Cardinals safety Tyrann Mathieu and the defense may need to lead the way following running back David Johnson's injury.

INDIANAPOLIS – It's a tough call, trying to decide which of these teams had a rougher opening weekend.

The Colts played without quarterback Andrew Luck last Sunday and were crushed by the Rams, 46-9, as the Los Angeles defense outscored them by five. The Cardinals blew an eight-point second-half lead to the Lions in a 35-23 defeat and then learned star running back David Johnson was headed to injured reserve with a dislocated wrist.

Hysteria has hit both cities, and with the weekly schedule of the NFL, the players have been unable to do anything but bide their time.

"We wish we could (have played) on Thursday," Colts wide receiver T.Y. Hilton said.

The teams will get back in the saddle at Lucas Oil Stadium on Sunday, and there is a feeling of desperation in the air. Indianapolis has been rocked by injuries and Luck's timetable to return is still fuzzy. The Cardinals were a chic pick to return to the playoffs this season but 0-2 would be an inauspicious start.

"We all understand what we did last week was unacceptable," wide receiver Larry Fitzgerald said, "and if we want to be a team that's contending to win an NFC West division title, we've got to play much better."

Multiple Cardinals have called it a must-win.

"Good teams, they don't lose two in a row," safety Tyrann Mathieu said.

The Cardinals offense gets a favorable matchup against a Colts defense that's below average normally and won't have top cornerback Vontae Davis or two other starters. However, it has problems of its own. Quarterback Carson Palmer played poorly in the opener, and the offensive line struggled to protect him.

Health is a major concern, as four starters – Johnson, wide receiver John Brown, left tackle D.J. Humphries and left guard Mike Iupati – have been ruled out of this game, and tight end Jermaine Gresham is questionable.

Kerwynn Williams will start at running back, while Andre Ellington, Chris Johnson and Elijhaa Penny are also expected to see time. Rookie wide receiver Chad Williams will make his NFL debut with Brown sidelined.

"I don't care who runs it, I just want four yards or more," offensive coordinator Harold Goodwin said. "If (coach Bruce Arians) throws it, catch it. I don't care who gets the yardage, who gets the glory. I just want to win."

The Cardinals might have to lean on the defense in this game and for the foreseeable future. It held down a talented Lions defense for three quarters on Sunday before the floodgates opened. Defensive lineman Robert Nkemdiche (calf) will make his season debut and could have a fruitful day as Indianapolis is without starting center Ryan Kelly.

The Colts will start either Jacoby Brissett or Scott Tolzien at quarterback in place of Luck – NFL Network reported it will be Brissett -- and the defense must find the balance of making splash plays while still sticking to its assignments.

"I think we have six or seven guys who probably think they are legit superstars," Mathieu said. "At the end of the day, we have to understand that we do have a talented defense. I don't have to make every play. Chandler (Jones) doesn't have to get every sack.

"Sometimes it's just about containing the run or containing the pass, rather than losing technique to get a sack, or me undercutting the ball to get an interception. We've got to understand that we've got a good group back there and we've got to trust each other."

If the defense plays well and the offense avoids turnovers, the Cardinals can get back to .500 and put the ugly opening week behind them. The next few months will be challenging without Johnson to lean on, but the Cardinals aren't waving a white flag.

"We won a lot of games before David got here," Goodwin said. "We're going to continue to win games without David being out there. David's one man. At the end of the day, it's still 11 guys on offense, defense and special teams. One man doesn't make a team. It's got to be a group effort. It's got to be a team effort. That's how we move forward."