AUTHOR=Steffan Breanne N. , Calise Dante , Park Sung Chul , Niu Mengyao , Yang Jun , Hammock Bruce D. , Jones MaryJane , Steele Chad , Keller Nancy P. 

TITLE=Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1173544

DOI=10.3389/fimmu.2023.1173544

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p><italic>Aspergillus fumigatus</italic> is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and <italic>Aspergillus</italic> developmental programs. <italic>Aspergillus</italic> synthesizes 8-HODE and 5,8-diHODE that have structural similarities to 9-HODE and 13-HODE, which are known ligands of the host G-protein-coupled receptor G2A (GPR132).</p></sec><sec><title>Materials and methods</title><p>Oxylipins were extracted from infected lung tissue to assess fungal oxylipin production and the Pathhunter β-arrestin assay was used to assess agonist and antagonist activity by fungal oxylipins on G2A. An immunocompetent model of <italic>A. fumigatus</italic> infection was used to assess changes in survival and immune responses for G2A-/- mice.</p></sec><sec><title>Results</title><p>Here we report that <italic>Aspergillus</italic> oxylipins are produced in lung tissue of infected mice and <italic>in vitro</italic> ligand assays suggest 8-HODE is a G2A agonist and 5,8-diHODE is a partial antagonist. To address the hypothesis that G2A could be involved in the progression of IPA, we assessed the response of G2A-/- mice to <italic>A. fumigatus</italic> infection. G2A-/- mice showed a survival advantage over wild-type mice; this was accompanied by increased recruitment of G2A-/- neutrophils and increased levels of inflammatory markers in <italic>A. fumigatus</italic>-infected lungs.</p></sec><sec><title>Conclusions</title><p>We conclude that G2A suppresses host inflammatory responses to <italic>Aspergillus fumigatus</italic> although it remains unclear if fungal oxylipins are involved in G2A activities.</p></sec>