Facing the New England Patriots — even a Patriots squad weakened by injuries and murder investigations — in their NFL season opener was already a tough enough assignment for the Buffalo Bills.

Now, it appears the Bills will have to play the Sept. 8 clash with either a rookie with hardly any preseason reps or an undrafted free agent.

Kevin Kolb, who signed with Buffalo during the offseason, suffered what is believed to be at least his third career concussion during the Bills’ third preseason game against the Washington Redskins. There is concern the concussion could be career-ending, so it certainly seems likely Kolb won’t be ready for the opener against New England.

E.J. Manuel, the Bills’ first pick in this year’s draft, would likely get the call against the Pats — if he’s healthy enough to go himself. The Florida State product suffered a minor knee injury in training camp and is sidelined the rest of the postseason.

The injuries to Kolb and Manuel left the Bills with just one QB on the active roster, undrafted free agent Jeff Tuel. Buffalo signed former USC prodigy-turned-clipboard-holder Matt Leinart Sunday and traded for another backup QB, Thaddeus Lewis, who started one game for the Browns last year.

“I’m not going to sit here and say everything is fine and dandy. It’s a concern,” Bills coach Doug Marrone told reporters Saturday.

Kolb isn’t exactly Joe Montana. He is coming off two disappointing years in Arizona, playing just 15 games in those two seasons. But he was the most experienced pivot on the Bills’ roster, even though Manuel might have beat him out for the opening-day starting job anyway.

Marrone said he is optimistic Manuel will be ready for the start of the season.

Oddsmakers aren’t quite so sure, however. Buffalo was a 7-point underdog for Week 1, but the injury situation at quarterback led most sportsbooks to make the Bills 9.5-point dogs.

Pats QB Tom Brady is 20-2 all-time against the Bills.