As his infection takes hold, Sam attacks Ellie, but Henry shoots him and then commits suicide out of grief.

They ally with two brothers, Henry (Brandon Scott) and Sam (Nadji Jeter) after they escape the city, Sam is bitten by an infected but hides it from the group. Driving into Pittsburgh, they are ambushed by bandits and their car is wrecked. Earl Brown), a smuggler who owes Joel a favor, they acquire a working vehicle. Joel decides to find Tommy, a former Firefly, in the hope that he can locate the remaining Fireflies. Tess reveals she has been bitten by an infected believing in Ellie's importance, Tess sacrifices herself against pursuing military soldiers so Joel and Ellie can escape. The trio make their way to their destination through hordes of infected, but find that the Fireflies there have been killed. Full infection normally occurs in under two days, but Ellie claims she was infected three weeks ago and that her immunity may lead to a cure. Joel, Tess, and Ellie sneak out in the night, but after an encounter with a patrol, they discover Ellie is infected.

The leader of the Fireflies, Marlene (Merle Dandridge), promises to double their stolen cache in return for smuggling a teenage girl, Ellie (Ashley Johnson), to Fireflies hiding outside of the quarantine. Before Tess kills him, Robert reveals that he traded the goods to the Fireflies, a rebel group opposing the quarantine zone authorities. They hunt down Robert (Robin Atkin Downes), an arms dealer, to recover a stolen weapons cache.

Joel works as a smuggler with his friend Tess (Annie Wersching) in a Boston quarantine zone. Survivors live in heavily policed quarantine zones, independent settlements and nomadic groups. Twenty years later, most of civilization has been destroyed by the infection.

As Joel, his brother Tommy (Jeffrey Pierce), and Sarah flee the chaos, Sarah is shot by a soldier and dies in Joel's arms. One night, an outbreak of a mutant Cordyceps fungus ravages the United States, transforming its human hosts into cannibalistic monsters. In 2013, Joel (voiced and motion captured by Troy Baker) is a single father living near Austin, Texas, with his twelve-year-old daughter Sarah (Hana Hayes).

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