Plausibility concept/research for TL: POD for a dangerous North American disease

I'm very interested in ways to change history so that Native North Americans fare better against the white settlers. I'm aware of the Columbian Exchange, and its disease component. What I'm asking is, could a disease plausibly come about in North America, that would be especially dangerous to the settlers, or even cross into the Old World and ravage it like the Black Death had? Transmission vectors would preferably be animals that usually inhabit North America(buffaloes, wild canids, rodents...), but later could expand to include dogs and rats that come with ships.

I apologize if I sound silly to some biologist/infectologist. But any insight would be much appreciated, because a timeline might come out from this attempt at research.
 
Most epidemic diseases are zoonoses, ie jumped from animals to man. Thats far more likely to happen if the humans and animals are living close together. Iotl, the natives had rather few domesticates, and most of those were kind of localized - llamas and guinea pigs didnt make it into North America, for instance.

Give them a bunch more domesticates, and a) youll have stronger societies, and b) theyll likely have diseases to share in the Columbian exchange.

See Peccari Rex for a good example of such a tl.
 
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