{"doi":"10.1101/2025.06.27.661835","title":"Differences between human and rodent nitric oxide production dictate susceptibility to tick-borne <i>Rickettsia</i>","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555638,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1454443,"name":"A. Guzman","orcid":null,"position":1,"is_corresponding":false},{"id":516030,"name":"Alexis Bouin","orcid":"0009-0008-6712-9163","position":2,"is_corresponding":false},{"id":561839,"name":"Nir Drayman","orcid":"0000-0003-4460-9558","position":3,"is_corresponding":false},{"id":568501,"name":"Thomas Burke","orcid":"0000-0002-1385-8757","position":4,"is_corresponding":false},{"id":1454442,"name":"Anh Phuong Luu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:54:59.329539Z","pmid":"40667323","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}