β₂-microglobulin inhibits Escherichia coli biofilm formation via selectively blocking curli assembly

Bacteria have evolved a remarkable strategy to thrive in hostile environments by creating well-organized microcommunities known as biofilms. Biofilms pose a serious global health challenge due to their contribution to antibiotic resistance and suppression of the effectiveness of immune responses, thereby exacerbating pathogenic conditions. Biofilm-dwelling bacteria are difficult to eliminate since the cells are embedded within a self-produced, intricate 3D extracellular matrix composed of protein polymers (amyloids), polysaccharides, and extracellular nucleic acids. The robustness of the matrix poses a significant challenge to curb biofilm infections. Moreover, there is a lacuna in understanding how biofilm may be controlled under physiological conditions. Therefore, it is imperative to investigate the role of host proteins in keeping a check on biofilm formation. In the present study, we have established β₂-microglobulin (β₂m), a human protein integral to innate immunity, as a potent inhibitor of biofilm formation in Escherichia coli. Our comprehensive biophysical, biochemical, computational, microscopic, and in vivo analyses revealed that β₂m effectively prevents E. coli biofilm formation by specifically inhibiting amyloid curli, a major matrix component of E. coli biofilm. In a rat skin wound infection model, β₂m significantly accelerated wound healing, underscoring its therapeutic potential against biofilm infections. Our results illustrate a crucial function of β₂m as an endogenous antibiofilm and anticurli protein, provides a host-derived strategy to combat biofilm infections, and presents a method to augment existing antimicrobial therapies.