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

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 μg/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 < 0.01 ). The nanH gene was highly expressed in drug-resistant strains. Its deletion ( ΔnanH ) reduced bacterial adhesion by 57 % ( P < 0.01 ), decreased mouse mortality by 70 % ( P < 0.005 ), and inhibited the transcription of COX-2 and TNF-α. The autophagy-targeted chimeric (NanH-AUTAC) designed based on the targeted protein degradation (TPD) strategy achieved a degradation rate of 60 % for NanH-EGFP at 40 μM. 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.