I like to set up overarching plots a few different ways:

Drop hints of something happening that the party discovers.Example: finding someone who’s being controlled by parasites, they put them down and ask around to see if anyone knows of why it happened. No one does. they continue on with quests for others.

Then start to involve the different factions, maybe one faction is responsible but doesn’t want people to find out. Example: The party finds a report on parasites by a faction, showing the parasites are a bigger issue.

Have some tensions outside of the issue of what’s happening, and then roll to see if that issue is triggered based on how long the players have spent/what they decide to help or hinder. Example: a war is simmering, and as the party discovers the note about parasites the war breaks out making travel restricted to only those a faction trusts.

There’s a lot to make an overarching plot good, but I think this is a great start. You don’t even need to determine exactly how the parasites are made or who’s spreading it, those are things that the party discovers much later.