Why are archaea not pathogenic? A hypothesis based on metabolism-habitat covariation

Pathogenicity, the ability to cause infectious diseases in multicellular eukaryotes, is widespread among bacteria and eukaryotes but has not been reliably identified in archaea. To explore possible reasons for this disparity, we perform comparative analyses of thousands of bacterial and archaeal isolates. Our results show that isolated bacterial pathogens possess the ability to use organic compounds as sources of energy, electrons, and carbon (chemo-organo-heterotrophy or COH), suggesting that COH is a metabolic prerequisite for pathogenicity. Moreover, we find that isolated archaea capable of COH do not inhabit multicellular eukaryotes and instead predominantly inhabit extreme environments that preclude such eukaryotes. In contrast, all isolated archaea that inhabit multicellular eukaryotes are incapable of COH metabolism. This metabolism-habitat covariation in isolated archaea, together with COH as a potential prerequisite for pathogenicity in bacteria, suggests that the absence of archaeal pathogens may be due to a combination of the two factors: COH-capable archaea lack the environmental opportunity to inhabit multicellular eukaryotes, while non-COH archaea lack the metabolic prerequisite for pathogenicity.IMPORTANCEPathogenicity-the ability to cause infectious disease-is widespread among bacteria and eukaryotes but conspicuously absent from archaea, the third domain of life. To understand why archaea are non-pathogenic, we performed comparative analyses of thousands of bacterial and archaeal isolates. We found that the absence of pathogenic archaea can be explained by a combination of metabolic and environmental factors. Specifically, archaea living within eukaryotic, multicellular hosts lack a metabolic capability correlated with pathogenicity-chemo-organo-heterotrophy-whereas those possessing this metabolism typically live under extreme conditions, such as high temperature, and therefore lack the environmental opportunity to interact with eukaryotic hosts. These findings advance our understanding of microbes by revealing important links between their metabolism, habitats, and pathogenicity.