A Novel C5a-Derived Immunobiotic Peptide Reduces Streptococcus agalactiae Colonization through Targeted Bacterial Killing

Streptococcus agalactiae (groupB Streptococcus [GBS]) is a Gram-positive bacterium that colonizes the cervicovaginal tract in approxi-mately 25%of healthywomen. Although colonization is asymptomatic, GBS can be vertically transmitted to newborns peripartum, causing severe disease such as pneumonia andmeningitis. Current prophylaxis, consisting of late gestation screening and intrapartum antibiotics, has failed to completely prevent transmission, andGBS remains a leading cause of neonatal sepsis andmeningitis in the United States. Lack of an effective vaccine and emerging antibiotic resistance necessitate exploring novel therapeutic strategies.We have employed a host-directed immunomodulatory therapy using a novel peptide, known as EP67, derived from theC-terminal region of human complement component C5a. Previously, we have demonstrated in vivo that EP67 engagement of the C5a receptor (CD88) effectively limits staphylococcal infection by promoting cytokine release andneutrophil infiltration.Here, using our establishedmouse model ofGBS vaginal colonization,we observed that EP67 treatment results in rapid clearance ofGBS from themurine vagina.How-ever, thiswas not dependent on functional neutrophil recruitment orCD88 signaling, as EP67 treatment reduced the vaginal bacterial load inmice lackingCD88 or themajor neutrophil receptor CXCr2. Interestingly, we found that EP67 inhibits GBS growth in vitro and in vivo and that antibacterial activity was specific to Streptococcus species. Ourwork establishes that EP67-mediated clearance of GBS is likely due to direct bacterial killing rather than to enhanced immune stimulation.We conclude that EP67mayhave potential as a therapeutic to controlGBS vaginal colonization