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Manu (24) was forced off with a foot injury in Friday night's match against the Chiefs at Forsyth Barr Stadium.
Highlanders coach Jamie Joseph said Manu had dislocated a ligament in his foot and was due to have an operation on it last night.
''That will be six weeks out for Nasi for not bearing any weight on it and then another six weeks in a moon boot. And after that he is going to have to get fit again, so that is going to be a long spell on the sideline,'' Joseph said.
The loss of Manu is a big blow for the Highlanders. The No 8 has been a damaging ball-runner and a virtual ever-present in the team in the past couple of seasons.
With another mainstay, blindside flanker Adam Thomson, taking up a contract in Japan, the Highlanders are going to field a rejigged loose forward trio.
Southland No 8 Elliot Dixon came on to fill in for Manu against the Chiefs and did an admirable job. Joe Wheeler and John Hardie completed the loose trio.
''With Manu and Thomson there, they played nearly every game for us, so there is going to be a change,'' Joseph said.
''But that just means an opportunity for someone else to come along and make that position their own.''
He said a replacement for Manu, who played his 49th Super 15 game on Friday night, could be called into the squad but there would be no rush as there was adequate cover in the meantime.
Otago captain Paul Grant joined the squad last month as injury cover for Jake Paringatai and Doug Tietjens and is likely to continue his stay. Paringatai has recovered from a broken hand and is playing again.
Having viewed the tape of the 41-27 loss to the Chiefs in the season opener, Joseph said the Highlanders had created enough chances to win the game but did not finish off.
He also said the defence was disappointing from his side, and that needed to be improved.
Captain Andrew Hore missed last Friday's game in the final game of his suspension received from the All Black test against Wales last year.
The Highlanders will enjoy getting their skipper back but big lock Brad Thorn is still not at full fitness. Joseph said they had a little time to get him fit before the next game, against the Cheetahs in Invercargill on March 9.
The Highlanders have the bye this week and are spending the next couple of days in Maniototo, training at the area school in Ranfurly.
Paringatai played for the Highlanders development side on Saturday against the Crusaders Knights in Christchurch and helped his side to a 36-15 win after leading 15-8 at halftime.
Shaun Treeby scored two tries, while other tryscorers were Buxton Popoali'i, Jamie Mackintosh, Michael Collins and Jason Emery. Trent Renata slotted two conversions and Colin Slade, who played 40 minutes, kicked one conversion.