Captain Sergio Parisse had already been ruled out after suffering suspected concussion playing for his club Stade Francais.
Parisse - Italy's 136-cap record appearance-holder - has remained with the squad as they bid to snap a run of 19 straight Six Nations defeats dating back to 2015.
Hooker Leonardo Ghiraldini, capped 101 times, takes the captain's armband for the 17th time.
The 34-year-old is the only remaining member of the Italy team that claimed their sole victory in 19 games against the Irish - a 22-15 win in Rome on March 16, 2013.
"We've chosen players who can be 100 percent physically ready," said Irishman O'Shea.
"If we can work on the things we can control, we can be very competitive against Ireland.
"The intensity must always be high: the road is the right one, I'm sure, but the results must start to come too."
Parisse's absence in the back row has resulted in Braam Steyn moving to number 8 with Maxime Manda coming in as flanker in his first appearance in nearly a year.
"I've waited a long time for this and I will give 100 percent to try to achieve a positive result," warned Zebre forward Manda, 26
"We worked hard this week and studied Ireland who have a very unpredictable style of play."
New Zealand-born flanker Jimmy Tuivaiti has been given the nod ahead of Sebastian Negri, who is suffering from a fever.
Federico Ruzza will get his first start in the second row, having earned nine caps off the bench.
Prop Simone Ferrari has been retained, while Andrea Lovotti returning after missing the game against Wales because of flu.
Scrumhalf Tito Tebaldi is also back after picking up an injury in the warm-up to their match against Scotland.
Fullback Edoardo Padovani scored tries in both of Italy's first two matches.
Italy lost their opening game 33-20 to Scotland and then fell 26-15 at home to Wales. Thay are bottom of the Six Nations table.
Ireland are fourth after losing their opening game to leaders England 32-20 before beating Scotland a week later 22-13.
Play starts on Sunday at 17:30 SA time.
15 Jayden Hayward; 14 Edoardo Padovani, 13 Michele Campagnaro, 12 Luca Morisi, 11 Angelo Esposito; 10 Tommaso Allan, 9 Tito Tebaldi, 8 Braam Steyn, 7 Maxime Mbanda, 6 Jimmy Tuivaiti, 5 Dean Budd, 4 Federico Ruzza, 3 Simone Ferrari, 2 Leonardo Ghiraldini (capt), 1 Andrea Lovotti
Substitutes: 16 Luca Bigi, 17 Cherif Traore, 18 Tiziano Pasquali, 19 David Sisi, 20 Alessandro Zanni, 21 Guglielmo Palazzani, 22 Ian McKinley, 23 Tommasso Castello