Group B Streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive bacterium commonly encountered as part of the microbiota within the human gastrointestinal tract. A common cause of infections during pregnancy, GBS is responsible for invasive diseases ranging from urinary tract infections to chorioamnionitis and neonatal sepsis. Diabetes mellitus (DM) is a chronic disease resulting from impaired regulation of blood glucose levels. The incidence of DM has steadily increased worldwide to affecting over 450 million people. Poorly controlled DM is associated with multiple health comorbidities including an increased risk for infection. Epidemiologic studies have clearly demonstrated that DM correlates with an increased risk for invasive GBS infections, including skin and soft tissue infections and sepsis in non-pregnant adults. However, the impact of DM on risk for invasive GBS urogenital infections, particularly during the already vulnerable time of pregnancy, is less clear. We review the evolving epidemiology, immunology, and pathophysiology of GBS urogenital infections including rectovaginal colonization during pregnancy, neonatal infections of infants exposed to DM in utero, and urinary tract infections in pregnant and non-pregnant adults in the context of DM and highlight in vitro studies examining why DM might increase risk for GBS urogenital infection.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction.A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and also restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies. Significance StatementFine tuning of the immune response is critical to health. This fine tuning is lost in autoimmunity and cancer and must be restored to prevent undesirable outcomes. Immune cell metabolism can regulate the immune response but to date chronic interventions have been needed to produce any biologic effect. Our study in lupus-prone animals demonstrates that disease-associated changes in immune cell metabolism create a barrier to immune tolerance, which can be reset by short term metabolic treatment with 2-deoxyglucose and metformin. Metabolic therapy restored normal expression of extracellular receptors, which was required for successful immune therapy.These findings reveal the role of glycoregulation in the immune response and indicate an important interaction between immune metabolism and responsiveness to immune therapy. the spleen (Figure 1 B&C) (33). Anti-CD45RB treatment leads to a B cell dependent expansion of CD4+ Foxp3+ Tregs to promote longterm tolerance induction (23,32). We hypothesized that this B cell mobilization would expand CD4+ Foxp3+ Tregs in both SLE123 and B6 mice. Analysis of the Foxp3 + and CD25 + fractions of the CD4 + population revealed expansion of Tregs in both B6 and SLE123 mice following anti-CD45RB therapy (Figure 1 D&E). Anti-CD45RB uncovers inappropriate effector responses to tolerogenic signaling.While expansion of Tregs is important for long-term tolerance in anti-CD45RB treatment, the effector compartment must also be temporarily modulated to facilitate adequate regulation (34,35). In healthy B6 mice, anti-CD45RB inhibits the Germinal Center (GC) response and temporarily cripples antibody production (28,35). In clinical SLE and in the mouse model of disease, there is an expansion of T-follicular helper (Tfh) cells and GC B cells that collaborate to generate autoantibodies that occlude and damage the nephron...

No abstract

MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway-dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, co-dependencies of MEK, TAK1 and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacological studies and cell cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G1 accumulation, in a distinct subset of cell lines. Furthermore, TAK1 inhibition causes G2/M cell cycle blockade and polyploidy in many of the cell lines. MEK plus TAK1 inhibition causes reduced G2/M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1-dependent cell lines as well as a subset of BRAF-mutant cells. Mechanistically, sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation, which promote expression of NFκB-dependent proinflammatory cytokines, driving tumor cell survival and proliferation. MEK/TAK1 inhibition causes reduced mTOR, Wnt and NFκB signaling in TAK1/MEK-dependent cell lines concomitant with apoptosis. A Wnt/NFκB transcriptional signature was derived that stratifies primary tumors into three major subtypes: Wnt-high/NFκB-low, Wnt-low/NFκB-high and Wnt-high/NFκB-high, designated W, N and WN, respectively. These subtypes have distinct characteristics, including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype. Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines. Therefore, N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics.