Open AccessCyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish
Author(s) -
Savini Thrikawala,
Mengyao Niu,
Nancy P. Keller,
Emily E. Rosowski
Publication year - 2022
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010040
Subject(s) - biology , zebrafish , aspergillus fumigatus , phagocyte , innate immune system , microbiology and biotechnology , immune system , aspergillosis , signal transduction , cyclooxygenase , immunology , enzyme , gene , biochemistry
Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva- Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Increased germination and invasive hyphal growth is also observed in infected F0 crispant larvae with mutations in genes encoding for COX enzymes ( ptgs2a/b ). Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E 2 (PGE 2 ) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE 2 -EP2 pathway to increase control A . fumigatus hyphal growth by phagocytes in zebrafish larvae.