Low iron mitigates viral survival: insights from evolution, genetics, and pandemics—a review of current hypothesis

BACKGROUND: Upon re-examination of our human history, evolutionary perspectives, and genetics, a prevailing iron deficiency phenotype appears to have evolved to protect the human race from extinction. BODY: In this review, we summarize the evolutionary and genetic perspectives pointing towards the hypothesis that low iron mitigates infection. The presence of infection promotes the generation of resistance alleles, and there are some evolutionary and genetic clues that suggest the presence of an iron deficiency phenotype that may have developed to protect against infection. Examples include the relative paucity of iron overload genes given the essential role of iron, as well as the persistence of iron deficiency among populations in spite of public health efforts to treat it. Additional examination of geographic areas with severe iron deficiency in the setting of pandemics including H1N1, SARS, and COVID-19 reveals that areas with higher prevalence of iron deficiency are less affected. RNA viruses have several evolutionary adaptations which suggest their absolute need for iron, and this dependency may be exploited during treatment. CONCLUSION: RNA viruses pose a unique challenge to modern healthcare, with an average of 2–3 new pathogens being discovered yearly. Their overarching requirements for iron, along with human evolutionary and genetic adaptations which favored an iron deficiency phenotype, ultimately suggest the potential need for iron control in these infections.