Here, Press Association Sport examines five talking points heading into Saturday's showdown.
Full metal jacket
Italy coach Conor O'Shea described the threequarters picked by Eddie Jones as England at "full metal jacket"- and with good reason. Ben Te'o and Manu Tuilagi are united in the centres for the first time while Joe Cokanasiga wins his fourth cap on the right wing. The trio of Pacific Islands heritage are destructive carriers with the power to overrun the Azzurri.
And if it works?
Even if Italy are scattered by Te'o, Tuilagi and Cokanasiga – who weigh a combined 53 stones – then the combination is unlikely to be retained for the climax to the tournament against Scotland. It is the backline Jones has longed to pick ever since England conceded 8kgs per threequarter to Australia in 2016, and while clearly a useful option to have available, it lacks the guile needed to beat New Zealand at a World Cup.
Jones once described them as his two bowling balls and for the first time Kyle Sinckler and Ellis Genge will start together in the same front row. The rookie props bristle with aggression to the point they even wanted to fight their own team-mates during the 2016 tour to Australia. The challenge facing them and England is to channel their appetite for the fight in the right direction.
Despite the setback in Cardiff, England remain fully engaged in the title race. The destiny of the 2019 Six Nations crown is no longer in their hands but a bonus-point win against Italy would keep the pressure on Grand Slam-chasing Wales, who face a more demanding climax to the tournament against Scotland and Ireland.
Italy have lost their last 20 Six Nations matches in a sequence dating back to 2015 and are ranked 60-1 underdogs to prevail at Twickenham. Against this backdrop they are fighting for their Championship credibility, knowing Georgia are pressing hard for inclusion amongst Europe's elite. As O'Shea has noted, "We play for the future of Italian rugby every day we go out on to the pitch".