people start complaining about a flu, then start dying, more and more people fall sick and panic ensues.
you happen to be immune, and spies report group of rogue necromancers have unleashed an evil they did not intend. They have since fled their hideout up in the mountains and you begin tracking them down one by one to interrogate them and find out what exactly they were experimenting with.
you explore their hideout, now abandoned, several rotting necromancers appear at your feet, research notes and journals explain in detail the slow lingering death all will face if you do not find a cure.
a demon from oblivion could be the source, one not written about in TES lore.. destroying it will eliminate the disease once and for all.
Quests could deal with managing the riotous panic, delivering messages, helping the sick, making antedotes etc..
Even if not the MQ a lengthy side-quest imo.
Call it TESV: the eternal grey.