Restoration of Type 17 Immune Signaling is Not Sufficient for Protection During Influenza-associated Pulmonary Aspergillosis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Feb 14

PMID 39949778

Authors

Aijaz Ahmad

Ravineel B Singh

Kara L Nickolich

Matthew J Pilewski

Caden Ngeow

Kwame Frempong-Manso

Keven M Robinson

Affiliations

Soon will be listed here.

Abstract

Introduction: Influenza-associated pulmonary aspergillosis (IAPA) is a severe complication of influenza infection that occurs in critically ill patients and results in higher mortality compared to influenza infection alone. Interleukin-17 (IL-17) and the Type 17 immune signaling pathway cytokine family are recognized for their pivotal role in fostering protective immunity against various pathogens. In this study, we investigate the role of IL-17 and Type 17 immune signaling components during IAPA.

Methods: Wild-type mice were challenged with influenza A H1N1 (flu) and then exposed to ATCC42202 resting conidia on day 6 post-influenza infection, followed by the quantification of cytokines and chemokines at 48 h post-fungal infection.

Results And Discussion: The gene and protein expression levels revealed that IL-17 and Type 17 immune cytokines and antimicrobial peptides are downregulated during IAPA compared to mice singularly infected solely with . Restoration of Type 17 immunity was not sufficient to provide protection against the increased fungal burden observed during IAPA. These findings contrast those observed during post-influenza bacterial super-infection, in which restoration of Type 17 immune signaling protects against exacerbation seen during super-infection. Our study highlights the need for future studies to understand the immune mechanisms that increase susceptibility to fungal infection.

References

Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T . The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases. Mediators Inflamm. 2017; 2017:3908061. PMC: 5337858. DOI: 10.1155/2017/3908061. View

Feys S, Goncalves S, Khan M, Choi S, Boeckx B, Chatelain D . Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study. Lancet Respir Med. 2022; 10(12):1147-1159. PMC: 9401975. DOI: 10.1016/S2213-2600(22)00259-4. View

Goncalves S, Pereira I, Feys S, Cunha C, Chamilos G, Hoenigl M . Integrating genetic and immune factors to uncover pathogenetic mechanisms of viral-associated pulmonary aspergillosis. mBio. 2024; 15(6):e0198223. PMC: 11237550. DOI: 10.1128/mbio.01982-23. View

Cua D, Tato C . Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010; 10(7):479-89. DOI: 10.1038/nri2800. View

Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe G . IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation. Cell Rep. 2018; 22(10):2642-2653. PMC: 5884137. DOI: 10.1016/j.celrep.2018.02.044. View

Wang C, Akalu Y, Suarez-Farinas M, Gonzalez J, Mitsui H, Lowes M . IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. J Invest Dermatol. 2013; 133(12):2741-2752. PMC: 3830693. DOI: 10.1038/jid.2013.237. View

Valeri M, Raffatellu M . Cytokines IL-17 and IL-22 in the host response to infection. Pathog Dis. 2016; 74(9). PMC: 5975231. DOI: 10.1093/femspd/ftw111. View

Arastehfar A, Carvalho A, van de Veerdonk F, Jenks J, Koehler P, Krause R . COVID-19 Associated Pulmonary Aspergillosis (CAPA)-From Immunology to Treatment. J Fungi (Basel). 2020; 6(2). PMC: 7346000. DOI: 10.3390/jof6020091. View

Ye P, Garvey P, Zhang P, Nelson S, Bagby G, Summer W . Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 2001; 25(3):335-40. DOI: 10.1165/ajrcmb.25.3.4424. View

10.

Sahoo M, Ceballos-Olvera I, Del Barrio L, Re F . Role of the inflammasome, IL-1β, and IL-18 in bacterial infections. ScientificWorldJournal. 2011; 11:2037-50. PMC: 3217589. DOI: 10.1100/2011/212680. View

11.

Kao C, Chen Y, Thai P, Wachi S, Huang F, Kim C . IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. J Immunol. 2004; 173(5):3482-91. DOI: 10.4049/jimmunol.173.5.3482. View

12.

Romani L . Immunity to fungal infections. Nat Rev Immunol. 2011; 11(4):275-88. DOI: 10.1038/nri2939. View

13.

Arkel A, Rijpstra T, Belderbos H, van Wijngaarden P, Verweij P, Bentvelsen R . COVID-19-associated Pulmonary Aspergillosis. Am J Respir Crit Care Med. 2020; 202(1):132-135. PMC: 7328331. DOI: 10.1164/rccm.202004-1038LE. View

14.

Robinson K, Ramanan K, Clay M, McHugh K, Pilewski M, Nickolich K . The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice. JCI Insight. 2018; 3(7). PMC: 5928863. DOI: 10.1172/jci.insight.97470. View

15.

Gessner M, Werner J, Lilly L, Nelson M, Metz A, Dunaway C . Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus. Infect Immun. 2011; 80(1):410-7. PMC: 3255669. DOI: 10.1128/IAI.05939-11. View

16.

Aujla S, Chan Y, Zheng M, Fei M, Askew D, Pociask D . IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008; 14(3):275-81. PMC: 2901867. DOI: 10.1038/nm1710. View

17.

Malacco N, Rachid M, da Silva Gurgel I, Moura T, Henrique Ferreira Sucupira P, de Sousa L . Eosinophil-Associated Innate IL-17 Response Promotes s Lung Pathology. Front Cell Infect Microbiol. 2019; 8:453. PMC: 6336733. DOI: 10.3389/fcimb.2018.00453. View

18.

Sutton C, Lalor S, Sweeney C, Brereton C, Lavelle E, Mills K . Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009; 31(2):331-41. DOI: 10.1016/j.immuni.2009.08.001. View

19.

Tobin J, Nickolich K, Ramanan K, Pilewski M, Lamens K, Alcorn J . Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis. J Immunol. 2020; 205(2):480-488. PMC: 7416629. DOI: 10.4049/jimmunol.2000067. View

20.

Hardy S, Kitamura M, Dai Y, Phipps M . Construction of adenovirus vectors through Cre-lox recombination. J Virol. 1997; 71(3):1842-9. PMC: 191254. DOI: 10.1128/JVI.71.3.1842-1849.1997. View