The first known contact by Europeans on the southeastern coast came in 1521, roughly concurrent with Cortez’s conquest of Mexico. A party of Spanish slavers, led by Francisco Cordillo (sometimes spelled Gordillo), ventured to what’s now Port Royal Sound from Santo Domingo in the Caribbean. Naming the area Santa Elena, he kidnapped a few dozen Indian slaves and left, ranging as far north as the Cape Fear River in present-day North Carolina, and by some accounts even further up the coast.

The first serious exploration of the South Carolina coast came in 1526, when Lucas Vazquez de Ayllon and about 600 colonists made landfall at Winyah Bay near present-day Georgetown. They didn’t stay long, however, immediately moving down the coast and trying to establish roots in the St. Catherine’s Sound area of modern-day Liberty County, Georgia. That colony—called San Miguel de Gualdalpe—was the first European colony in America. (The continent’s oldest continuously occupied settlement, St. Augustine, Florida, wasn’t founded until 1565.) The colony also brought with it the seed of a future nation’s dissolution: slaves from Africa. San Miguel lasted only six weeks due to political tension and a slave uprising.

Hernando de Soto’s infamous expedition of 1539–1543 began in Florida and went through southwest Georgia before crossing the Savannah River somewhere near modern-day North Augusta, South Carolina. He immediately came in contact with emissaries from the Cofitachequi empire of Mississippian Indians. Sort of a Native American superpower, the Cofitachequi nation was the culmination of years of consolidation among regional tribes. They had attained a high level of sophistication and military and economic prowess, with the rule of their eponymous queen, Cofitachequi, recognized for about 250 miles in every direction—in other words, over almost all of South Carolina.

When de Soto and his men arrived near the Cofitachequi capital near modern-day Camden, he was met on the shores of the Wateree River by Queen Cofitachequi herself. She had heard the tales of de Soto’s previous atrocities against Indian villages who refused to aid him in his quest for gold, and she was savvy enough to receive him diplomatically. According to a Spanish account, the queen “was a young girl of fine bearing…and she spoke to the governor quite gracefully and at her ease,” born on a platform covered with pillows and carried by strong young men.

While de Soto found no fabled cities of gold, he was impressed by the quality and quantity of the Cofitachiqui great homes and the massive quantities of copper and pearls they had amassed. In true conquistador fashion, de Soto decided to take the queen herself hostage to guarantee his safe passage through the rest of her empire. The queen proved smarter than her captor, however. During their journey across South Carolina, at one point she excused herself into the woods to attend to bodily functions. She immediately vanished, heading back to her people.

Long after his departure and eventual death of fever in Alabama, de Soto’s legacy was felt throughout the Southeast in the form of various diseases for which the Mississippian tribes had no immunity whatsoever: smallpox, typhus, influenza, measles, yellow fever, whooping cough, diphtheria, tuberculosis, and bubonic plague.

While the barbaric cruelties of the Spanish certainly took their toll, far more damaging were these deadly diseases to a population totally unprepared for them. As the viruses they introduced ran rampant, the Europeans themselves stayed away for a couple of decades after the ignominious end of de Soto’s quest. During that quarter-century, the once-proud Mississippian culture, ravaged by disease, disintegrated into a shadow of its former greatness.