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South Africa-born flanker CJ Stander will make his Test debut in Sunday's RBS 6 Nations opener against Wales, with Sean O'Brien and Rob Kearney taking Ireland's injury toll to nine frontline stars.
Munster back-rower Stander will start at blindside at Dublin's Aviva Stadium, the 25-year-old having completed his Ireland qualification on residency grounds.
Leinster duo O'Brien and Kearney have both failed to beat hamstring trouble in time to face Wales, so Tommy O'Donnell slots in at openside flanker and Simon Zebo at full-back.
O'Brien and Kearney sat out training on Friday, but Ireland will hope to have two of their most experienced men fit in time for the second-round clash against France in Paris.
"Sean O'Brien would have been just on the edge of being available to play," said Ireland head coach Joe Schmidt.
"But we'd have no concerns about next week for France.
"Rob Kearney should be fully fit at the latest by Thursday next week, but his is a very minor strain that should see him right to train on Tuesday.
"CJ Stander is a really committed character and I hope he's ready to step up. We felt he would make it a good mix in the absence of Sean O'Brien."
Flanker O'Donnell dislocated his hip in Ireland's 35-21 warm-up victory over Wales in Cardiff in August.
The 28-year-old has hit back to fitness and form with Munster, however, and will be a popular selection among Ireland's squad given his rotten injury luck in missing the World Cup.
Even leaving aside former captain Paul O'Connell, now retired from Test rugby, Ireland are still shorn of six regulars in their pack this weekend.
Props Cian Healy and Mike Ross, lock Iain Henderson, and flankers Peter O'Mahony and Chris Henry join O'Brien on the treatment table.
Only new skipper Rory Best, vice captain Jamie Heaslip and Devin Toner have retained their starting berths from Ireland's 43-20 World Cup quarter-final defeat to Argentina.
Stander's debut has been accelerated due to O'Mahony's absence, but the former Springboks Under-20s star has excelled in his three years with Munster.
The Thomond Park province's European Champions Cup captain would have risen to Test prominence earlier had he not had to bide his time for residency qualification.
Kearney's absence in the backline hands Munster's live-wire attacking talent Zebo a chance to impress, with Schmidt refusing to stray from a tried and tested midfield line-up.
Schmidt has restored his preferred midfield partnership of Robbie Henshaw and Jared Payne, refusing the temptation to pitch bullish Ulster centre Stuart McCloskey in for a Test debut.
With Tommy Bowe and Luke Fitzgerald both long-term absentees, Keith Earls partners Andrew Trimble on the wings.