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Ellie is going to become a clicker, but she'll still know who she is
From what I gathered playing the game, Ellie is infected with a mutated string of the fungus that doesn't make her zombie out, but it's still growing inside of her brain. Sooner or later it's going to grow just as much as the fungus of the clickers, and eventually even the bloaters, but without the side effect of being controlled by it.

Crash Bandicoot, Jak, Uncharted and TLOU are all in the same universe
Crash takes place on a prehistoric Earth (explains the animals) and Jak takes place millions of years later when all most the Crash fauna gave gone extinct except for the plants which have become domesticated in Samos' hut.

Uncharted takes place in present day where some remnants of Crash and Jak (like wumpa fruit and precursor orbs) are present in the world but ridiculously rare.

TLOU takes place in an alternate timeline where Nate failed to stop the baddies in U1 from escaping with El Dorado with the spores/dust that makes people into runners. People then experimented on that to accidentally create the mutated Cordecepys Fungus in the game.


There would be a Resistance shout out in the sequel.
SRPA crates, mentioning a fungus infused Super Soldier project, Grim-type infected, etc because Naughty Dog and Insomniac are friends.

The escape at the end of the game is a Dying Dream
At some point during the Firefly hospital, Joel gets shot, and as he lays bleeding out, imagines heroically rescuing Ellie. This is somewhat supported by the fact that red becomes the new "notice this" color; all throughout the rest of the game (the "real world"), as in the Uncharted games, it had been yellow. Additionally, there is an eye exam chart that seems to subliminally encourage Joel to keep running ("RUN YOU R NEARLY THERE DONT QUIT!!").

Savage Starlight will eventually be Defictionalized
Viewing the back of the comic covers in the inventory shows them as being published by Dark Horse Comics.

David is lying to Ellie when he says his group has women and children that are hungry.
Apart from the fact that we never see any, David just doesn't seem like the kind of guy who can be trusted with them. He's completely Ax-Crazy, and possibly a pedophile, it seems much more likely that his group has the same thought process as the Pittsburgh hunters, and would just rape, murder, and then eat them.

Humanity will die. Period.
The game's not called The Last of Us for nothing. It is literally a story set in humanity's last days, and it's more about how the survivors are coping with the inevitable. The depredation of women and children(which is a big thing in the story of the game) is killing humanity's chances to repopulate, and infrastructure and societal structure are so destroyed that it'd be impossible for any kind of centralized government to be reformed.

Alternatively, humanity will eventually recover.
The keyword here is eventually. While it is true that there are a lot of groups of scavengers who will stop at nothing to just survive (and a few that are outright villainous, like the Humvee group & David's gang), there are groups of people that are trying to keep humanity from completely dying out, and actually help it recover (FEDRA controlled quarantine zones may be pretty bad places to live in, but they're still miles better than being on the outside; and Tommy's place is completely self sustaining, even giving people a chance to live life how it was before the outbreak). With these factors in mind, it's possible to see that humanity (while far from perfect) is handling itself at least well enough to survive for a good 20 years.

The Last Of Us takes place in the future of the Left 4 Dead games.
  • As seen in Left 4 Dead 2, public opinion seems to turn against CEDA for their blatant inability to stop the fungal infection from spreading...but that's because they'd thought it was a virus. Not understanding that the spores could travel distances far larger than any airborne disease, their evacuations and quarantine procedures were laughably inadequate. Despite their bombings of whatever city Mercy Hospital's in being largely unsuccessful, the military took control and, after their bombings of New Orleans managed to wipe out a significant number of infected, the public opinion of the desperate U.S. turned in their favor, leading them to go on to destroy countless other huge cities. The (remaining) government put the U.S. under a state of martial law. Of course, fast forward 20 years and, while most of the more bizarre strains of the infection (Tanks, Boomers, etc.) have been wiped out, the martial law is still in effect and the infection has claimed more human lives than anyone could have ever predicted. Bill (the TLOU one) has had time since the very beginning of the outbreak to perfect his makeshift weapons, like molotovs and homemade bombs. Ellie has inherited her immunity from her mother, Zoey, who was killed some time after giving birth to Ellie, as shown by the letter in Ellie's bag. In a pretty crazy coincidence, she's watched over by none other than L4D Bill's son, Joel.
    • In Left 4 Dead, immunity is confirmed to be inherited from one's father so Ellie couldn't have inherited her immunity from Zoey.

