The study shows that a protein made by the bacteria Streptococcus suis (called PepO) can chop up the human antimicrobial peptide LL‑37, stopping it from killing the bacteria and from helping immune cells work properly. When the bacteria lack PepO, they become much more vulnerable to LL‑37 and cause less damage in mice.

<i>Streptococcus suis</i> is a zoonotic Gram-positive bacterium that causes invasive infections such as sepsis and meningitis, threatening public health worldwide. For successful establishment of infection, the bacterium should subvert the innate effectors of immune defence, including the cathelicidin family of host-defence peptides that combat pathogenic bacteria by directly disrupting cell membranes and coordinating immune responses. Here, our study shows that an extracellular endopeptidase O (PepO) of <i>S. suis</i> contributes to assisting the bacterium to resist cathelicidin-mediated killing, as the deletion of the <i>pepO</i> gene makes <i>S. suis</i> more sensitive to the human cathelicidin LL-37, as well as its mouse equivalent, mCRAMP. This protease targets and cleaves both LL-37 and mCRAMP, degrading them into shorter peptides with only a few amino acids, thereby abrogating their ability to kill <i>S. suis</i>. By cleaving LL-37 and mCRAMP, PepO impairs their chemotactic properties for neutrophil migration and undermines their anti-apoptosis activity, which is required for prolonging neutrophil lifespan. Also, PepO inhibits the ability of LL-37 and mCRAMP to promote lysosome development in macrophages. Moreover, the loss of PepO attenuates organ injury and decreases bacterial burdens in a murine model of <i>S. suis</i> bacteraemia. Taken together, these data provide novel insights into the role of the intrinsic proteolytic characteristics of PepO in <i>S. suis</i>-host interaction. Our findings demonstrate that <i>S. suis</i> utilizes the PepO protease to cleave cathelicidins, which is an immunosuppressive strategy adopted by this bacterium to facilitate pathogenesis.