[Warning: Spoilers for Red Dead Redemption 2 below]
Regardless of how Red Dead Redemption 2 is played, Arthur Morgan always contracts tuberculosis and passes away by the end of the game. There is actually a specific scene in which it’s made clear when Arthur gets TB in RDR2, but it may not be apparent during someone's first playthrough.
Tuberculosis (commonly called TB) is an infection caused by bacteria which often targets the lungs or any other area in the body with a lot of blood and oxygen flowing through it. Although there is treatment now for TB, back in the end of the 1800s when Red Dead Redemption 2 is set there were barely any available options for people unfortunate enough to contract the sickness. Most people who were unlucky enough to become infected succumbed to their illness, much like how Arthur will die of TB by the end of Red Dead Redemption 2's story (if he’s not killed off by Micah first).
Throughout the second half of Red Dead Redemption 2, it becomes clear Morgan is sick thanks to his incessant coughing and pale color. A doctor in Saint Denis confirms Arthur Morgan's tuberculosis diagnosis, and some Red Dead Redemption 2 players likely also noticed that he gets slower and less agile as the game’s conclusion draws near, paralleling how Arthur's body and abilities would deteriorate in real life.
The specific scene in which Arthur gets TB in RDR2 happens during the Money Lending and Other Sins III mission. During the quest, Leopold Strauss, the Van der Linde gang's loan shark, tasks Arthur with collecting a debt from the Downes family. Thomas Downes, like many other people who crossed the gang's path, made the mistake of borrowing money from Strauss, and Arthur finds him working in his garden when he comes to collect what’s due.
While Arthur is beating the unhealthy man, Thomas coughs blood in his face. Coughing blood is one of the major signs of TB, so not only did this confirm that Thomas Downes was sick, but it also confirms he was who gave Arthur TB, since coughing infected blood in someone’s face is a sure-fire way to give them tuberculosis in RDR2 as well as in real life. It’s impossible to prevent Downes from coughing on Arthur; even if the player doesn’t attack him, Thomas will still cough. Arthur barely pays any mind at the blood spewed in his face, and it’s only when the man’s wife breaks up the fight that Arthur relents.
The next time Arthur returns to where he got TB in Red Dead Redemption 2's story, he learns Thomas Downes has passed, having succumbed to his illness. While Arthur initially insists Thomas’ wife and son are responsible for the debt, later on in the game - when Arthur eventually sees the Downes widow working as a prostitute in town - the sight leads him to kick Leopold Strauss out of the Van der Linde gang for good, as he finally realizes the harm Strauss sows wherever he goes. Unfortunately, by this point Arthur has already contracted tuberculosis, eventually paving the way for the conclusion of Red Dead Redemption 2.
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