title: Scavenging nucleic acid debris to combat autoimmunity and infectious disease.
abstract: Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal's ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710; Duke Translational Research Institute, Duke University, Durham, NC 27599;
authors.forename: Eda K
authors.initials: EK
authors.lastname: Holl
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710; Duke Translational Research Institute, Duke University, Durham, NC 27599; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710;
authors.forename: Kara L
authors.initials: KL
authors.lastname: Shumansky
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC 27607;
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710; Duke Translational Research Institute, Duke University, Durham, NC 27599;
authors.forename: Angela D
authors.initials: AD
authors.lastname: Burnette
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710; Duke Human Vaccine Institute, Duke University, Durham, NC 27710.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sample
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710; Duke Human Vaccine Institute, Duke University, Durham, NC 27710.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ramsburg
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710; Duke Translational Research Institute, Duke University, Durham, NC 27599; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710; bruce.sullenger@duke.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism*; D015551:Autoimmunity / Q000187:drug effects; D053837:DNA Cleavage; D050091:Dendrimers / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008178:Lupus Erythematosus, Cutaneous / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009696:Nucleic Acids / Q000737:chemistry / Q000302:isolation & purification*; D011485:Protein Binding; D059367:RNA Cleavage; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D000974:Antibodies, Antinuclear; D050091:Dendrimers; D007155:Immunologic Factors; D009696:Nucleic Acids; C104700:PAMAM Starburst
keywords: autoimmunity; inflammation; influenza; nucleic acid; scavenger