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Striker Mason Greenwood will start the Europa League group game against Astana of Manchester United in Old Trafford on Thursday.
The 17-year-old has already made four substitute appearances in the Premier League this year.
England under-21 shield Axel Tuanzebe may also begin, alongside Brazilian midfielder Fred and reserve goalkeeper Sergio Romero.
Winger Daniel James misses out after picking up a knock against Leicester.
Even the 21-year-old Welshman, who has scored three goals in five league games this year, joins midfielder Paul Pogba, forward Anthony Martial and defender Luke Shaw on the injury list.
However, midfielder Jesse Lingard has recovered from illness and is very likely to be involved.
Greenwood had an impressive summertime for United, scoring in pre-season victories over Inter Milan and Leeds after making his debut in a 2-0 defeat to Arsenal in the Premier League at March.
He will begin his first game of the season on Thursday and manager Ole Gunnar Solskjaer says he’s”matured in the previous six months”.
“He’s still very young. I remember the child who only wanted to play with his teammates at the under-18s,” said Solskjaer. “Now he’s knocking on the door and his desire for soccer must be increasing.
“I simply don’t want to place too much stress on him. Mason’s one of the best finishers I have played with a couple decent ones and I’ve seen.
“If you’re 17, 18, 19 years old, the next game is obviously the most important one. It is irrelevant how many you scored last week.
“There will probably soon be 11 Astana players living the fantasy – it is one of the biggest games of their livelihood – but I need it to be a memorable one for our players too.”
Tuanzebe left his debut in a 4-0 win over Wigan in the FA Cup at January 2017 and has made eight first-team appearances in total for Manchester United.
But he’s played only one moment in the Premier League this year, coming on as a substitute in Saturday’s narrow victory over Leicester.
“It’s part of the practice of growing. I remember my glimpses in the first staff in 19 – it was not to be then but now I’m 21 and things are starting to open up more. I know where I want to be going,” said Tuanzebe.
Solskjaer added:”In case you do not throw them , you do not know what you’ve got. I really don’t find any means of accomplishing this.
“I have always done it where I’ve been, that is my belief for a mentor, to provide a chance, an opportunity.”
Despite attaining the quarter-finals of the Champions League last year, United entered the Europa League after a sixth-place end from the Premier League.
They won this contest in their last look in 2016-17 and have never failed to go past the group stages.
It is the first time they come up from Kazakh champions Astana, that are competing in the Europa League for the fourth consecutive season.
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