Joel and Ellie will meet more immune in the sequel.
  • Because this could be a great new IP for Naughty Dog and they might be feeling charitable enough towards Joel to make that ending Blatant Lies bit not as false.
    • Possible. Domains for The Last of Us 2 and The Last of Us 3 have been registered. Although, Word of God states that if they do a sequel, they don't plan to return to Joel and Ellie, since their story is finished.
    • Any word on if you'll be a Firefly hunting them down?

Somewhere in an abandoned house will be a PS3.

Ellie was bitten but not infected.
  • We know that she needs to be smuggled out of the city in a hurry after getting into some kind of trouble and the latest trailer has Tess insisting "What if it's true?". It's also heavily implied that Ellie is important for some reason. There's also a prequel comic featuring her attempting to escape the military city with an older teen. It will be revealed that during this escape attempt she was bitten (assuming the infection spreads via bites) but wasn't infected, thus explaining both her hasty exodus from the city and her importance- she might be the key to a vaccine for the fungus, but the military will likely kill her as a security risk if they find out.
    • Confirmed. Good guess.

The source of the fungus plague is man-made.
  • Naughty Dog have stated that the whole idea behind The Last of Us came when they saw a Planet Earth documentary segment on a cordyceps fungus-infected ant, where the fungus takes over its brain and produces growths from its head. The idea that this fungus jumps species to humans forms the basis of the premise. Now, some cordyceps species are sources of biochemicals with interesting biological and pharmacological properties which have been experimented on with the goal of developing new helpful immunosuppressive drugs. This involves adapting the cordyceps fungus to fit a human vector. It's not a stretch to imagine that one such experiment went awry or escaped containment, becoming ground zero for the global pandemic that decimates the human race.

Joel gets infected or is infected somehow.
  • Remember how in that trailer there is a brief moment of Joel on the ground and Ellie holding a gun? This might mean that...
    • Jossed. Joel survives and remains uninfected up to the end of the story.

Ellie has to shoot an infected Joel in order to stop the infection from spreading.
  • Jossed. Look up.

Ellie and Joel's friendship is doomed.
  • Because you don't name your last chapter after a a sick of each other breakup song without foreshadowing connotations.
    • Jackson is the name of the city that Joel's brother Tommy is the protector of and he invited Joel and Ellie to live there before they left to find the Fireflies. You can see the city's hydroelectric dam in the ending. It's entirely possible and even likely that Joel and Ellie's friendship will last and they will find peace in Jackson.
    • Word of God certainly seems to favor the first interpretation.

Had the Fireflies just asked Ellie if she was willing to go through with the cure experiment, Ellie would have agreed
  • It's not exactly out of character for Ellie, and while Joel would have resisted the idea just as he did in the game, Ellie could probably have convinced him it was for the best - after all, a small chance of getting a cure is better than no chance, right? Instead, they assumed that Ellie would resist, yet somehow came to the conclusion that Joel would be fine with it, and may well have doomed humanity for it.
    • Or perhaps Marlena, as desperate as she was, just wanted to cut to the chase and avoid any possibility that could be set up for failure, and took advantage of a already unconscious Joel and Ellie.

More immune will naturally occur as more people are born post-Apocalypse.
Just as the fungus mutated and spread, so will the human immune response. Latent low levels of the fungus are breathed in, anti-bodies mutate to fight them, and these are passed on from mother to child. Thus the best - and most ironic - solution/cure is to simply... wait it out and proceed as normal (pre-breakout).
  • Except the Fireflies explain that Ellie's immunity has nothing to do with her specifically, but rather because her fungus infection happened to mutate into a unique non-malignant strain while inside her.
    • Okay then flip it around, eventually the strains of cordyceps that turn people into crazy zombies will be run extinct by humans precautioning against its spread or something, leaving only the kind Ellie has. This is how humanity used to domesticate plants like the once poisonous almond.

