The role of neuraminidase NanH in drug-induced phagocytic resistance of G. parasuis and its targeted intervention.

Abstract

BACKGROUND: Glaesserella parasuis (G. parasuis) is the core pathogen of porcine respiratory disease syndrome (PRDC), and the co-evolution of its drug resistance and virulence has seriously threatened the biosecurity of the global pig farming industry. OBJECTIVE: This study aims to clarify the core function of neuraminidase (NanH) in the formation and pathogenic mechanism of G. parasuis resistance and explore its feasibility as a novel therapeutic target. METHOD: Drug-resistant strains were induced by tildipirosin combined with florfenicol (MIC increased to 16&#x202f;&#x3bc;g/mL), and the mechanism of drug resistance was systematically analyzed by transcriptomics, gene knockout and multi-model infection experiments. RESULT: The activity of the ABC transport system in drug-resistant strains was enhanced, the virulence genes VapC and artM were upregulated, the smoothness of the cell wall increased, and host autophagy was significantly inhibited (LC3-II transformation decreased, P&#x202f;<&#x202f;0.01). The nanH gene was highly expressed in drug-resistant strains. Its deletion (&#x394;nanH) reduced bacterial adhesion by 57&#x202f;% (P&#x202f;<&#x202f;0.01), decreased mouse mortality by 70&#x202f;% (P&#x202f;<&#x202f;0.005), and inhibited the transcription of COX-2 and TNF-&#x3b1;. The autophagy-targeted chimeric (NanH-AUTAC) designed based on the targeted protein degradation (TPD) strategy achieved a degradation rate of 60&#x202f;% for NanH-EGFP at 40&#x202f;&#x3bc;M. CONCLUSION: NanH is a key regulatory factor in the co-evolution of G. parasuis drug resistance and virulence, and can serve as a potential target for anti-infection treatment. The "disarming" strategy based on TPD provides a new direction for dealing with drug-resistant bacterial infections.