Elevated CO2 suppresses specific Drosophila innate immune responses and resistance to bacterial infection.
Elevated CO(2) levels (hypercapnia) frequently occur in patients with obstructive pulmonary diseases and are associated with increased mortality. However, the effects of hypercapnia on non-neuronal tissues and the mechanisms that mediate these effects are largely unknown. Here, we develop Drosophila as a genetically tractable model for defining non-neuronal CO(2) responses and response pathways. We show that hypercapnia significantly impairs embryonic morphogenesis, egg laying, and egg hatching even in mutants lacking the Gr63a neuronal CO(2) sensor. Consistent with previous reports that hypercapnic acidosis can suppress mammalian NF-kappaB-regulated innate immune genes, we find that in adult flies and the phagocytic immune-responsive S2* cell line, hypercapnia suppresses induction of specific antimicrobial peptides that are regulated by Relish, a conserved Rel/NF-kappaB family member. Correspondingly, modest hypercapnia (7-13%) increases mortality of flies inoculated with E. faecalis, A. tumefaciens, or S. aureus. During E. faecalis and A. tumefaciens infection, increased bacterial loads were observed, indicating that hypercapnia can decrease host resistance. Hypercapnic immune suppression is not mediated by acidosis, the olfactory CO(2) receptor Gr63a, or by nitric oxide signaling. Further, hypercapnia does not induce responses characteristic of hypoxia, oxidative stress, or heat shock. Finally, proteolysis of the Relish IkappaB-like domain is unaffected by hypercapnia, indicating that immunosuppression acts downstream of, or in parallel to, Relish proteolytic activation. Our results suggest that hypercapnic immune suppression is mediated by a conserved response pathway, and illustrate a mechanism by which hypercapnia could contribute to worse outcomes of patients with advanced lung disease, who frequently suffer from both hypercapnia and respiratory infections.
Helenius
Iiro Taneli
IT
Department of Biochemistry, Northwestern University, Evanston, IL 60208, USA.
Krupinski
Thomas
T
Turnbull
Douglas W
DW
Gruenbaum
Yosef
Y
Silverman
Neal
N
Johnson
Eric A
EA
Sporn
Peter H S
PH
Sznajder
Jacob I
JI
Beitel
Greg J
GJ
D000138:Acidosis / Q000150:complications / Q000276:immunology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001424:Bacterial Infections / Q000150:complications / Q000276:immunology*; D002245:Carbon Dioxide / Q000494:pharmacology*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000254:growth & development / Q000276:immunology* / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006935:Hypercapnia / Q000150:complications / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D029721:Drosophila Proteins; C101626:Rel protein, Drosophila; D014157:Transcription Factors; D002245:Carbon Dioxide; D009569:Nitric Oxide