All of BioShock Infinite is a horrible dream Joel had while sick with that infection.
  • The characters are really similar and it makes sense in a Jungian way. Joel has fears over being a father figure to Ellie after his daughter dying and BioShock Infinite is a whole game of father issues. With that in mind the ending of BioShock Infinite with Elizabeth drowning Booker to keep the whole unpleasantness from happening is Joel's subconscious saying he'll have to sacrifice himself and Ellie for the greater good and that it's what she would want. Comstock and Booker are different personas of Joel, Marlene is Daisy Fitzroy, and the Luteces are Tess.
    • Alternatively, Sarah is analogous Anna (he has repressed memories with both) with Ellie as Elizabeth, Marlene is still Daisy, and the Luteces are bizzaro versions of Tess and Bill (they got Joel/Booker going didn't they?), Henry is a Big Daddy which oddly makes Sam the Little Sister. The Hunters and the Cannibals are splicers and the Fireflies are the Vox with the remaining security forces as the Founders. Oh, and David is Songbird. He holds Ellie/Elizabeth prisoner and there are a few other parallels I don't want to get into. Any way you cut it though, please make this a good a fanfic.
      • Bill is Cornelius Slate. Tommy is Robert Lutece because he's more sympathetic to Joel but still wants him to deliver Ellie to the Fireflies. "Bring us the girl and wipe away the debt." How did I not think of that! Ellie is "the girl", the fireflies are "us", and "the debt" is his obligation to Tess. Anyway, fanfic: Joel slipped off the horse outside the university and into unconsciousness. He had a dream that was the entirety of Bioshock: Infinite and maybe a bit of original Bioshock for context. Afterwards he woke up, in a basement, in the Colorado mountains during winter. Ellie isn't around. He goes on a murderous Ellie saving killing spree safe in the knowledge that it's a damn good thing that he doesn't have to deal with themes of American exceptionalism and poorly handled historical topics of race on top of everything else. The End. Epilogue: The night before David dreamt Spec Ops: The Line, find how that goes in the sequel.
      • You sir, just won the internet.

Ellie is short for Elizabeth.
  • Because those BioShock Infinite comparisons need a clincher.
    • The dark-haired teenage girl in Bioshock 2 you develop an intense father-daughter bond with? Eleanor.
      • Would you call Ellie's hair dark? It seems pretty light for a brunette to me. Compare the hints of red in her hair to Joel's.

The Fireflies missed a blindingly obvious alternative to brain extraction.
  • The whole point of removing Ellie's brain was to be able to study the fungus in a controlled environment, right? But they forget that Ellie technically isn't immune to the fungus; she's still very much infected. She just has a benign strain, which has the side effect of making it impossible for her to be infected again. Why does this matter, you ask? Because she should still be able to infect other people with her own strain, the same as the usual type of Infected. Just take a blood sample and inject it into somebody else's bloodstream, then see what happens.
    • That would explain why David seemed fine after Ellie bit him. Well, as fine as he can be.
    • Though the problem with this is that injecting a person with blood of a person that has a different blood type leads to a rather unpleasant death by blood clotting. So in order to get a cure for everyone they still need a sample of the fungus. Though that brings up the question why they didn't just try find someone willing to sacrifice themself for humanity who has the same blood type that Ellie has.
    • Unless Ellie's blood type is O.

David is Nathan Drake
  • Nate ended up losing Elena, Sully and Chloe to the infection and subsequently went insane with grief, adopting an alternate persona for himself as he had done before when claiming ancestry from Francis Drake, and turned to cannibalism to survive.

David is Captain Martin Walker after the Road to Glory ending
  • After killing the search team sent to rescue him, the now totally broken Walker made his way back to America while the plague was raging. Having already crossed both the Moral Event Horizon and Despair Event Horizon in Dubai, it would've been very easy for him to turn to cannibalism to survive. He adopted the "David" identity to keep the remnants of the US military off his trail.The cordyceps plague would also explain why there was no aid for Dubai after the sandstorm-the rest of the world was simply too preoccupied with a bigger crisis.

When Emma Bennett from the show Revolution got killed off in episode 15...
  • ...She came back as Tess in this game. Of course, considering that Tess gets killed off later on, it seems likely that she'll come back as a different character in a different place. Hopefully she'll have better luck in the next place.

The Last of Us takes place at the same time as Metro 2033.
Both games have some sort of cataclysm that begins in 2013, and then skip 20 years to the "present". The nuclear war that devastated Russia was a result of the ensuing panic of the Cordyceps outbreak. In addition to the radiation, the air is thick with Cordyceps spores, which necessitates the gas mask, and the mutant creatures and Dark Ones are creatures mutated by a combination of both the Cordyceps and radiation poisoning.
  • Wait, wouldn't the radioactive particles from such an act carry over to the US (and elsewhere) like they did after Chernobyl?
    • Probably, but not in sufficiently dangerous amounts like what the Russians have to deal with.
    • Well yeah but if Russia is going through Metro 2033 then the US is at least in Threads territory.
  • If the nuclear war started as a result of the Cordyceps outbreak, perhaps it was caused by either infected US military personnel firing rockets at Russia in the throes of fungus-induced madness, or the government mistaking the outbreak for a pre-emptive Russian biological weapons attack (presumably something launched from D6) and launching a retaliatory strike. And of course, these would probably have come after some kind of period of political tension between the two countries, giving them a reason to suspect the other of planning an attack.

