C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.
C5
C5aR1
Candida
avacopan
candidemia
candidiasis
complement
eculizumab
kidney
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
22 06 2023
22 06 2023
Historique:
received:
15
06
2022
revised:
10
03
2023
accepted:
21
04
2023
pmc-release:
22
06
2024
medline:
26
6
2023
pubmed:
24
5
2023
entrez:
23
5
2023
Statut:
ppublish
Résumé
Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
Identifiants
pubmed: 37220746
pii: S0092-8674(23)00465-8
doi: 10.1016/j.cell.2023.04.031
pmc: PMC10330337
mid: NIHMS1896551
pii:
doi:
Substances chimiques
Antifungal Agents
0
Complement C5
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2802-2822.e22Subventions
Organisme : NIAID NIH HHS
ID : R00 AI141622
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138283
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AI001175
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Cell Host Microbe. 2022 Apr 13;30(4):530-544.e6
pubmed: 35316647
PLoS Pathog. 2015 Dec 17;11(12):e1005293
pubmed: 26679537
Blood. 2008 Sep 1;112(5):1759-66
pubmed: 18567839
J Clin Invest. 2002 Dec;110(12):1823-30
pubmed: 12488432
J Immunol. 2013 Apr 15;190(8):3831-8
pubmed: 23564577
Nat Rev Immunol. 2015 Oct;15(10):599-614
pubmed: 26403194
J Clin Invest. 2006 Feb;116(2):512-20
pubmed: 16453025
Sci Immunol. 2023 Feb 3;8(80):eabp9547
pubmed: 36735773
Eur J Immunol. 2009 Dec;39(12):3343-56
pubmed: 19795417
Comput Struct Biotechnol J. 2020 Dec 26;19:647-663
pubmed: 33510868
Cell Rep. 2012 Dec 27;2(6):1762-73
pubmed: 23200858
Clin Exp Immunol. 2000 Aug;121(2):226-33
pubmed: 10931135
Infect Immun. 2009 Sep;77(9):3679-85
pubmed: 19581397
PLoS Pathog. 2014 Jul 17;10(7):e1004276
pubmed: 25033445
J Clin Invest. 2013 Dec;123(12):5035-51
pubmed: 24177428
Med Mycol. 1999 Dec;37(6):419-26
pubmed: 10647123
PLoS One. 2016 Mar 02;11(3):e0149704
pubmed: 26934706
J Immunol. 1997 Mar 1;158(5):2356-62
pubmed: 9036985
Immunol Cell Biol. 1993 Jun;71 ( Pt 3):221-5
pubmed: 8349305
Immunity. 2013 Jan 24;38(1):79-91
pubmed: 23273845
Front Immunol. 2020 Jul 08;11:1397
pubmed: 32733463
Cell. 2004 Oct 29;119(3):431-43
pubmed: 15507213
Cell Death Differ. 2012 Feb;19(2):310-20
pubmed: 21779001
N Engl J Med. 2021 Feb 18;384(7):599-609
pubmed: 33596356
J Leukoc Biol. 2016 Nov;100(5):1113-1124
pubmed: 27312848
J Immunol. 2015 Feb 1;194(3):1199-210
pubmed: 25539819
Br J Haematol. 2019 Apr;185(2):297-310
pubmed: 30768680
J Immunol. 2004 Sep 1;173(5):3437-45
pubmed: 15322209
Mol Immunol. 2009 Sep;46(14):2753-66
pubmed: 19477527
Immunohorizons. 2021 Feb 17;5(2):90-101
pubmed: 33597177
Am Rev Respir Dis. 1984 Jan;129(1):82-6
pubmed: 6703488
Science. 2002 Jun 21;296(5576):2225-9
pubmed: 12029063
Nat Metab. 2020 Jan;2(1):110-125
pubmed: 32128508
Immunity. 2021 May 11;54(5):1002-1021.e10
pubmed: 33761330
J Immunol. 2014 Dec 1;193(11):5387-401
pubmed: 25355927
Annu Rev Immunol. 2011;29:1-21
pubmed: 20936972
Nat Rev Dis Primers. 2018 May 11;4:18026
pubmed: 29749387
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4954-60
pubmed: 26230759
Immunity. 2016 Aug 16;45(2):240-54
pubmed: 27533012
Sci Immunol. 2021 Apr 7;6(58):
pubmed: 33827897
Sci Immunol. 2021 Dec 24;6(66):eabf2489
pubmed: 34932384
Nat Commun. 2014 Sep 08;5:4675
pubmed: 25197941
Nat Immunol. 2017 Nov 16;18(12):1288-1298
pubmed: 29144501
Cell. 2022 Feb 3;185(3):493-512.e25
pubmed: 35032429
Immunology. 2000 Jan;99(1):38-45
pubmed: 10651939
Annu Rev Immunol. 2018 Apr 26;36:157-191
pubmed: 29237128
J Infect Dis. 2005 Jul 15;192(2):336-43
pubmed: 15962230
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6610-5
pubmed: 12740444
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Cell. 2021 Aug 19;184(17):4495-4511.e19
