Conor Murray will miss Ireland's autumn internationals due to ongoing neck troubles, in a sizeable blow to head coach Joe Schmidt's plans.
Ireland must now face Italy in Chicago, then Argentina, New Zealand and the USA in Dublin without stellar British and Irish Lions and Munster scrum-half Murray.
The 29-year-old has not played since Ireland's summer tour to Australia and, while he has returned to Munster training, he is not yet ready for match action.
Ulster's John Cooney steps up in Murray's absence, with Will Addison, Sam Arnold and Ross Byrne the three uncapped players in Ireland's 42-man squad.
Murray moved to explain his injury situation on Wednesday, with updates on his neck troubles having been previously intermittent.
Asked when he might be back in action, Murray told reporters: "A couple of weeks; obviously the (Ireland) squad is being named today and I haven't chatted to anyone.
"I've been over and back and they know where I am with the injury.
"I'd have been lucky to be named in it because I haven't played and you need that - especially with the calibre of Argentina and the All Blacks in particular. You're going to have to be ready.
"So, in and around the end of November hopefully."
Murray had asked the Irish Rugby Football Union (IRFU) and Munster not to lay bare his injury profile, evidence that players are starting to protect their personal medical data.
The 29-year-old has now insisted any lack of information was purely because there was no clear timescale on his playing return.
"This thing has snowballed, big time," said Murray.
"When I was injured at the beginning we didn't know when I was going to come back so I requested that we just say that I am just managing my injury because we were still trying to figure out how long it would be."
England Under-20s graduate Addison has earned his first Ireland call-up, qualifying to represent Schmidt's men with his mother hailing from Fermanagh.
The 26-year-old has starred at full-back since his summer switch to Ulster, but his versatility across the backline will boost boss Schmidt's resources.
Munster centre Arnold and Leinster fly-half Byrne complete the trio of uncapped faces in Schmidt's line-up.
Evergreen hooker Rory Best continues as captain, with Johnny Sexton and Peter O'Mahony named as vice captains.
Ireland start their four-match series by facing Italy in Chicago on Saturday, November 3, with the eagerly-anticipated clash with back-to-back world champions New Zealand at Dublin's Aviva Stadium on Saturday, November 17.
"As always there have been a number of close calls in selection, meaning that some very good players have missed out in this particular window," said head coach Schmidt.
"The upcoming series offers an exciting opportunity for the squad but will also be very challenging."
— Irish Rugby (@IrishRugby) October 24, 2018
Ireland squad for autumn internationals
FORWARDS: R Best (CAPTAIN, Ulster), F Bealham (Connacht), T Beirne (Munster), J Conan, S Cronin, T Furlong, C Healy (all Leinster), I Henderson, R Herring (both Ulster), D Kilcoyne (Munster), D Leavy, J McGrath (both Leinster), J Murphy (Ulster), S O'Brien (Leinster), P O'Mahony (Munster), A Porter (Leinster), Q Roux (Connacht), R Ruddock, James Ryan (both Leinster), John Ryan, N Scannell, CJ Stander (all Munster), D Toner, J van der Flier (both Leinster).
BACKS: W Addison (Ulster), B Aki (Connacht), S Arnold (Munster), R Byrne (Leinster), J Carbery, A Conway (both Munster), J Conney (Ulster), K Earls (Munster), R Henshaw, R Kearney, J Larmour (all Leinster), K Marmion (Connacht), S McCloskey (Ulster), L McGrath, G Ringrose, J Sexton (all Leinster), J Stockdale (Ulster), D Sweetnam (Munster).