David's Villainous Breakdown is a result of getting bitten by Ellie
.Now, it could be that David was always a bit unhinged and did a good job of hiding it, but since Ellie is acting as a carrier for a mutated Cordyceps strain, it's possible that that one of the side effects of biting and infecting another person with it is some sort of insanity.
  • If I may provide an alternative here: maybe Ellie biting David set him off to; "Well I'm screwed, might as well get revenge on that damn girl."

Ellie is wrong. The people the infected were once are still in there, and they remain completely conscious of their situation until they bite a bullet
The fungus slowly takes control over their bodies and there is nothing they can do about it. They don't want to chase you or bite you, but can't stop their infected body from doing it. And the 'fresh' runners screaming is them doing the last thing they can do by their own choice before the fungus takes it away from them.

There will be a DLC showing what Joel and Ellie did between Pittsburgh and Wyoming

The sequel will be closer in time to the outbreak and follow Ish's story
  • Nolan North will voice Ish as manic slightly crazy guy is right in the non-Drakeian area of the Northern wheelhouse.
  • Would that mean that travel by boat and fishing for extra supplies would be gameplay mechanics? (maybe with some pirates to fight?)

The Fireflies are behind the initial outbreak.
Isn't it a bit suspicious that such a well organized militia group spawned so quickly after the infestation began? Perhaps the plan was to introduce the infection, let the government crumble a bit and then swoop in as the 'saviors' of the U.S, so as to install their own government. Sure, perhaps this would work better with a cure ready to whip out, but maybe there was a cure at first, until things went horribly wrong and it somehow got lost. It's also very possible that the Fireflies seen in-game are a far different band than the original, so known Fireflies like Mareen aren't necessarily part of this conspiracy.

The rest of the world, outside of the U.S.A, is perfectly fine.
It only takes an hour to turn, so it doesn't seem likely that many infected could manage to travel to any place that requires traveling over ocean. The spores are deadly but they can't travel THAT far. There are certainly a few different ways i can imagine a worldwide epidemic occurring, but since there's no evidence for it in the game it seems equally likely that the world is normal, and simply letting the U.S die out of fear of the consequences of any intervention.

Spores are no longer infective, but the characters don't know it
Spores is the usual method of dispersion in Cordyceps type fungus. These show up in game being released after an infected has been completely overtaken by the fungus and dies as a result, and as part of the "grenades" thrown by bloaters. Although these take a bit of Joel's (and Ellie's!) life bar, the bloaters' spore bombs don't seem capable of infecting the playable characters, even when they have their gas masks off. This is because the humans' immune system is now capable of destroying the spores. The fungus strains more dependent on spores died out as the humans either died, or got access to anti-spore breathing masks. On the other hand, the strains that dispersed mostly through bites - which transmitted hifae rather than spores - became majority, and eventually displaced the others completely.
  • Alternatively, if one assumes that the spores are actually a deliberately-engineered bioweapon, perhaps they were designed to start out at maximum level of virulence before slowly degrading to near-harmlessness over time.
  • The bombs launched by bloaters, while appearing similar to the spore clouds you encounter in some areas, actually contain some sort of poison rather than spores. The infected don't produce fruiting bodies until after their death.

Ellie really is the key to a vaccine.
But not the way Marlene thinks. Ellie can transmit her mutated, benign cordyceps just like any other Infected, through contact with body fluids... but if she bites someone, there's a good chance they're going to end up dead anyway, so no one's had a chance to notice.

A Sequel or DLC will take place between the events of the prologue and the main game
20 years is a very long time, so it's entirely plausible that Joel would've had to go through some trials before the start of the game.
  • And it doesn't have to be DLC about Joel either. It could be focused on any of the characters: Bill and Frank claiming their city, Tess and her trials before she met Joel, Tommy and his morally ambiguous tutelage under Joel and how they ended up parting ways and him finding his wife, even a Marline DLC expanding on her relationship with Ellie or her mom and the rest of the Fireflies.
    • Or Ish. Or Maria, before she met Tommy. Hell, maybe even David.
  • Confirmed! The DLC, Left Behind, involves Ellie with her friend, Riley. We'll most likely see how they got infected.

