That's my thought as well - the just massive influx of pandemics once the Spanairds started colonizing Mesoamerica. One Dominican friar recorded 9 of them in 5 years, each killing off about 10% of the population. The Mesoamerican city states had enough population to overcome that. In North America the tribal societies didn't. Jared Diamond postulates that the village size was just large enough for everyone to get the viruses, just small enough to not survive repeated pandemics, but still the right size so a few people lived to pass them on to the next village over. No wonder the Christian missionaries ended up having success with the native americans. It must have appeared as if their gods had forsaken them. Even though it was the Christian missionaries who were the first to bring the diseases. Much later Wovoka, aka Jack Wilson, started the Ghost Dance movement, and believed himself to have had a vision from God in heaven and that Jesus Christ was to be reincarnated among the native tribes in the late west to save them from colonialism. Not too different from the Taiping Rebellion, where Chinese leaders who believed themselves reincarnations of Christ led the bloodiest rebellion in Chinese history. I also wonder how events would have played out without the Great Dying. There were up to 150 million native Americans in all of North America and the Caribbean. It seems even with technological advantages that it would have been impossible to subjugate such a large group forever. If it hadn't been for the diseases, most of us wouldn't be here, there'd be several native nations now after throwing off colonial rule, much like in India.