Ben Te'o will make his first England appearance in almost a year after being picked at outside centre for the NatWest 6 Nations clash with Italy in Rome.
Te'o has ousted Jonathan Joseph from the No.13 jersey after completing his recovery from the high ankle sprain that ruled him out for three months, a spell that included the autumn series.
Head coach Eddie Jones has opted for the rugby league convert's powerful ball-carrying and smart running lines over the slick footwork of Joseph, who is included on the bench.
"We've decided to give Ben Te'o a run but Jonathan is unlucky not to start and will play a significant role as a finisher," said Jones.
The Stadio Olimpico showdown on Sunday will be the first time Te'o, who won two caps for the British and Irish Lions last summer, has played since October.
His only previous start for England was also against Italy 12 months ago when he crossed for a late try in a match dubbed "ruckgate" because of the tactics employed by Conor O'Shea's Azzurri.
Ben Youngs has held off the challenge of Danny Care at scrum-half and will link up with George Ford at half-back with Owen Farrell assigned as the foil to Te'o in midfield.
The void at No.8 created by injuries to Billy Vunipola and Nathan Hughes is filled by Sam Simmonds, the in-form Exeter back-row who serves as an effective ball-carrier despite lacking the size of his rivals for the position.
"Sam is a good young kid, he does the simple things well, he runs hard, tackles hard, works hard," Jones said.
"He is a humble boy, he's really fitted into the team well and his enthusiasm for ball carrying is going to be important on Sunday.
"We don't want to rely on one dominant ball-carrier because if you rely on one then the opposition find a way to stop that ball-carrier and you're stopped going forward."
Courtney Lawes slots in at blindside flanker and Chris Robshaw at openside with Maro Itoje present at lock, where he partners Joe Launchbury.
"It's important to have three regular jumpers and we have that with Maro, Courtney and Joe," said Jones.
"Chris Robshaw is also an accomplished jumper so it gives us three and half jumpers."
Dylan Hartley leads a starting XV containing 689 caps in what will be his 90th appearance.
England are seeking to become the first team to win three successive outright Championship titles and enter the tournament as favourites.
"Test match rugby never changes, it doesn't matter who you are playing and where you are playing them," Jones said.
"You've got to get your set piece right, you've got to be strong defensively and you've got to play with aggression and energy."
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