The Cannibals from Winter are the same bandits who were hassling Tommy at the Dam
Mostly a feel good guess because that would mean Joel and Ellie effectively wiping out that group means they wouldn't be around to bother Tommy and his settlement anymore. After all if it's conceivable that they got to the university from Tommy's city on horseback, and that group they encountered were the cannibals they deal with in Winter, it certainly isn't a stretch geography wise.
  • If this were true that would mean David is the leader of a decent sized nation if it stretches from Northwestern Wyoming across to Central (if not Eastern) Colorado with it centered somewhere in the Western portion of Colorado (that's where most of the lakes are). I find this improbable at best.
    • David's area of control doesn't need to extend further than Colorado. The Wyoming people could be a long-ranging raiding party.

Damn it Jim, I'm a brain surgeon not a mycologist!
  • AKA: The Firefly doctors had no idea how to cook up a vaccine properly from Ellie because such a thing was outside their medical field, so they went with the quickest thing they could shoestring together-cutting out a little girl's brain.

There is a healthy population of escaped zoo big cats in the US that feeds on clickers
Clickers don't hide, make constant noise, are easily ambushed from behind and have fragile skulls. A cat's idea of paradise! Their heads might be bursting with fungus, but those bodies could still make a good meal.

Ellie has 2 types of fungus in her
When she was bitten, she also picked up a parasite that limits the growth of the cordyceps. This parasite stops it from driving her berserk, but it has a different means of spreading than the cordyceps-meaning she can still bite and infect people. This secondary fungus is descended from one of the real-life parasites that stop cordyceps growth in real life, only having jumped to targeting human cordyceps instead.

The Last Of Us is a prequel to God Eater.
At the current point in which The Last Of Us takes place, the infected will soon start mutating into Aragami. Considering how The Last Of Us is set in 2033 and God Eater takes place in 2071, it's quite possible that Fenrir was established in that period of time and the first God Arcs were made as well.

The world of The Last Of Us is a result of the Reason of Yosuga.
If the Demi-Fiend follows the Reason of Yosuga, he ushers in a world where the strong survive and the weak perish. Thus, to carry on Chiaki's wishes for the new world, he uses his demonic power to create a scenario where only the strong can find glory in the world. Of course, he'll be busy in Tokyo, still commanding an army of demons, and perhaps thinking about challenging the outside world.

Alternatively, the cordyceps outbreak was caused by YHVH.
In the MegaTen universe, God Is Evil is in full force. In the first SMT game, he caused a nuclear war just to whittle down humanity into mindless followers. In this, he may have started the outbreak via demons, rather than use the demons themselves. The American Military can be thought of as Law, whilst Firefly could be considered Chaos, leaving Joel as the Hero and Ellie as the Heroine who stays by him. Following this, Firefly may every well have been founded by a 'Louis Cyphere'...

There will be a DLC which will contain Ellie beating the shit out of David for 20 minutes
Just to please the fans that wanted to do that in game.

The cordyceps was God crying out in horror
Because Naughty Dog replaced Nolan North with Justin Bieber.

The cure would just cause more problems
It would be available just in America not the rest of the world.America would probably keep the cure for its self and try to sell it to other countries for high prices.Eventually wars would rise over the cure,killing even more innocent people.Only shitty people would stay alive and the world would be an even worse place.In the end Joel did a favor to the world.
  • This "America" would just be a Firefly dictatorship claiming to be the real successor of the United States.
  • I've actually put a lot of though into this myself because if you think about it, it's no secret that the worse enemies, the more evil, cruel and dangerous ones, were humans. Between the martial law enforcing government, the hunters and the cannibals and even the fireflies, opportunistic humans have grabbed power in the world over the past 20 years, Tommy's town shows that a decent community can survive without turning to savagery, the other factions could take routes like that, but choose not to. But why haven't they tried to expand their territories? The infected. The infected keep people isolated, but they prevent the ambitions of the bandits throughout the country from spreading, because they don't want to risk wasting ammo and soldiers fighting the infected causing them to loose upcoming fights for control. Take the infected away and...

