Abstract

A thorough understanding of the functions of virulence regulators inBacillus anthracisevolution and host adaptation, particularly the systematic host responses they trigger, requires an efficient infection model capable of resolving subtle mechanisms. This study constructed a high-resolution host immune response decoder based onGalleria mellonellato analyze the specific response profiles elicited by different virulence regulators in a capsule-deficient background. By integrating transcriptomic, histopathological, and bacterial colonization analyses, the research delineated distinct host immune stress profiles regulated by AtxA and PlcR. The results showed that the AtxA-deficient strain failed to elicit significant host responses; wild-type infection activated broad systemic immune recognition pathways, while the PlcR-activated strain induced a unique response profile characterized by perturbations in oxidative stress pathways. Its enhanced virulence was associated with the expression of downstream hydrolases and occurred without strong systemic immune activation. This work successfully advanced theG. mellonellamodel from a phenotypic screener to a mechanistic resolver, providing a new methodological framework for distinguishingB. anthracisvirulence regulatory mechanisms at the host response level. This approach not only deciphers pathogen-specific immune signatures but also offers a practical platform for rapid anti-virulence compound screening and guides the design of targeted validation in mammalian systems, thereby accelerating therapeutic strategy development against anthrax.