MprF-mediated immune evasion is necessary for Lactiplantibacillus plantarum resilience in the Drosophila gut during inflammation.

Multiple peptide resistance factor (MprF) confers resistance to cationic antimicrobial peptides (AMPs) in several pathogens, thereby enabling evasion of the host immune response. The role of MprF in commensals remains, however, uncharacterized. To close this knowledge gap, we used a common gut commensal of animals, Lactiplantibacillus plantarum, and its natural host, the fruit fly Drosophila melanogaster, as an experimental model to investigate the role of MprF in commensal-host interactions. The L. plantarum ΔmprF mutant that we generated exhibited deficiency in the synthesis of lysyl-phosphatidylglycerol (Lys-PG), resulting in increased negative cell surface charge and increased susceptibility to AMPs. Susceptibility to AMPs had no effect on ΔmprF mutant's ability to colonize guts of uninfected flies. However, we observed significantly reduced abundance of the ΔmprF mutant after infection-induced inflammation in the guts of wild-type flies but not flies lacking AMPs. Additionally, we found that the ΔmprF mutant compared to wild-type L. plantarum induces a stronger intestinal immune response in flies due to the increased release of immunostimulatory peptidoglycan fragments, indicating an important role of MprF in promoting host tolerance to commensals. Our further analysis suggests that MprF-mediated lipoteichoic acid modifications are involved in host immunomodulation. Overall, our results demonstrate that MprF, besides its well-characterized role in pathogen immune evasion and virulence, is also an important commensal resilience factor.

Pediatric acute kidney injury and adverse health outcomes: using a foundational framework to evaluate a causal link.

Acute kidney injury (AKI) is a major global health problem, expensive to manage, and its associations with negative pediatric health outcomes have been clearly demonstrated. One of the most fundamental questions to consider as we use previous epidemiological information to advance research and care paradigms is the strength of the causal link between pediatric AKI and health outcomes. In this review, we apply the foundational framework of the Bradford Hill criteria to evaluate the extent to which a causal link exists between AKI and the associated adverse outcomes in children. Available data in children support a causal link between AKI and short-term outcomes including mortality, length of stay, and ventilation time. Clarifying the causal nature of longer term associations requires further high-quality observational studies in children, careful consideration of what defines the most meaningful and measurable longer term outcomes after pediatric AKI, and integration of evolving biological data related to mechanisms of disease. Preventing or mitigating AKI should lead to improved outcomes. Demonstrating such reversibility will solidify confidence in the causal relationship, improve child health, and highlight an aspect which is highly relevant to clinicians, scientists, and policy makers.