Yor is a descendant of Ellie.
The movie takes place long after the apocalypse has happened, and it's possible that by then, technology would have managed to advance, and thanks to Ellie, the immunity would be passed on to her off springs, and spread around for generations to come. Dinosaurs would exist. Strange purple people could be another mutation of the virus. Yor himself could be from the great line of children started from Ellie. Plus, Ellie is capable of wiping out an entirely army single handed-ly (with or without Joel), and so is Yor, only he can wipe them out with hardly any trouble.

One of the DLCs will be called Believe in the Fireflies.
If you're wondering those are the last lines of the opening credits. It just sounds like a great name for either some Tommy DLC, Marlene DLC, other Firefly related DLC.

The Fireflies would have just killed Joel and Tess had they successfully rendezvoused with them at the Capitol.
The Fireflies are a ruthless bunch, Joel and Tess are just two people, and their usefullness would be done once they delivered Ellie. Had the revolutionaries not gotten themselves killed by the military, chances are good they would have just shot the pair before leaving with Ellie and the guns in tow.

Joel is infected with a mutated strain
Throughout the game Joel and Ellie end up being feared by groups that vastly outnumber them with access to good weaponry because Joel uses hearing mode and is kinda tough. Those weren't gameplay elements those were canon from him having been infected a few years ago without having noticed. The only things in game that are supposed to use echo location are stalkers, clickers, and bloaters. They don't develop the skill to replace eyesight, otherwise stalkers wouldn't be able to use it, its just coincidence like the mushroom armor plating. Joel just never noticed his hearing became amazing because it feels natural. The mutation is farther from the original than Ellie's also mutated version so his doesn't show up when he is scanned. There are two other humans that use echo-location; Ellie, who despite being a little girl is still much tougher than ordinary mooks, being bit around a year before she uses the ability, it wasn't quite as refined as Joel's, and David, who about an hour after being bit manages to stalk you down just like you've been doing to enemies, but since he should barely be a runner by this point, it isn't even as good as Ellie and still survived three times the damage that should have killed him.
  • This actually makes a decent amount of sense, particularly as Joel and Tess were frequently in and around areas of infection as smugglers, and the idea of the cordyceps continuing to evolve, considering that it had to mutate to infect people in the first place, and the fungus finding a way to form a symbiotic link would make sense.

Joel and Ellie met Ish at Tommy's.

One note you find in the abandoned neighbourhood after escaping the sewers reveals that he got out alive, so why not? Guessing just for heartwarming purposes.

Ellie after the ending would at some point start calling Joel "dad".

It's implied she grew to see him as a father just like he grew to see her as a daughter, so if I can be allowed to be sentimental I'm guessing she would attempt to call him "dad" at some point, and while he would find it difficult to hear at first, he'd eventually come to terms with it and even realize it feels nice.

Ellie is an adept thief.
Given the fact that she was born during the zombie apocalypse she had to start developing the skill of theft at an early age given it was needed to pretty much to survive much like a whole shit load of other crimes. She appears to have a nack for plundering such as when she took the picture of Joel and his daughter and how she "found" Bill's magazine stash.

Naughty Dog will intentionally drag their ass on the production of the sequel.
Let me elaborate. It's no secret to anyone except for X-box gamers maybe that Th Lo U was pretty much the shit judging by the ridiculous amount of copies sold, reviews and so forth; even though it's been out for quite some time already gamers are still buying it(probably because it's being recommended to them by other gamers and even store clerks). Making video games is not just about satisfying fellow gamers, it's also about raking in the moolah and with so copies of the first still selling why do they need to make a sequel right away.See? As sad as this a sequel might not come out until approximately 2020, that's one hell of a wait, but hey a game company's got to make it's money right?

Marlene knew that the fireflies weren't at the Capitol building from the start.
She knew it but she didn't tell Joel and Tess, because she knew that if she told Tess and Joel that they had to escort Ellie to the St. Marys hospital she would of probably got a big "HELL NO" as well as a fight for her life for the stolen merchandise. In the near end of the game notice how Marlene was in the hospital with Joel despite how she wasn't so called "up to the task at first". She wanted Ellie to get to the hospital to get her brains tore out for a CHANCE to make a cure but simply didn't feel like escorting Ellie herself. So by playing her cards right she managed to get Joel and Tess to do the pain in ass job for her.
  • While there WERE fireflies at the Captiol Building, the idea that Marleen expected they would be dead and Joel and Tess would need to take Ellie the whole way makes a lot of sense when you think about it. Joel is a toughened survivor who lost a child close to Ellies age, and had no connection to Ellie at the start, by the time they got to Salt Lake city he saw her as a daughter and, whatever other reasons he had, was willing to end to world to save her. Marleen was supposed to be more caring, she was regretful enough as it is about the idea, she never would've gone through with it if she'd had to escort Ellie that far. She'd hoped that more jaded Joel and Tess wouldn't develop that kind of bond but the idea of a cure would cause them to finish the mission.

