Set during a long and hot summer day and night, a deadly infection breaks out on Mulberry Street in downtown Manhattan, causing humans to devolve into blood-thirsty monstrosities. Most of the information in the film comes from TV news broadcasts where as a result of constant urban decay, pollution and unbearable heat, the sewer rats of Manhattan are quickly spreading an unknown and horrible disease that causes its victims to mutate into ravenous and bloodthirsty rat-creatures. Once bitten, people quickly turn into rabid-like creatures with the appearance and eating habits of rats, and they only look at their former friends and neighbors as a source of food. Clutch, a retired boxer, nervously awaits the homecoming of his soldier daughter, Casey, recently back from a tour of duty in Iraq, but first he has to protect the other tenants as the rat-zombies are quickly infesting the entire neighborhood.
Initially emergency services and city authorities attempt to contain the spread by shutting down public transportation, and closing roads, but soon hospitals are inundated with the wounded, and the virus begins to spread island wide. By the time Clutch and the rest of the film's characters realize the severity of the situation, the infected have overrun much of the city and the streets are highly dangerous, with police seemingly overwhelmed and unable to respond. The survivors barricade themselves in their apartments as the news of the outbreak and subsequent quarantine of Manhattan breaks on TV and radio, waiting on promised rescue from the military, which the government promises will begin to restore order in Manhattan soon.
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