According to Aztec tradition, the Mexica people ventured south after being commanded by their god of war, Huitzilopochtli, to settle in the first place they saw an eagle perched upon a cactus, devouring a snake. This divine symbol was first seen on a small island in Lake Texcoco, which is where they combined their advanced engineering with their intuitive design to build Tenochtitlan — a lush metropolis of stone pyramids and floating gardens.
Two centuries after the founding of one of history’s most glorious empires, it would fall — not only to Spanish arms and the growing resentment of nearby independent states, but also to the smallpox virus carried across the Atlantic by the very people who came to conquer it.
The Aztecs were incredibly dedicated to many fields, such as urban engineering and city planning, hydrology, the arts, agriculture, and especially religion. Their religious beliefs were so deeply integrated into their daily lives that they ceremoniously sacrificed prisoners of war captured during military campaigns to honour Huitzilopochtli. Conquered states were required to provide jade, gold, rubber, bird feathers, cacao beans, and other valuable goods. The states faced severe military punishment if they failed to deliver their tribute.
Hernán Cortés arrived in 1519 with around 500 soldiers, many of whom grew uneasy as they learned more about the powerful Aztec Empire. Cortés, an extraordinarily ambitious conquistador, knew that retreat was not an option. He had assembled an expedition and secretly set sail despite the Governor of Cuba’s decision to revoke his commission. In openly defying the governor, Cortés had staked his future on one outcome: conquering the Aztecs.
So, he ordered the ships to be dismantled and, according to later accounts, told the quivering soldiers and sailors: “As for me, I have determined to succeed or die. If any of you are faint-hearted or fear death, you are welcome to leave. But how will you do it? There are no ships left.”
While still strategising on the coast, a different tribe known as the Totonacs gave him two extremely valuable pieces of information — firstly, there was a massive, unimaginably wealthy city inland known as Tenochtitlan. Secondly, another kingdom lay right on the way to Tenochtitlan, known as the Tlaxcalans, who despised the Aztecs. After starting his journey inland, he expected the Tlaxcalans to welcome him with open arms as an enemy of the Aztecs, but instead, they attacked his troops. They fought for days on end, and most of Cortés’ men were pushed to their limits, while the Tlaxcalans observed the power of Spanish swords and firearms. So, they agreed on a compromise — to become allies and defeat the Aztecs together. The Tlaxcalans awarded him thousands of their finest fighters. Now, with the advanced weaponry of that era and some of history’s most ferocious warriors, Cortés was nearly unstoppable. He was confident that strategic political positioning, military tactics, and his soldiers would carry him to victory. What didn’t he know? The most powerful, unseen weapon in his arsenal was a virus, which would become the catalyst for his conquest.
Cortés, along with his soldiers, marched into Tenochtitlan. The current ruler, Moctezuma II, invited them inside and treated them as foreign ambassadors while he tried to figure out the motive behind their sudden arrival. Inside the palace, Cortés commanded his soldiers to capture Moctezuma II and hold him hostage. Through this, Moctezuma essentially became a puppet ruler and was completely under Cortés’ control for many months. One day, Cortés received news that the Governor of Cuba had sent troops to capture him for committing treason. He rushed to the coast and fought the troops, ultimately winning — which helped him expand his army, as he absorbed the surviving troops into his own. But while he was gone, the soldiers in Tenochtitlan believed this was a massive ploy by the Aztecs to distract Cortés and regain control of the empire. Because of this, they panicked and ended up killing multiple unarmed Aztec nobles. Cortés returned to find the city in complete chaos. His soldiers were under attack and were fighting thousands of enraged Aztecs. Cortés and his reinforced army rushed back into the bloodbath to rescue their trapped garrison. Realising they were completely outnumbered and cut off, the Spanish attempted a desperate nighttime escape across the narrow causeways leading out of the city.