Ellie is a late bloomer of the female kind.
It's a known fact that when girls hit Ellie's age they start getting their little "curves". While Ellie is developed to a very limited extent she still resembles a child more than a little young woman. This is not accidental in fact it's actually intentional. The reason why Naughty Dog designed Ellie this way is to avoid unnecessary and more likely critical controversy. As good as the gameplay and the story itself was Naughty Dog wanted to play it safe and not jeopardize the reviews that T Lo U was soon to get. Naughty Dog didn't want to make a 14 year old girl "sexy" not even in the natural sense to avoid giving off the illusion of creating pedo fanservice and even a unsuccessful but still pain in the ass lawsuit filed against them.
  • Girls going through puberty at 12 or even earlier is a result of the better nutrition brought by the industrialized world. Before industrialization, puberty hit females later, and the same would be in a famine-striken Crapsack World like The Last Of Us.

    • To be fair, while in universe the second point is true, the real world reason is probably what the first point theorized.

Tess & Joel were not boyfriend and girlfriend, they were literally "friends" with benefits.
Their relationship didn't consist of all the stereotypical dating rituals, infact they were just friends with a mutaul potent relationship and those friends just so happened to be sexually active because they were really close and last but definitely not least they were opposite genders unlike the Bill and Frank duo. They were sexually active mostly to Tess' delight hence Joel saying "and you always brushed me off.

Ellie is like Typhoid Mary
She is immune to the cordyceps but every non-immune that gets the cordyceps from her in the future (through biting, sex, giving birth) will be infected and die just the same.

The Last of Us is an intentional subversion of wish-fulfillment tropes usually associated with the Zombie Apocalypse genre.
During the past decade or so, movies and video games centered around zombies have tended toward a sort of wanton violence intended to satisfy the reptile part of the audience's collective brain in a guilt-free way. Wave after wave of people get mowed down with machine gun fire, driven over in cars, and sometimes literally chopped to pieces with improvised chainsaw-motorcycles, but it's okay, because they're zombies. The genre, while nominally horror, really ends up being like an action movie taken to its logical conclusion by stripping all humanity away from the bad guys. The apocalyptic setting is theoretically a Crapsack World, but it generally ends up being a sort of playground where people can do what they want without the limitations of society. It goes without saying that, in the case of the hero, this will include joyriding abandoned sports cars, throwing thousand dollar guitars around, and exploring the ruins of civilization rather than anything evil.

In this game, though, all of that goes out the window. A large number of enemies that the player character faces are very human, and through listening in on their conversations, you can even develop a certain amount of sympathy for them. Killing the infected is difficult, and sometimes something to be outright avoided if possible. Sure, you can run in guns blazing like you would in some other popular zombie games, but if you do that, you'll have your throat ripped out by a clicker or your jaw torn off by a bloater before you can get more than three kills. Beyond that, the infected are genuinely unnerving, and some runners seem to have shreds of human consciousness left, as evidenced by their sobbing while tearing a victim apart. The radical freedom common in zombie horror is replaced with a more realistic system where the government has been replaced by martial law, and the Well Intentioned Extremists fight to restore things to the way they used to be.

All of this goes together to make what looks like an intentional subversion of the entire modern genre of zombie horror. The Last of Us probably developed a large part of its unique gameplay features and genuinely unnerving atmosphere as a result of the developers' desire to create a game that intentionally subverted the above mentioned "wish-fulfillment" aspects for the sake of horror.

A sequel is most definitely going to come out. The reason why Naughty Dog said that there is a 50/50 chance that it'll come out was to play "hard to get".
Pretty much self explanitory. This game has sold over 7 million copies worldwide, also that doesn't include the crapload of DLC they've cashed in on as well. Naughty Dog is simply practicing an effective marketing strategy with the whole "don't really care" facade. Even if the sequel does suck ND can still make a fortune off of it because of the reputation of the first installment.
  • Confirmed, a sequel has been announced.

