England No.8 Nathan Hughes and lock Courtney Lawes have been ruled out for about three months due to knee ligament injuries and are set to undergo surgery later this week.
Things went from bad to worse for Eddie Jones on Wednesday with captain Dylan Hartley and Elliot Daly also in doubt for the Six Nations closer against Twickenham.
Hughes and Lawes both sustained their injuries during last weekend's 22-16 defeat by France in the Six Nations, leading Don Armand to be called up into the 32-man training squad for Saturday's match against newly-crowned champions Ireland.
"Hughes is expected to be out for 12 weeks while Lawes will require 14 weeks of rehabilitation," the Rugby Football Union said in a statement.
England have lost consecutive matches in a single Six Nations campaign for the first time since 2009 and head coach Jones is expected to make significant changes against a dominant Ireland side at Twickenham to prevent a third defeat.
Captain Hartley had been expected to return against Ireland but just hours after he and Elliot Daly were cleared the pair emerged as doubts.
Defence coach Paul Gustard insisted that the pair had recovered from their respective calf and foot problems and were available for selection.
But following training on Wednesday afternoon, their availability was placed in jeopardy by medical checks, the Rugby Football Union said.
England have delayed their team announcement until Thursday lunchtime to give the duo as much time as possible to recover from their injuries.
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