pubmed: 34289345
JCI Insight. 2018 Feb 8;3(3):
pubmed: 29415879
Cell Host Microbe. 2018 Jan 10;23(1):121-133.e4
pubmed: 29290576
J Fungi (Basel). 2018 Jan 11;4(1):
pubmed: 29371503
J Infect Dis. 2006 May 15;193(10):1419-26
pubmed: 16619190
Nat Rev Immunol. 2019 Aug;19(8):503-516
pubmed: 31048789
J Immunol. 2001 Sep 1;167(5):2446-51
pubmed: 11509581
Immunity. 2015 Jun 16;42(6):1033-47
pubmed: 26084023
JCI Insight. 2017 Jun 2;2(11):
pubmed: 28570272
J Infect Dis. 1997 Apr;175(4):847-55
pubmed: 9086140
J Clin Invest. 2020 Jun 1;130(6):3238-3252
pubmed: 32154791
Haematologica. 2014 Sep;99(9):1410-20
pubmed: 25176982
Science. 2021 Jan 15;371(6526):
pubmed: 33446526
Sci Transl Med. 2020 Jun 17;12(548):
pubmed: 32554707
Annu Rev Immunol. 2018 Apr 26;36:309-338
pubmed: 29677470
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Cell Rep. 2022 May 31;39(9):110851
pubmed: 35649359
Cell Rep. 2022 May 3;39(5):110777
pubmed: 35508133
Science. 2014 Sep 26;345(6204):1250684
pubmed: 25258083
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
J Innate Immun. 2011;3(2):180-99
pubmed: 21063074
Nucleic Acids Res. 2019 May 7;47(8):e47
pubmed: 30783653
PLoS One. 2011;6(8):e22919
pubmed: 21829669
Immunity. 2010 Aug 27;33(2):266-78
pubmed: 20727790
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Antimicrob Agents Chemother. 2001 Nov;45(11):3162-70
pubmed: 11600372
J Biol Chem. 2005 Dec 2;280(48):39677-80
pubmed: 16204243
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Am J Pathol. 2002 Nov;161(5):1849-59
pubmed: 12414531
Nat Rev Immunol. 2023 Jul;23(7):433-452
pubmed: 36600071
Nat Rev Drug Discov. 2019 Sep;18(9):707-729
pubmed: 31324874
Virulence. 2022 Dec;13(1):89-121
pubmed: 34964702
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
J Clin Invest. 1976 Jun;57(6):1626-34
pubmed: 932197
Immunity. 2017 Jun 20;46(6):1059-1072.e4
pubmed: 28636955
Bioinformatics. 2005 Jan 15;21(2):263-5
pubmed: 15297300
J Vis Exp. 2011 Dec 08;(58):
pubmed: 22215135
J Immunol. 1994 May 15;152(10):5000-8
pubmed: 8176217
Am J Physiol Renal Physiol. 2022 Jun 1;322(6):F597-F610
pubmed: 35379003
Sci Transl Med. 2016 Jan 20;8(322):322ra10
pubmed: 26791948
PLoS Pathog. 2013;9(10):e1003634
pubmed: 24098114
Mediators Inflamm. 2016;2016:1313027
pubmed: 26989329
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Science. 2016 Jun 17;352(6292):aad1210
pubmed: 27313051
Genome Res. 2015 May;25(5):679-89
pubmed: 25858952
J Immunol. 2015 Feb 15;194(4):1841-55
pubmed: 25589074
Nat Med. 2012 Sep;18(9):1401-6
pubmed: 22922409
Transgenic Res. 1999 Aug;8(4):265-77
pubmed: 10621974
PLoS Pathog. 2015 Jul 09;11(7):e1004912
pubmed: 26158781
Infect Immun. 2004 Oct;72(10):5868-76
pubmed: 15385488
Immunity. 2020 Mar 17;52(3):513-527.e8
pubmed: 32187519
Eukaryot Cell. 2014 Feb;13(2):329-40
pubmed: 24376002
Nat Commun. 2022 Sep 22;13(1):5545
pubmed: 36138043
Blood. 2020 Mar 26;135(13):1049-1057
pubmed: 31932840
Clin Exp Immunol. 1997 Jan;107(1):1-7
pubmed: 9010248
Nat Commun. 2018 Oct 15;9(1):4260
pubmed: 30323213
Infect Immun. 2006 Aug;74(8):4439-51
pubmed: 16861630
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8093-8
pubmed: 9223320
Nat Genet. 2021 Sep;53(9):1300-1310
pubmed: 34475573
Nat Rev Immunol. 2018 Jun;18(6):374-389
pubmed: 29581532
Nat Genet. 2003 Jan;33(1):55-60
pubmed: 12483212
Sci Immunol. 2017 Jan;2(7):
pubmed: 28529998
Sci Immunol. 2020 Jun 5;5(48):
pubmed: 32503877
Life Sci Alliance. 2021 Feb 19;4(5):
pubmed: 33608410
Genome Med. 2021 Jul 5;13(1):108
pubmed: 34225776
Immunol Rev. 2016 Nov;274(1):16-32
pubmed: 27782335
Cell Death Differ. 2019 Dec;26(12):2622-2636
pubmed: 30944411
J Fungi (Basel). 2017 Oct 18;3(4):
pubmed: 29371573