CD1 and iNKT cells mediate immune responses against the GBS hemolytic lipid toxin induced by a non-toxic analog

• Published in: PLoS pathogens Vol. 19; no. 6; p. e1011490
• Main Authors: Furuta, Anna, Coleman, Michelle, Casares, Raquel, Seepersaud, Ravin, Orvis, Austyn, Brokaw, Alyssa, Quach, Phoenicia, Nguyen, Shayla, Sweeney, Erin, Sharma, Kavita, Wallen, Grace, Sanghavi, Rhea, Mateos-Gil, Jaime, Cuerva, Juan Manuel, Millán, Alba, Rajagopal, Lakshmi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.06.2023
• Subjects: Adoptive transfer; Amino acids; Analysis; Antibiotics; Antibodies; Antigens; B cells; Biology and Life Sciences; CD1d antigen; CD4 antigen; Control; Cytotoxicity; Cytotoxins; Diseases; Disseminated infection; Health aspects; Identification and classification; Immune response; Immune serum; Immune system; Immunization; Infants (Newborn); Infection; Lipids; Lymphocytes; Lymphocytes B; Lymphocytes T; Medical research; Medicine and Health Sciences; Medicine, Experimental; Neonates; Neutrophils; Pregnancy; Research and Analysis Methods; Streptococcus agalactiae; Streptococcus infections; T cell receptors; T cells; Toxins; Vaccination; Vaccines; Virulence; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011490

Although hemolytic lipids have been discovered from many human pathogens including Group B Streptococcus (GBS), strategies that neutralize their function are lacking. GBS is a leading cause of pregnancy-associated neonatal infections, and adult GBS infections are on the rise. The GBS hemolytic lipid toxin or granadaene, is cytotoxic to many immune cells including T and B cells. We previously showed that mice immunized with a synthetic nontoxic analog of granadaene known as R-P4 had reduced bacterial dissemination during systemic infection. However, mechanisms important for R-P4 mediated immune protection was not understood. Here, we show that immune serum from R-P4-immunized mice facilitate GBS opsonophagocytic killing and protect naïve mice from GBS infection. Further, CD4+ T cells isolated from R-P4-immunized mice proliferated in response to R-P4 stimulation in a CD1d- and iNKT cell-dependent manner. Consistent with these observations, R-P4 immunized mice lacking CD1d or CD1d-restricted iNKT cells exhibit elevated bacterial burden. Additionally, adoptive transfer of iNKT cells from R-P4 vaccinated mice significantly reduced GBS dissemination compared to adjuvant controls. Finally, maternal R-P4 vaccination provided protection against ascending GBS infection during pregnancy. These findings are relevant in the development of therapeutic strategies targeting lipid cytotoxins.