Ireland captain Johnny Sexton, halfback Conor Murray and lock James Ryan have been ruled out of the Six Nations clash with France in a massive setback for coach Andy Farrell as he seeks to keep his side's tournament hopes alive.
Sexton and Ryan, two of Farrell's most important players, were replaced due to suspected concussions during last week's opening 21-16 loss to Wales.
Ireland played most of the game with 14 men following Peter O'Mahony's 14th minute red card.
Billy Burns will win just his fifth cap in place of Sexton.
The Ulster flyhalf made a costly error in the final seconds in Cardiff when he attempted to kick for an attacking lineout five metres out, but booted the penalty too long.
Ulster's Iain Henderson ably filled the big hole left by Ryan last Sunday and will captain the side for the first time while the in-form Rhys Ruddock slots in to the backrow as O'Mahony begins a three-match suspension.
News of Murray's hamstring injury in training this week was a late blow with Jamison Gibson Park coming in at nine.
For Ruddock, whose father Mike coached Wales to a grand slam in 2005, it means a first Six Nations start more than a decade after making his Test debut at the age of 19 and having since captained his country on a number of occasions.
The 30-year-old has been unlucky with injury and years of intense back-row competition at club and country but is playing some of best rugby of his career, having won Leinster's player of the month for three successive months to December.
Meanwhile for France, Damian Penaud has returned to the right wing and Anthony Jelonch has been picked at flanker in two changes to their team.
Coach Fabien Galthie has replaced try-scoring winger Teddy Thomas and back rower Dylan Cretin from the team that opened its campaign with a 50-10 rout of Italy in Rome last weekend.