Ireland captain Johnny Sexton and centre Robbie Henshaw will miss Saturday's Autumn Nations Cup clash with England through injury, a major blow for Andy Farrell's side ahead of the potential Pool A decider.
Sexton left the opening 32-9 win over Wales after less than half an hour with a hamstring strain and the Irish Rugby Football Union said on Monday that the fly-half had been ruled out of the Twickenham test following a scan.
Henshaw, who has been one of Ireland's best performers this autumn and was replaced late in the Wales game, has an adductor strain. Fellow Leinster centre Garry Ringrose had already been ruled out of the tournament with a broken jaw.
Billy Burns, who replaced Sexton to make his Ireland debut but did not finish the game after being removed for a head injury assessment, will follow the return to play protocols.
Sexton's backup at Leinster, Ross Byrne, is the other option at fly-half for Saturday with Munster's Joey Carbery a long-term casualty.
Lock Iain Henderson will return to training on Monday after he and Ulster teammate Jacob Stockdale were ruled out of the Wales game shortly before kickoff. Stockdale will continue his calf rehab in camp with a view to training later in the week.
The four best Pool A sides will face off against the correspondingly placed Pool B teams in the tournament finale on Dec. 5-6.
Six Nations champions England beat Georgia 40-0 in the other Pool A game on Saturday.
France fly-half Romain Ntamack has also been ruled out of his side's game against Scotland on Sunday.