Ireland captain Johnny Sexton has been ruled out of Saturday's Autumn Nations Cup clash with England following a scan on a hamstring injury.
Fly-half Sexton limped off in the first half of Friday's 32-9 win over Wales.
Centre Robbie Henshaw, who sustained an abductor strain against Wayne Pivac's side, will also be unavailable on Saturday at Twickenham.
"Johnny Sexton has had a scan on the hamstring that forced his removal from the game on Friday night and has been ruled out of this week's fixture against England," read a statement on the IRFU website.
"Robbie Henshaw picked up an abductor strain and is also ruled out of this week's game."
Head coach Andy Farrell has a potential selection headache for the No 10 jersey going into the game against Eddie Jones' men as, in addition to Sexton's absence, understudy Billy Burns is undergoing a head injury assessment.
Scrum-half Conor Murray finished Friday's game at fly-half after the enforced withdrawals of Sexton and Burns.
Lock Iain Henderson has returned to training after being absent due to an unspecified medical issue, while back Jacob Stockdale will continue rehab on his calf problem with a view to resuming training later in the week.
'Ireland our most important game of the year'
Eddie Jones has described England's game against Ireland as their most important of the year.
Both teams recorded big wins in their opening fixtures, Ireland beating Wales 32-9 in Dublin on Friday night before England whitewashed Georgia 40-0 at Twickenham.
"We realise the Ireland game is going to be the most important game of the year," said Jones, whose side have been comprehensive winners in their last three matches against Ireland, including a 24-12 victory at Twickenham during this year's Six Nations.
"We'll go away and have a good preparation. Ireland will be cock‑a‑hoop after their big win against Wales so they'll come with plenty of confidence and swagger."
Jamie George scored a hat-trick against Georgia, becoming the first England hooker to achieve that feat in a Test match.
Debutant Jack Willis, Elliot Daly and Dan Robson also crossed and Jones conceded the final score should have been more emphatic.
"Georgia produced a challenge in the set-piece and our set-piece cohesion was absolutely outstanding," said Jones.
"We probably would have liked to have been a bit sharper in terms of our execution with the ball we won.
"We probably left another 20 points out there, but we are pretty happy with the display. I was delighted with the resolve and attitude of the side.
"Ireland will be a completely different game. I'd like us to execute a bit better."
Murray: Ireland must improve to beat England
Ireland scrum-half Conor Murray admits a repeat of the performance which comfortably dispatched Wales will be insufficient to defeat England.
Ireland's dominant Dublin success - in a game pockmarked by penalties - was a welcome return to winning ways after they agonisingly missed out on the Six Nations title following a costly loss to France.
"We know already that that won't be good enough at Twickenham but we've got to be realistic, we took a step forward," said Murray.
"There's a good feeling in the dressing room, especially that we left a little bit out there and we can make that extra improvement that we will need to do to play at Twickenham and to get a result.
"We know we've great potential in this team and I think everyone is searching to reach that, which is exciting."