Mycoplasma pneumoniae CARDS toxin hijacks annexin A2 to enhance clathrin-mediated endocytosis and induce a cytopathic effect
Year: 2026
Type: article
Abstract: ABSTRACT Mycoplasma pneumoniae is a primary cause of bacterial community-acquired pneumonia. One of its key virulence factors, the community-acquired respiratory distress syndrome (CARDS) toxin, replicates most clinical symptoms of the infection. Although CARDS toxin exhibits multi-receptor binding affinity, the mechanisms governing its cellular entry remain poorly understood. In this study, we characterized the toxin entry pathway mediated by the host protein annexin A2 (AnxA2). Using flow cytometry and biotinylated membrane protein analysis, we demonstrate that CARDS toxin induces a rapid, transient translocation of AnxA2 to the plasma membrane, peaking at 15 min post-exposure. This recruitment occurs via a phosphorylation-independent mechanism, distinguishing it from the Src-dependent recruitment typically observed in other physiological contexts. Co-immunoprecipitation (co-IP) of the clathrin heavy chain revealed an enhanced AnxA2-clathrin association that accelerates clathrin-mediated endocytosis of toxin. Endosomal fractionation, immunofluorescence, and co-IP studies confirmed the time-dependent co-localization and physical interaction of CARDS toxin with AnxA2 within early endosomes. Furthermore, CRISPR/Cas9-mediated knockout of AnxA2 in A549 cells demonstrated that this protein is essential for the internalization of CARDS toxin; its absence not only reduces the toxin binding but also effectively impairs the rapid cellular uptake required to trigger the downstream cytopathic effects and vacuolation. These results establish that CARDS toxin modulates host surface remodeling through AnxA2 cell surface translocation to facilitate efficient cellular entry, identifying a rate-limiting step in M. pneumoniae pathogenesis.
Source: Infection and Immunity
DOI: 10.1128/iai.00553-26
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7225662027