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While House of the Dead franchise is known for it's Excuse Plot, it does actually has one (a quite tangled one).
Here you have it:
It all begins on December 18th, 1998. AMS agent Tom Rogan and his partner G are sent to deal with a disaster at the converted mansion laboratory of famed geneticist Dr. Roy Curien. Summoned by a distress call from Rogan's fiancee, Sophie, the pair discover the mansion is brimming with droves of undead (and other abominations) created by Curien's research into the unknown. Fighting through the mansion, the agents eventually confront Curien just as he's releasing his final masterpiece: The Magician. The creature promptly kills Curien, believing itself to be superior and - after a lengthy battle - is destroyed by the agents. It's all over. The End - or Is It??
On February 26th in the year 2000, the madness begins again. Agent G had tracked remnants of Curien's operation to Venice. When G goes missing, AMS rookies James Taylor and Gary Stewart are sent to investigate and discover that a much larger undead horde has descended upon all of Venice. The pair set off to stop whomever is behind the resurrection of Curien's work. Through G's notes and further investigation, it is discovered that Curien's work was funded by Caleb Goldman, the sinister CEO of the DBR Corp. However, Goldman is not interested in monetary gain - rather, he believes that mankind has inflicted too much damage to nature to be allowed to exist at its present capacity, and so he plans to kill off most of the global population.
Goldman saw great promise in Curien's work, and so he has fused Curien's experiments in genetic manipulation with his own work on the human genome. The resulting army of undead threatens not only Venice, but the entire globe. The AMS agents fight their way through the older sections of Venice - losing comrades along the way - before making it to Goldman's private skyscraper. James and Gary are then pitted against a resurrected Magician before confronting Goldman himself; Goldman unveils The Emperor, a supremely powerful creature designed to rule over nature and "destroy and hate mankind". Upon the demise of The Emperor, Goldman commits suicide... but not before pledging that a successor would come. Just the ravings of a madman, right...?
Three years later, James Taylor and AMS newcomer Kate Green are gathering information at the fifth basement of the AMS's European branch; James still has the events of the "Goldman Case" on his mind. Suddenly, the building is shattered by an earthquake and infiltrated by undead creatures that look an awful lot like the monsters Dr. Curien's work loosed on the world; they've already turned the surrounding area into a ruined wasteland. It gets worse when Taylor and Green discover that a nuclear launch is imminent; mutually-assured-destruction is about to glass the globe. Who is responsible for all this? It turns out that Goldman is responsible - from beyond the grave - for everything. James and Kate rush to Goldman's old headquarters to avert the nuclear launch, but Goldman has one last trick up his sleeve: a project codenamed Pandora's Box. The project is opened, revealing The World. Even though James and Kate square off against the monstrosity in an epic battle, weakening it greatly, The World refuses to die, forcing James to sacrifice his life to destroy The World in a massive explosion. The human race manages to survive yet again...
Fast-forward to 2019. Things have gotten much worse since the turn of the millennium; the massive zombie hordes that Goldman posthumously unleashed have brought about worldwide collapse. Tom Rogan managed to track down the source of the endless zombies to an abandoned, monolithic facility. He takes an experienced strike team with him... and doesn't return. Cue his daughter, Lisa, teaming up with Agent G to storm the place and bring her father home safely. Flashbacks reveal the original catalyst that drove Dr. Curien into his dark research: he sought to save the life of his terminally ill son, Daniel. Lisa and G reunite with Rogan and then team up with the now-adult Daniel to destroy Curien's final undead legacy: The Wheel of Fate.
The story is far from over, though; who knows what will happen next...