The Bills’ defense got lit up by Stevan Ridley and the Patriots last week. Can they rebound against the 49ers? (US Presswire)

Bills at 49ers -- Week 5

Where: Candlestick Park, San Francisco (grass, outdoors)

When: Sunday, 4:25 p.m., ET (CBS)

Spread: 49ers by 9.5

Forecast: Mild, 60 degrees, mixture of sun and clouds

Records: Bills (Overall: 2-2, AFC East: 0-2); 49ers (Overall: 3-1, NFC West: 0-0)

Past results: Two most recent meetings -- Nov. 30, 2008: 49ers 10, Bills 3; Dec. 26, 2004: Bills 41, 49ers 7. Series record: Tied 5-5.

What matters: Can the Buffalo Bills bounce back from their embarrassing home loss to the New England Patriots? It won’t be easy with a difficult West Coast trip on the schedule. The No. 1 priority for the Bills will be stopping the run after getting torched by the Patriots in Week 4. In the 52-28 loss, the Patriots had two running backs -- Brandon Bolden and Stevan Ridley -- top the 100-yard mark. San Francisco is the epitome of smash-mouth football, a throwback on offense that tries to impose its will on opponents. Veteran RB Frank Gore just keeps plugging along and has 326 yards and five touchdowns this season. The 49ers are third in the league in rushing with an average of 167 yards per game. If the Bills don’t quickly shore up their run defense, they could be in for a long day.

Who matters: DE Mario Williams, QB Ryan Fitzpatrick, defensive coordinator Dave Wannstedt. Williams has come under fire after a slow start to his Bills career. He has just 1.5 sacks and nine tackles in four games, and the Bills didn’t give him a $100 million contract to be just another guy. Fitzpatrick is always important to any Bills success. He threw for 350 yards and four TDs against the Patriots but also had four interceptions, as well as several incompletions he’d like back. The Bills have allowed a combined 100 points in their two division losses this year, putting Wannstedt in the hot seat. The Bills have struggled with in-game adjustments on defense and could use some more flexibility on that side of the ball.

Key matchups: 49ers OLB Aldon Smith vs. LT Chris Hairston; RBs C.J. Spiller and Fred Jackson vs. 49ers LBs Patrick Willis and NaVorro Bowman. Smith is one of the top young pass rushers in the NFL and has 4.5 sacks this year. He had 14 sacks as a rookie a year ago. The Bills are shorthanded on the offensive line, and Hairston will get his first start this year in place of injured rookie Cordy Glenn (ankle). It won’t be a surprise if the Bills give Hairston some help with TEs and RBs because he faces an awfully difficult task. Spiller and Jackson played in Week 4 but were not close to 100 percent. They struggled against the Patriots (combining for 62 yards), though some of that can be attributed to poor offensive line play. They practiced fully all week and are making progress on the injury front but will be up against the best inside linebacker combination in the league in Willis and Bowman.

Injuries of note: LT Cordy Glenn (ankle), RG Kraig Urbik (ankle) and DT Spencer Johnson (ankle) are out. RG Chad Rinehart (calf) will be listed as questionable but is expected to play after suffering an injury Thursday. If he can go, he’ll start in place of Urbik. FS Jairus Byrd (hip) is expected to play.

Inside stuff: Expect a 50-50 rotation at RB with Spiller and Jackson for the next few weeks. The Bills would like to wait until they are both healthy before deciding how the reps should be split. Jackson began the season as the starter, but Spiller was exceptional when Jackson was hurt.

Connections: 49ers S Donte Whitner was the eighth overall pick of the Bills in 2006, spending his first five years in the league with Buffalo. Whitner never lived up to expectations as a Bill but has fit in nicely with the 49ers, with 62 tackles, two INTs and 10 passes defensed in 2011.

Stat you should know: The Patriots ran for 19 first downs against the Bills in Week 4, compared to four rushing first downs for the Bills. 

Record watch: RB Fred Jackson needs 12 rushing yards to move into fourth on the team’s all-time rushing list (passing Travis Henry, 3,849 yards).

Looking ahead: Instead of returning to Buffalo after the game, the Bills will stay out west with the Arizona Cardinals next on the schedule. The Bills will practice at Arizona State University during the week. The Bills will be fortunate to win one of their two games on the difficult trip. The 49ers host the Super Bowl Champion New York Giants in Week 6.

Prediction: 49ers 24, Bills 10

For more updates on the Bills, follow correspondent Mark Ludwiczak on Twitter @CBSBills and @MarkLud12.