3-Hydroxykynurenine targets kainate receptors to promote defense against infection.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.

A tryptophan metabolite modulates the host response to bacterial infection via kainate receptors.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxy-kynurenine protects from lethal gram-negative bacterial infection. 3-hydroxy-kynurenine, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages by targeting kainate-sensitive glutamate receptors. These findings reveal new mechanisms by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with significant implications for the coordination between the immune and nervous systems in pathological conditions.

Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants.

Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8+ T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML180-188) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.

Foster Care Reentry: A survival analysis assessing differences across permanency type.

Foster care reentry is an important factor for evaluating the overall success of permanency. Rates of reentry are typically only measured for 12-months and are often evaluated only for children who exit foster care to reunification and not across exit types, also known as 'permanency types'. This study examined the odds of reentry across multiple common permanency types for a cohort of 8107 children who achieved permanency between 2009 and 2013. Overall, 14% of children reentered care within 18-months with an average time to reentry of 6.36 months. A Kaplan-Meier survival analysis was used to assess differences in reentry across permanency types (including reunification, relative guardianship and non-relative guardianship). Children who achieved guardianship with kin had the lowest odds of reentry overall, followed by guardianship with non-kin, and reunification with family of origin. Children reunifying against the recommendations of Children and Family Services had the highest odds of reentry. A Cox regression survival analysis was conducted to assess odds of reentry across permanency type while controlling for demographics, services, and other risk factors. In the final model, only permanency type and cumulative risk were found to have a statistically significant impact on odds of reentry.