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

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.

Adolescent and youth-friendly health interventions in low-income and middle-income countries: a scoping review.

BACKGROUND: Adolescents comprise one-sixth of the world's population, yet there is no clear understanding of the features that promote adolescent-friendly services (AFS). The lack of clarity and consistency around a definition presents a gap in health services. METHODS: The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a scoping review of peer-reviewed empirical studies to explore AFS in low-income and middle-income countries (LMICs) published between January 2000 and December 2022. The databases searched were CAB Direct (n=11), CINAHL (n=50), Cochrane Databases (n=1103), Embase (n=1164), Global Health Medicus (n=3636) and PsycINFO (n=156). The title, abstract and full text were double screened by three independent reviewers. Three independent reviewers assessed the study's quality using the Joanna Briggs Initiative Quality Appraisal and Cochrane Risk of Bias 2 tools. RESULTS: We identified the key components, barriers and facilitators of AFS. The following emerged from our review: a non-judgmental environment, culturally appropriate and responsive interventions and a focus on supporting marginalised communities often living in high-poverty settings. Using these components, we have extended guidance around a possible framework and tool assessing quality of AFS. INTERPRETATION: As LMICs are heterogeneous and unique, it was assumed that the operational definition of 'adolescent-friendly' might vary depending on different contexts, but there must be core components that remain consistent. Possible limitations of our review include a lack of grey literature. Potential future implications include training healthcare providers, testing these attributes for service improvement and future development and localisation of policy guidelines. KEY HIGHLIGHTS: Our review has mapped the research framing of AFS and provided a comprehensive review of barriers and facilitators to implementing a holistic outlook of AFS set-up in a tightly controlled research and real-world context. Our paper is one of the few efforts to synthesise behavioural and mental health elements underpinning AFS.

GBS hyaluronidase mediates immune suppression in a TLR2/4- and IL-10-dependent manner during pregnancy-associated infection.

IMPORTANCE: Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial factors during infections in the placenta is not fully understood. GBS secretes a hyaluronidase enzyme that is thought to digest host hyaluronan into immunosuppressive disaccharides that dampen TLR2/4 signaling, leading to increased bacterial dissemination and adverse outcomes. In this study, we show that GBS HylB mediates immune suppression and promotes bacterial infection during pregnancy that requires TLR2, TLR4, and IL-10. Understanding the interaction between host and bacterial factors can inform future therapeutic strategies to mitigate GBS infections.