San Francisco has too many injuries on defense to keep it close against Peyton Manning. Since Manning joined Denver, the Broncos have won 17 of 19 regular season home games. Manning has thrown 59 touchdown passes in the 19 games.

This also is a tough situational spot for the 49ers, traveling on a short week after having played on the road this past Monday against the Rams.

Denver has upgraded its defense ranking fourth in fewest yards allowed and fifth in run defense. The 49ers need to run to be successful and they are averaging just 3.6 yards per carry on the road compared to 4.7 at home.