The Plague of Athens (430-427 BC): Integration of Historical, Clinical, and Ancient DNA Data Supports an Invasive Non-Typhoidal Salmonella enterica Etiology.

The Plague of Athens represents one of the earliest and most detailed descriptions of a large-scale epidemic in recorded history. Emerging in 430 BC during the second year of the Peloponnesian War, it caused extensive mortality, including the death of Pericles, the leader of Athenian democracy at the time. Thucydides, the famous historian, provides an eyewitness account with a rich clinical narrative encompassing symptomatology, complications, mortality rates, epidemic dynamics, post-infection immunity, and animal involvement. In this narrative review, we integrate Thucydides' account with modern clinical knowledge, archaeological evidence, and ancient DNA data to reassess the most plausible cause of the epidemic. DNA analysis from dental pulp of skeletons found in a mass burial of the Kerameikos cemetery demonstrated the DNA presence of Salmonella enterica among individuals who died during the outbreak. Human-restricted pathogens traditionally proposed as causes of the Plague of Athens fail to account for the zoonotic features emphasized in the historical record. By contrast, non-typhoidal Salmonellae enterica (NTS) are zoonotic and, under conditions of crowding, malnutrition, and sanitation breakdown, are capable of causing invasive, systemic disease with high mortality. We propose that the cause of the epidemic is most consistent with an unusually virulent, invasive strain of non-typhoidal Salmonella enterica. While precise serovar identification remains speculative, this interpretation provides the most coherent synthesis of the historical, clinical, archaeological, and molecular data currently available. A structured differential diagnosis against other zoonotic pathogens further supports this conclusion.