A chaotic, terrifying clash of bodies exploded in the darkness. Fighting hand-to-hand for their lives, soldiers were screaming, gasping, and clashing in suffocatingly close quarters. While the Aztecs successfully drove the invaders out, this physical victory came at a catastrophic biological cost. Among the new troops Cortés had brought from the coast was a soldier carrying the smallpox virus. In the heavy breathing and frantic shouting of that brutal melee, respiratory droplets carrying the virus spread directly to the Aztec warriors, leaving behind an invisible executioner.
By the 1500s, smallpox was a common childhood disease and had circulated around Europe for centuries. Those who were exposed to smallpox and survived — about 70% of people who caught it — developed lifelong immunity due to the presence of B-cells and T-cells.
The smallpox virus spreads primarily through respiratory droplets. When they land on a person’s face, a few droplets, or virions, do end up inside a person’s nasal or oral cavity. Once on the mucous membrane, which is designed to catch germs and pathogens, the virus produces specific proteins that allow it to pass through the mucous barrier without getting trapped, allowing it to make contact with the living epithelial cells beneath the mucous membrane.
The smallpox virion is covered with small, specific proteins called glycoproteins. Our epithelial cells are also covered in various molecules to help communicate or absorb nutrients. The main molecules the smallpox virus targets are glycosaminoglycans, specifically one called heparan sulphate. Once the glycoproteins on the smallpox virus bind to the epithelial cells, the virus sends a signal to the cell that tricks it into thinking it is a harmless nutrient, and the cell opens up and swallows the virus. Once the virus is inside, it dissolves the vesicle, freeing itself into the cell’s cytoplasm. The virus then sheds its protein coat and exposes its double-stranded DNA, after which it uses its own enzymes to copy its DNA while using the host cell’s ribosomes to produce viral proteins. Eventually, the host cell is filled with viral clones and becomes so bloated that it literally bursts. After a cell dies such a violent death, macrophages quickly rush to the area to eliminate the dead cell and initiate tissue repair. Macrophages try to engulf the virus by trapping it in a phagosome and using acid and enzymes to destroy it, but the virus has adapted specifically for this situation. The low pH acts as a trigger for the virus and activates specific proteins, allowing it to break out into the macrophage’s cytoplasm before it can be destroyed by the enzymes.
After infecting the macrophages, it travels to the lymph nodes and then to the thoracic duct, which empties into the bloodstream. It targets organs such as the spleen, liver, and bone marrow, which are rich in white blood cells. Here, the virus replicates massively. About 9 to 13 days later, the new army of clones bursts out, triggering a high fever, extreme muscle pain, and painful headaches while the body tries to combat the overwhelming viral load. Finally, the virus spreads to the dermis and infects the capillaries, along with the outer layers of the skin, as they are also covered with the same molecules as the epithelial cells mentioned earlier. As the virus replicates there too and the cells burst, cytokines — chemical distress signals — are released into the bloodstream, and the area is flooded with white blood cells to fight the infection. The massive accumulation of dead cells has nowhere to go, so it forms the deeply painful, fluid-filled pustules associated with smallpox.
Since smallpox had circulated throughout Europe for centuries, most Spanish people had survived it and developed immunity thanks to B-cells and T-cells, which recognise the virus’s glycoproteins on its surface and rapidly produce the required antibodies if another infection occurs. Because of this prior immunity, most Spanish people were protected. But the Aztecs had never faced anything like this before. After their victory against the Spanish, massive celebrations began. However, about two weeks afterwards, people started falling sick in huge numbers. The virgin soil epidemic had begun. Because their bodies had never encountered anything like this before, they were left completely defenceless. They couldn’t even get up to eat or drink water, let alone treat themselves. In 70 days nearly 50% of the population was wiped out, including warriors and their newly crowned emperor Cuitláhuac. When Cortés returned in 1521, expecting to find the advanced civilization stronger than ever, he instead found a silent city, with barely any residents, compared to its earlier glorious years. The greatest empire in Mesoamerica had not fallen to swords alone, but to a virus invisible to the human eye.
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