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^*

^*Corresponding author for this work

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	2802-2822.e22
Number of pages	22
Journal	Cell
Volume	186
Issue number	13
DOIs	https://doi.org/10.1016/j.cell.2023.04.031
Publication status	Published - 22-Jun-2023

Keywords

avacopan
C5
C5aR1
Candida
candidemia
candidiasis
complement
eculizumab
kidney

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C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infectionFinal publisher's version, 13.6 MBLicence: Taverne

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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{980e9e6e2e004521860c12ec22bad9d9,

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.",

keywords = "avacopan, C5, C5aR1, Candida, candidemia, candidiasis, complement, eculizumab, kidney",

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, vol. 186, no. 13, pp. 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.

KW - avacopan

KW - C5

KW - C5aR1

KW - Candida

KW - candidemia

KW - candidiasis

KW - complement

KW - eculizumab

KW - kidney

UR - http://www.scopus.com/inward/record.url?scp=85162129479&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.04.031

DO - 10.1016/j.cell.2023.04.031

M3 - Article

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

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