Differences between human and rodent nitric oxide production dictate susceptibility to tick-borne Rickettsia

Arthropod-borne pathogens cause serious human infections, yet they only cause limited disease in rodent reservoirs. Wild type mice resist infection by tick-borne Rickettsia parkeri, which causes spotted fever in humans, and it remains unclear why humans are vulnerable. Here, we report that whereas mouse type I interferon (IFN-I) or interferon-γ (IFN-γ) dramatically restrict R. parkeri in macrophages, human interferons do not. Differential RNA-seq revealed a significant induction of nitric oxide synthase 2 ( Nos2, encoding inducible nitric oxide synthase, iNOS) in infected mouse but not human macrophages upon interferon treatment. Chemical iNOS inhibition or Nos2 deletion restored IFN-γ-mediated restriction in mouse cells. Human cells treated with cytokine cocktails or with iNOS cofactors and substrates were still unable to restrict R. parkeri . In vivo , whereas wild type mice restricted R. parkeri , infected Nos2 ^-/- mice developed mild skin eschars, recapitulating a key human disease manifestation. Together, our findings suggest that there is a threshold of NO production required to restrict R. parkeri, which mouse cells reach but human cells do not, and this is a key explanation for why humans develop tick-borne rickettsial diseases while rodents can be tolerant, asymptomatic reservoirs. Differences in NO abundance may provide an evolutionary explanation for human susceptibility to pathogens that propagate themselves in rodent reservoirs.