title: Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice.
abstract: There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa-/-) or factor B (Bf -/-) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection.
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Hua Hua
authors.initials: HH
authors.lastname: Tong
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Garrett
authors.initials: G
authors.lastname: Lambert
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Yong Xing
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Douthitt
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Clancy
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America; Department of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing, Sichuan, P. R. China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bowman
mesh_terms: D000208:Acute Disease; D000818:Animals; D060085:Coinfection; D003167:Complement Activation; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics; D015926:Complement C3a / Q000235:genetics / Q000276:immunology; D015936:Complement C5a / Q000235:genetics / Q000276:immunology; D011415:Complement Factor B / Q000172:deficiency / Q000235:genetics; D005064:Eustachian Tube / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000821:virology; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D010033:Otitis Media / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics*; D012720:Severity of Illness Index; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D015922:Complement C1q; D015926:Complement C3a; D015936:Complement C5a; D011415:Complement Factor B
references.citation: Front Immunol. 2012 Dec 10;3:368
references.pmid: 23233853
references.citation: Auris Nasus Larynx. 1985;12 Suppl 1:S188-90
references.pmid: 3835903
references.citation: Infect Immun. 1984 Feb;43(2):457-62
references.pmid: 6693167
references.citation: Nat Genet. 1998 May;19(1):56-9
references.pmid: 9590289
references.citation: Hear Res. 2006 Sep;219(1-2):12-23
references.pmid: 16887307
references.citation: J Clin Microbiol. 2011 Nov;49(11):3750-5
references.pmid: 21900518
references.citation: J Leukoc Biol. 2010 Feb;87(2):213-22
references.pmid: 19843575
references.citation: PLoS One. 2013 May 16;8(5):e64443
references.pmid: 23696894
references.citation: Laryngoscope. 2000 Oct;110(10 Pt 1):1745-9
references.pmid: 11037838
references.citation: Ann Otol Rhinol Laryngol. 1987 Mar-Apr;96(2 Pt 1):199-206
references.pmid: 3566060
references.citation: Pediatr Infect Dis J. 1996 Apr;15(4):281-91
references.pmid: 8866795
references.citation: PLoS One. 2011 Mar 09;6(3):e17377
references.pmid: 21408070
references.citation: J Clin Invest. 2011 Oct;121(10):3943-53
references.pmid: 21926466
references.citation: Infect Immun. 2001 Jan;69(1):602-6
references.pmid: 11119562
references.citation: Vaccine. 2008 Mar 17;26(12):1501-24
references.pmid: 18295938
references.citation: Virology. 2006 Sep 1;352(2):418-26
references.pmid: 16777168
references.citation: J Immunol. 2013 Apr 15;190(8):3831-8
references.pmid: 23564577
references.citation: Clin Exp Immunol. 2001 Jun;124(3):369-76
references.pmid: 11472396
references.citation: Adv Exp Med Biol. 2013;735:1-22
references.pmid: 22990692
references.citation: Curr Allergy Asthma Rep. 2012 Dec;12(6):551-8
references.pmid: 22968233
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8720-5
references.pmid: 9238044
references.citation: Infect Immun. 2002 Aug;70(8):4292-301
references.pmid: 12117938
references.citation: J Leukoc Biol. 2003 Dec;74(6):966-70
references.pmid: 12960283
references.citation: N Engl J Med. 1999 Jan 28;340(4):260-4
references.pmid: 9920949
references.citation: Int J Pediatr Otorhinolaryngol. 2013 Jun;77(6):911-7
references.pmid: 23537925
references.citation: Ann Otol Rhinol Laryngol. 2000 Nov;109(11):1021-7
references.pmid: 11089992
references.citation: Infect Immun. 2000 Jul;68(7):4024-31
references.pmid: 10858218
references.citation: Infect Immun. 2003 Oct;71(10):5531-40
references.pmid: 14500471
references.citation: J Immunol. 2013 Apr 15;190(8):3839-47
references.pmid: 23564578
references.citation: Infect Immun. 2011 Jul;79(7):2578-85
references.pmid: 21502587
references.citation: Infect Immun. 2013 Mar;81(3):645-52
references.pmid: 23319557
references.citation: Infect Immun. 1980 Nov;30(2):445-50
references.pmid: 7439990
references.citation: J Virol. 2007 Apr;81(7):3487-94
references.pmid: 17202212
references.citation: Microbiol Immunol. 2011 Mar;55(3):191-8
references.pmid: 21244468
references.citation: Laryngoscope. 1991 Feb;101(2):165-9
references.pmid: 1992267
references.citation: Clin Exp Otorhinolaryngol. 2008 Sep;1(3):117-38
references.pmid: 19434244
references.citation: Cell Health Cytoskelet. 2012 Jul 1;4:73-82
references.pmid: 23576881
references.citation: Am Rev Respir Dis. 1991 May;143(5 Pt 1):1062-6
references.pmid: 2024815
references.citation: Infect Immun. 2013 Mar;81(3):625-8
references.pmid: 23319561
references.citation: J Infect Dis. 2011 Dec 15;204(12):1857-65
references.pmid: 21930608
references.citation: Curr Opin Infect Dis. 2013 Jun;26(3):277-83
references.pmid: 23571695
references.citation: Infect Immun. 1981 Apr;32(1):311-7
references.pmid: 7216490
references.citation: Clin Microbiol Rev. 2006 Jul;19(3):571-82
references.pmid: 16847087
references.citation: Infect Immun. 2010 Mar;78(3):976-83
references.pmid: 20065024
references.citation: FASEB J. 2013 Mar;27(3):855-64
references.pmid: 23239822
references.citation: Infect Immun. 1982 Apr;36(1):289-96
references.pmid: 7076299
references.citation: Nat Immunol. 2010 Sep;11(9):785-97
references.pmid: 20720586