Ireland duo Johnny Sexton and James Ryan will both miss Sunday's Six Nations Test with France in Dublin, having failed to recover from concussion in time.
Experienced scrum-half Conor Murray is also absent in a further blow due to a hamstring in strain, while Rhys Ruddock starts in the back-row in a fourth alteration.
Ulster pair Billy Burns and Iain Henderson come in to start at out-half and second row respectively, with Leinster's Jamison Gibson-Park at nine.
Already missing Peter O'Mahony to suspension after his red card to Wales in Cardiff last week, Ireland are down perhaps their four biggest leaders in what takes on a must-win clash in the championship.
Despite playing for 66 minutes with a man less in Wales, Ireland controlled large passages and will have been mightily frustrated to have finished with a 21-16 defeat.
Lock Henderson captains the side in the absence of Sexton, Ryan and O'Mahony, while Burns is likely to take on goal-kicking duties despite not being Ulster's regular kicker at club level - that job falls to scrum-half John Cooney.
Other changes to the squad see Connacht second row Ultan Dillane, Leinster out-half Ross Byrne and uncapped Munster scrum-half Craig Casey added to the replacements bench in place of the promoted Henderson, Burns and Gibson-Park.
Leinster loosehead prop Ed Byrne is also in for Munster's Dave Kilcoyne - the latter of whom had a big impact off the bench against Wales last week.
Ireland: 15 Hugo Keenan, 14 Keith Earls, 13 Garry Ringrose, 12 Robbie Henshaw, 11 James Lowe, 10 Billy Burns, 9 Jamison Gibson-Park; 1 Cian Healy, 2 Rob Herring, 3 Andrew Porter, 4 Tadhg Beirne, 5 Iain Henderson (c), 6 Rhys Ruddock, 7 Josh van der Flier, 8 CJ Stander.
Replacements: 16 Ronan Kelleher, 17 Ed Byrne, 18 Tadhg Furlong, 19 Ultan Dillane, 20 Will Connors, 21 Craig Casey, 22 Ross Byrne, 23 Jordan Larmour.