David believed that Joel was an Ephebophile, like himself.
Because in his mind, there couldn't have any been any other reason why an older man would travel around with a little girl who wasn't his daughter, and his comment that, "You won't survive long out there. I can protect you," doesn't make much sense if it's not meant to refer to David protecting Ellie from Joel, specifically, since he should know that Ellie is perfectly capable of fighting off infected and finding food. He may have believed (or wanted to Ellie to believe) that he could "rescue" her from what he thought was an abusive relationship.

In the live action film, David will be played by John Hawkes
Just look at him!

The game's cordyceps is not a fungus, but a lichen
And the long time infected don't starve and rot because the fungus gives them nutrients from photosynthesis for as long as it can.

Ellie is unknowingly Joel's daughter
Considering that Ellie is 14 years old in 2033, it isn't a stretch to think that Joel may have impregnated a random woman between 2018 and 2019. That woman turns out to be Anna, and she later moves into Boston Quarantine Zone and gives birth to Ellie. The reason why Ellie is a redhead while Joel is dark-haired maybe because she takes after her mother more, who has only been mentioned but never seen.
  • That would really downplay how touching their strangers-to-father&daughter relationship is though if they already were.

Sarah isn't actually dead and will turn up in the sequel
We don't see what happens in the immediate aftermath of Sarah mistakenly getting shot in the beginning, so it's entirely possible that she wasn't actually dead (just in shock or something) and that someone came along and managed to save her. It would be interesting if she showed up in the sequel (as say a member of the Fireflies), which would force Joel to confront his feelings of guilt over what he did at the end of the game to save Ellie.

Riley will turn up in the sequel and also turn out to be immune
Hear me out here, since both Ellie and Riley were bitten by the same zombie, it's entirely possible that Riley isn't actually dead yet because she has the same immunity to the virus that Ellie has. So maybe Riley decided to go off on her own and Ellie merely assumed she died but Never Found the Body as proof. So i'm guessing that Riley will make a surprising appearance in the sequel with the revelation of her own immunity to the virus, and she ends up taking over leadership of the Fireflies and tries to find a cure for the virus via blood sample from her and Ellie.

Connected to the theory of the cure making people worse off, Joel came to this conclusion due to a dream he had while injured
It's implied that Joel was in a coma for quite a while between the university and David. It is possible he had some kind of dream, seeing how bad the world had gotten, and that the vaccine would make things worse for the world. We know he was already turning against Ellie helping the fireflies (he kept trying to talk Ellie out of it before they were captured by the fireflies) was he just selfish? Was he trying to invoke Laser-Guided Karma or had he seen the truth of the world, and was simply trying to stop the Fireflies making it worse.

David was suffering from the early stages of Kuru or a similar prion disease.
It's known in real life that a cannibalistic diet can lead to such an infection, and him having it would explain why he seemed to be so unhinged even compared to the rest of his people. As for why it only affected him and not them, though? He's the leader of the group, and has been described as having "pets" like Ellie before she came around, so it's not unreasonable to believe that he perhaps has his own personal supply of meat that's separate from the scraps his followers get. Therefore, he was already in the process of losing his mind by the time he came upon Ellie in the wood, and across the day or so they knew each other, he only got crazier and crazier right up until the end.

Joel doesn't believe that humanity deserves a cure.
It's mentioned above that the game's worst antagonists are the human characters, not the infected. And Joel has seen these people up close, whether against them in the game or as a hunter himself as he suggested at one point. Marleen and the Fireflies on the other hand were idealists seeing the good in humanity that may not actually be there now. This would explain why to them Ellie would be an acceptable sacrifice to save humanity while Joel would not.

If the Ellie had been conscious then she wouldn't have been okay with sacrificing herself.
Related to the above, if Ellie had got to the Firefly lab right away she would've seen Marleen's point, particularly while mourning Riley and likely feeling guilty for getting her killed. However through her journey with Joel she has been exposed to the worst of Humanity and potentially may have seen Joel's side by the end, that Humanity didn't deserve a cure, or at least she didn't want to die for it.

The infection is Gaia's Vengeance.
It's mentioned above that currently the Cordyceps can't infect humans, at least not like it does in the game. It's also mentioned in Heartwarming that nature is taking the planet back, what if these things are not separate but that nature itself caused the Cordyceps in order to kill humanity off so that the planet can recover.

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