C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Jigar V. Desai; Dhaneshwar Kumar; Tilo Freiwald; Daniel Chauss; Melissa D. Johnson; Michael S. Abers; Julie M. Steinbrink; John R. Perfect; Barbara Alexander; Vasiliki Matzaraki; Brendan D. Snarr; Marissa A. Zarakas; Vasileios Oikonomou; Lakmali M. Silva; Raju Shivarathri; Emily Beltran; Luciana Negro Demontel; Luopin Wang; Jean K. Lim; Dylan Launder; Heather R. Conti; Muthulekha Swamydas; Micah T. McClain; Niki M. Moutsopoulos; Majid Kazemian; Mihai G. Netea; Vinod Kumar; Jörg Köhl; Claudia Kemper; Behdad Afzali; Michail S. Lionakis

doi:10.1016/j.cell.2023.04.031

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Jigar V. Desai, Dhaneshwar Kumar, Tilo Freiwald, Daniel Chauss, Melissa D. Johnson, Michael S. Abers, Julie M. Steinbrink, John R. Perfect, Barbara Alexander, Vasiliki Matzaraki, Brendan D. Snarr, Marissa A. Zarakas, Vasileios Oikonomou, Lakmali M. Silva, Raju Shivarathri, Emily Beltran, Luciana Negro Demontel, Luopin Wang, Jean K. Lim, Dylan LaunderHeather R. Conti, Muthulekha Swamydas, Micah T. McClain, Niki M. Moutsopoulos, Majid Kazemian, Mihai G. Netea, Vinod Kumar, Jörg Köhl, Claudia Kemper, Behdad Afzali, Michail S. Lionakis^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

86 Zitate (Scopus)

Abstract

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.

Originalsprache	Englisch
Zeitschrift	Cell
Jahrgang	186
Ausgabenummer	13
Seiten (von - bis)	2802-2822.e22
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2023.04.031
Publikationsstatus	Veröffentlicht - 22.06.2023

Fördermittel

This work was supported by the DIR of NIAID , NIDDK , NHLBI , NIDCR , and NINDS ( IRP support; L.N.D.) and grants from NIAID ( R00AI141622 ; J.V.D.), NIGMS ( R35GM138283 ; M.K.), NIDCR ( 1K99DE030124-01A1 ; L.M.S.), University of Toledo ( de Arce-Koch Memorial Endowment Fund ; H.R.C.), ERC grant (# 833247 ; M.G.N.), German Research Foundation ( FR 3851/2-1 ; T.F.), and Spinoza Grant of the Netherlands Organization for Scientific Research (M.G.N.). L.N.D. and E.B. were supported by the Departamento de Histología y Embriología, Universidad de la República, Uruguay and the NIH Oxford-Cambridge Scholars Program , respectively. We thank the NIAID animal facilities and research technology branch.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.21-05 Immunologie
2.22-22 Klinische Immunologie und Allergologie

Dokumente

10.1016/j.cell.2023.04.031

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Entschlüsselung der Rolle von CD46 im Rahmen von T Zell Entwicklungsentscheidungen
Freiwald, T. (Projektleiter*in (PI)), Kemper, C. (Supervisor) & Afzali, B. (Supervisor)
01.01.19 → 31.12.22
Projekt: DFG Einzelprojekte › DFG-Stipendien: Research Fellowships

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Desai, J. V., Kumar, D., Freiwald, T., Chauss, D., Johnson, M. D., Abers, M. S., Steinbrink, J. M., Perfect, J. R., Alexander, B., Matzaraki, V., Snarr, B. D., Zarakas, M. A., Oikonomou, V., Silva, L. M., Shivarathri, R., Beltran, E., Demontel, L. N., Wang, L., Lim, J. K., ... Lionakis, M. S. (2023). C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection. Cell, 186(13), 2802-2822.e22. https://doi.org/10.1016/j.cell.2023.04.031

@article{caeedd9edb5940619b4ac93d776589f1,

title = "C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection",

abstract = "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.",

author = "Desai, \{Jigar V.\} and Dhaneshwar Kumar and Tilo Freiwald and Daniel Chauss and Johnson, \{Melissa D.\} and Abers, \{Michael S.\} and Steinbrink, \{Julie M.\} and Perfect, \{John R.\} and Barbara Alexander and Vasiliki Matzaraki and Snarr, \{Brendan D.\} and Zarakas, \{Marissa A.\} and Vasileios Oikonomou and Silva, \{Lakmali M.\} and Raju Shivarathri and Emily Beltran and Demontel, \{Luciana Negro\} and Luopin Wang and Lim, \{Jean K.\} and Dylan Launder and Conti, \{Heather R.\} and Muthulekha Swamydas and McClain, \{Micah T.\} and Moutsopoulos, \{Niki M.\} and Majid Kazemian and Netea, \{Mihai G.\} and Vinod Kumar and J{\"o}rg K{\"o}hl and Claudia Kemper and Behdad Afzali and Lionakis, \{Michail S.\}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jun,

day = "22",

doi = "10.1016/j.cell.2023.04.031",

language = "English",

volume = "186",

pages = "2802--2822.e22",

journal = "Cell",

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Desai, JV, Kumar, D, Freiwald, T, Chauss, D, Johnson, MD, Abers, MS, Steinbrink, JM, Perfect, JR, Alexander, B, Matzaraki, V, Snarr, BD, Zarakas, MA, Oikonomou, V, Silva, LM, Shivarathri, R, Beltran, E, Demontel, LN, Wang, L, Lim, JK, Launder, D, Conti, HR, Swamydas, M, McClain, MT, Moutsopoulos, NM, Kazemian, M, Netea, MG, Kumar, V, Köhl, J , Kemper, C, Afzali, B & Lionakis, MS 2023, 'C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection', Cell, Jg. 186, Nr. 13, S. 2802-2822.e22. https://doi.org/10.1016/j.cell.2023.04.031

TY - JOUR

T1 - C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

AU - Desai, Jigar V.

AU - Kumar, Dhaneshwar

AU - Freiwald, Tilo

AU - Chauss, Daniel

AU - Johnson, Melissa D.

AU - Abers, Michael S.

AU - Steinbrink, Julie M.

AU - Perfect, John R.

AU - Alexander, Barbara

AU - Matzaraki, Vasiliki

AU - Snarr, Brendan D.

AU - Zarakas, Marissa A.

AU - Oikonomou, Vasileios

AU - Silva, Lakmali M.

AU - Shivarathri, Raju

AU - Beltran, Emily

AU - Demontel, Luciana Negro

AU - Wang, Luopin

AU - Lim, Jean K.

AU - Launder, Dylan

AU - Conti, Heather R.

AU - Swamydas, Muthulekha

AU - McClain, Micah T.

AU - Moutsopoulos, Niki M.

AU - Kazemian, Majid

AU - Netea, Mihai G.

AU - Kumar, Vinod

AU - Köhl, Jörg

AU - Kemper, Claudia

AU - Afzali, Behdad

AU - Lionakis, Michail S.

PY - 2023/6/22

Y1 - 2023/6/22

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85162129479

UR - https://www.mendeley.com/catalogue/c666089a-a7d8-3f2f-96b7-31b260f840f0/

U2 - 10.1016/j.cell.2023.04.031

DO - 10.1016/j.cell.2023.04.031

M3 - Journal articles

C2 - 37220746

AN - SCOPUS:85162129479

SN - 0092-8674

VL - 186

SP - 2802-2822.e22

JO - Cell

JF - Cell

IS - 13

ER -

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Abstract

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Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

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Entschlüsselung der Rolle von CD46 im Rahmen von T Zell Entwicklungsentscheidungen

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