 2-1 win at Nottingham Forest on Friday, while Rashford suffered a knock during Manchester United's 3-1 FA Cup quarter-final victory against Fulham on Sunday.
Tottenham's Fraser Forster has been called up to replace Pope, though England boss Gareth Southgate has decided not to bring in cover for Rashford or Mount.
Veteran goalkeeper Forster has been getting game-time for Tottenham since Hugo Lloris' injury in February.
The 35-year-old has played 13 times for Spurs this season, keeping five clean sheets with a save percentage of 68.8.
Losing Rashford will be a particular blow for Southgate, with the United forward in the form of his life having scored 27 goals in 44 appearances for his club this season.
England play Italy at Stadio Diego Armando Maradona on March 23 before hosting Ukraine at Wembley Stadium three days later.
Mancini defends Retegui call-up and bemoans Italy's lack of attacking options
Roberto Mancini defended calling up Argentina-born forward Mateo Retegui as he bemoaned Italy's lack of attacking options.
Mancini has turned to former Argentina under-19 and under-20 international Retegui for the start of the Azzurri's Euro 2024 qualifying campaign.
The Italy head coach did not expect the 23-year-old, on loan at Tigre from Boca Juniors, to accept the invitation to play for the European champions.
Eyebrows were raised when Retegui, whose grandmother was born in Italy, was named in Mancini's squad ahead of a Group C opener against England at Stadio Diego Armando Maradona on Thursday.
Mancini said on Monday: "We've been following him for some time, he has quality and he's a young boy. We didn't think he'd say yes, we hesitated a bit and instead he immediately said yes. The hope is that it can be important, he's a bright and young boy."
The Azzurri boss has changed his stance over calling up players who were born in a different country.
"Years ago I said that players born in Italy should play for the national team, but this problem didn't exist yet and the world has changed." he said.
"All the European national teams have players naturalised from other countries. We have had players who were taken by the national team of other nations.
"And we are doing the same thing. It is useless to talk, in Italy there are few. We are worse off than [England boss Gareth] Southgate, if there is the possibility of taking new we get players."
Mancini is concerned by the lack of options at his disposal.
He said: "In Italy nobody plays on the street anymore. We used to play three-four hours on the street and then we went to train, today this doesn't happen anymore.
"It's no coincidence that players are still born in those countries, such as Uruguay, Argentina or Brazil, where they still play a lot on the street."
Mancini added: "I have no idea why so few forwards come out. we are really very limited in the offensive department.
"We have three teams in the quarter-finals of the Champions League, but out of three teams, there are seven or eight Italians at the most. This is the reality."
Mancini is waiting to discover if Federico Chiesa and Federico Dimarco will be fit to face England in Naples.
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