Journal
PLOS PATHOGENS
Volume 17, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1009467
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Funding
- National Research Foundation (NRF) - Ministry of Science, ICT and Future Planning, Republic of Korea [2017R1A2133009815]
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Xenorhabdus hominickii suppresses the immune responses of target insects by inhibiting eicosanoid biosynthesis through the suppression of phospholipase A(2) (PLA(2)) activation mediated by Se-DSP1 and the Toll immune signalling pathway. Additionally, X. hominickii metabolites prevent the release of Se-DSP1, leading to immunosuppression against bacterial infection in target insects.
Author summary Immune responses of insects are highly effective in defending various entomopathogens. Xenorhabdus hominickii is an entomopathogenic bacterium that uses a pathogenic strategy of suppressing host insect immunity by inhibiting phospholipase A(2) (PLA(2)) which catalyzes the committed step for eicosanoid biosynthesis. Eicosanoids mediate both cellular and humoral immune responses in insects. This study discovers an upstream signalling pathway to activate PLA(2) in response to bacterial challenge. Se-DSP1 is an insect homolog of vertebrate HMGB1 that acts as a damage-associated molecular pattern. Upon bacterial infection, Se-DSP1 is released to the circulatory system to activate Spatzle, an insect cytokine that can bind to Toll receptor. Toll immune signalling pathway can activate antimicrobial peptide gene expression and PLA(2). A deletion mutant against a Toll gene abolished immune responses mediated by Se-DSP1. Indeed, X. hominickii can produce and secrete secondary metabolites including salicylic acid analogs that can strongly bind to Se-DSP1. These bacterial metabolites prevented the release of Se-DSP1, which impaired the activation of PLA(2) and resulted in a significant immunosuppression of target insects against bacterial infection. Xenorhabdus hominickii, an entomopathogenic bacterium, inhibits eicosanoid biosynthesis of target insects to suppress their immune responses by inhibiting phospholipase A(2) (PLA(2)) through binding to a damage-associated molecular pattern (DAMP) molecule called dorsal switch protein 1 (DSP1) from Spodoptera exigua, a lepidopteran insect. However, the signalling pathway between DSP1 and PLA(2) remains unknown. The objective of this study was to determine whether DSP1 could activate Toll immune signalling pathway to activate PLA(2) activation and whether X. hominickii metabolites could inhibit DSP1 to shutdown eicosanoid biosynthesis. Toll-Spatzle (Spz) signalling pathway includes two Spz (SeSpz1 and SeSpz2) and 10 Toll receptors (SeToll1-10) in S. exigua. Loss-of-function approach using RNA interference showed that SeSpz1 and SeToll9 played crucial roles in connecting DSP1 mediation to activate PLA(2). Furthermore, a deletion mutant against SeToll9 using CRISPR/Cas9 abolished DSP1 mediation and induced significant immunosuppression. Organic extracts of X. hominickii culture broth could bind to DSP1 at a low micromolar range. Subsequent sequential fractionations along with binding assays led to the identification of seven potent compounds including 3-ethoxy-4-methoxyphenol (EMP). EMP could bind to DSP1 and prevent its translocation to plasma in response to bacterial challenge and suppress the up-regulation of PLA(2) activity. These results suggest that X. hominickii inhibits DSP1 and prevents its DAMP role in activating Toll immune signalling pathway including PLA(2) activation, leading to significant immunosuppression of target insects.
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