The San Francisco 49ers are set to take on the defending AFC champion Denver Broncos on Sunday night. The 49ers come into the game with a 4-2 record, and are coming off a very physical Monday night contest that saw them lose Patrick Willis, Jimmie Ward and Mike Iupati. As a result, rookie inside linebacker Chris Borland will be making his first NFL start against a future Hall of Fame quarterback and there will be some juggling in the secondary and along the offensive line.

The Broncos come in with a 4-1 record, their only loss coming in overtime to the Seahawks in Seattle. In three games at Sports Authority Field in Denver, the Broncos have averaged 32 points per game. While the schedule makers didn't do the 49ers any favors by scheduling a road game after a Monday night road game, they may have also stretched the Broncos a bit by scheduling a conference game against division rival San Diego on Thursday night.

With that as a backdrop here are 5 burning questions to which the answers will be key to the outcome of the game.

1) Can the 49ers defense slow down Peyton Manning? - Manning comes into the game averaging over 300 yards per game so far in 2014. Add in 15 touchdowns with only 3 interceptions and the 49ers defense had it's work cut out for itself even before they lost Patrick Willis and Jimmie Ward.

Yesterday I wrote about this possibly being Trent Baalke's finest hour should the 49ers win, but the same thing could be said for Vic Fangio and the rest of the defensive coaching staff. They are facing an extremely tough task this week.

2) How will Colin Kaepernick follow up his Monday night performance? - This is a great opportunity for Kaepernick to quiet the naysayers who keep saying that he is too inconsistent. The fact that this game is being played on the road may actually play to his advantage. Over his last ten regular season road starts Kaepernick has thrown for 18 touchdowns, ran for another 4 and turned the ball over only once.

The 49ers will need this type of performance on Sunday night if they are going to have any chance to pull off the upset.

3) How will Joe Staley and Jonathan Martin hold up against DeMarcus Ware and Von Miller? - Ware and Miller have accounted for 12 of Denver's 19 sacks so far this season. Look for them to provide the 49ers with their biggest challenge since week two against the Chicago Bears when Kaepernick was sacked 4 times and had his worst game of the season with four turnovers.

4) Can the 49ers get the run game going without Mike Iupati? - The 49ers were without Iupati for four games in 2013 and had mixed results. In the first two games they were held to fewer than 3 yards per carry, while in the final two they were over 4.5 yards per carry.

While Iupati is among the best run blocking guards in the NFL he struggles in pass protection. Look for Joe Looney, the lone remaining member of the 2012 draft class, to get the start at left guard and possibly help shore up the inside pass protection to give Colin Kaepernick the time needed to make the throws.

5) How will the 49ers handle the short week? - This game reminds me a lot of Thanksgiving 2011 when the 49ers were forced to travel across the country on a short week to take on the Baltimore Ravens. In that game the 49ers were able to keep it close, and may have been able to pull off the win if not for a penalty that negated a 75 yard touchdown pass from Alex Smith to Ted Ginn.

Prediction Time:

49ers 24 Broncos 23

The 49ers win on a last second field goal from Phil Dawson.