Both the San Francisco 49ers (3-1) and Buffalo Bills (2-2) came in to the season with a fair amount of hype. The 49ers had brought back its number-one ranked defense by signing key players such as Ahmad Brooks and Carlos Rogers to contract extensions. Meanwhile, the Bills had the off season’s biggest splash, signing premier free agent Mario Williams to a 100 million dollar deal.

The 49ers thus far have had a fair amount of success, recently crushing the New York Jets 34-0 and allowing ESPN to talk about the Sanchez-Tebow controversy for another week. The Bills have had a rocky start to their season by beating teams they were supposed to beat but losing horrendously to superior teams. Their big free agent has thus far not been a factor.

This Sunday the Bills visit the 49ers at Candlestick and hope to pull off an upset, while the 49ers hope to start another win streak. Here are five key factors to look out for.

1. The Buffalo Bills’ Run Game: The 49ers only loss this season came against the Vikings and featured a strong running attack led by Adrian Peterson.  The Vikings used their run game to put up an early lead and the 49ers were never able to recover, losing 24-13 to the surprising Vikings squad. The Bills and their elite run game, ranked fourth in the league, have a chance to set the tone in the way that the Vikings did against the 49ers defense on the Vikings’ opening drive.

2. The Injury factor: Carlos Rogers and Navarro Bowman are significant 49ers players with lingering issues, but they seem to be able to play this week. For the Bills however, starting tackle Cordy Glenn and starting guard Glenn Urbik are ruled out for the game. Losing starting members of the offensive line can be a huge problem, particularly when the offense relies on a strong running attack. It is an even bigger problem when you are facing the 49ers. That leads to number three…

3. The 49ers Defensive Front v The Bills Offensive Line: The defensive front for the 49ers features Pro Bowler Justin Smith, alternate Pro Bowler Ray McDonald, and sack machine Aldon Smith (14 sacks in his rookie season). Needless to say this is a handful for any team, nevertheless the Bills who are starting a backup at left tackle and right guard. Aldon Smith, the 49ers leading rusher, will line up on Ryan Fitzpatrick’s blind side and face off against the back-up left tackle, causing some serious issues for the Bills. Anybody who watched the Steelers play the 49ers last year knows how Smith can change a game with his pass rushing ability.

4. The Jim Harbaugh Factor: Also contributing to the 49ers’ only loss was some of the play calling on the offensive side of the ball. Now I understand it is blasphemy to question Jim Harbaugh but part of the reason why the Vikings were able to upset the 49ers is due to the fact that the 49ers decided to be a pass-first team that game, as Frank Gore finished the game with only 12 carries. It will be important for Harbaugh not to get caught-up playing at home and attack the Bills porous defense by utilizing the 49ers’ biggest offensive strength: the strong run game.

5. Ryan Fitzpatrick: In order to counter some of the issues the Bills will face the veteran quarterback will have to be quick and decisive with his throws. The Bills offensive line will have a lot to deal with in terms of injury and matchups; thus Fitzpatrick will need to get rid of the ball quickly. The 49ers stout run defense may also force Fitzpatrick to throw even more. Ultimately, the 49ers are favored in this game and Fitzpatrick will have to be his best for the Bills to have a fighting chance.

Winner: The 49ers. Playing at home and facing a struggling mediocre Bills squad makes this game the 49ers game to lose.