Ireland trio Sean O'Brien, Mike McCarthy and Dave Kearney have been ruled out of the remainder of the Six Nations campaign through injury.
Lock McCarthy, who suffered a concussion in the defeat by France in Paris, will miss the rest of the season following advice from a specialist.
Flanker O'Brien has a grade two hamstring tear while winger Kearney has sustained a shoulder AC joint injury.
Fly-half Jonathan Sexton and winger Keith Earls are however back training.
Ireland face England in their next match at Twickenham on 27 February.
Joe Schmidt's side then finish their campaign with home games against Italy and Scotland on 12 March and 19 March.
The holders' chances of retaining the title they won for the last two years look remote, with just one point from their opening two fixtures.
Utility back Earls, who was concussed in the opening game against Wales, trained fully with the Ireland squad on Thursday and Friday.
Lions star Sexton has also received a clean bill of health after retiring hurt against the French, while centre Jared Payne is recovering from a grade one hamstring tear.
Winger Simon Zebo missed the loss against France with a knee injury.
|Upcoming live TV coverage|
|Fri, 26 Feb (20:05 GMT)||Wales v France||BBC One|
|Sat, 27 Feb (14:25 GMT)||Italy v Scotland||ITV|
|Sat, 27 Feb (16:50 GMT)||England v Ireland||ITV|
|Six Nations coverage on the BBC|