England must enter their seismic Guinness Six Nations clash against Ireland without their first choice inside centre after Ben Te'o suffered a side strain.
Te'o was set to start the opener in Dublin only for injury to strike during training on Monday, paving the way for Manu Tuilagi to be restored to the midfield against Joe Schmidt's Grand Slam holders.
In an additional blow, blindside flanker Brad Shields has failed to recover from his own side strain to ensure Mark Wilson will continue in the back row.
Giant Bath wing Joe Cokanasiga has also yet to reach full fitness from a knee problem, excluding him from Eddie Jones' plans.
It is hoped that all three will recover for the round two match against France and they are to stay at the squad's camp in the Algarve where they will continue to receive treatment.
"They're not far away from where we want them to be, but obviously for a game of this magnitude we need everyone at 100 per cent," assistant coach Neal Hatley said.
It is a cruel setback for Te'o, who only on Friday declared he was fully fit after enduring an injury-ridden 18 months plagued by serious ankle and thigh problems, adding "I feel great now".
Hatley continued: "It was a small side strain just in training – it was fairly innocuous.
"It's not like Ben is the only player who has run at 12 for us. We've tried different people in there making sure that if something like this comes up, there are contingencies in place."
Seven players have been trimmed from the training squad ahead of Thursday's team announcement, but Tuilagi is not among those heading home as he closes in on making a first Test start for four years.
England's backs doing conditioning work at their Portugal training camp. No Brad Shields or Ben Te'o at training pic.twitter.com/PRXBtrQjza — Duncan Bech (@DuncanBech) January 29, 2019
Te'o's absence points to a significant overhaul of the original plan with Tuilagi's power present at outside centre and George Ford and Owen Farrell restored as twin playmakers.
"Manu's been looking brilliant. You've seen some of his Champions Cup performances – for example against Scarlets at Welford Road," Hatley said.
"Manu's just got better and better and better as he's put games together. He's trained exceptionally well in the midfield for us. He's in a really good space.
"He's a physical player and guys like playing alongside blokes like that. He definitely has a positive effect."
Wilson, who is poised to deputise for Shields, was named England's player of the series last autumn with three superb appearances at number eight and one at openside flanker propelling him into World Cup contention.
The 29-year-old, who recently recovered from a shoulder injury, plays most of
his club rugby at Newcastle in the number six jersey.
England 25-man training squad retained in Portugal:
Forwards: L Cowan-Dickie (Exeter Chiefs), T Curry (Sale Sharks), E Genge (Leicester Tigers), J George (Saracens), N Hughes (Wasps), M Itoje (Saracens), G Kruis (Saracens), J Launchbury (Wasps), C Lawes (Northampton Saints), K Sinckler (Harlequins), B Vunipola (Saracens), M Vunipola (Saracens), H Williams (Exeter Chiefs), M Wilson (Newcastle Falcons).
Backs: C Ashton (Sale Sharks), M Brown (Harlequins), E Daly (Wasps), O Farrell (Saracens, capt), G Ford (Leicester Tigers), J May (Leicester Tigers), J Nowell (Exeter Chiefs), D Robson (Wasps), H Slade (Exeter Chiefs), M Tuilagi (Leicester Tigers), B Youngs (Leicester Tigers).
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