How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.

BackgroundLyme neuroborreliosis (LNB) is a frequent manifestation of Lyme disease in children and its current diagnosis has limitations. The elevation of the chemokine CXCL13 in the cerebrospinal fluid (CSF) of adult patients with LNB has been demonstrated and suggested as a new diagnostic marker. Our aim was to evaluate this marker in the CSF of children with suspected LNB and to determine a CXCL13 cut-off concentration that would discriminate between LNB and other central nervous system (CNS) infections.MethodsFor this single-center retrospective case-control study we used a diagnostic-approved ELISA to measure CXCL13 concentrations in the CSF of 185 children with LNB suspicion at presentation. Patients were classified into definite LNB (cases), non-LNB (controls with other CNS affections), and possible LNB. A receiver-operating characteristic curve was generated by comparison of cases and controls.ResultsCXCL13 was significantly elevated in the CSF of 53 children with definite LNB (median 774.7 pg/ml) compared to 91 control patients (median 4.5 pg/ml, p < 0.001). A cut-off of 55 pg/ml resulted in a sensitivity of 96.7% and a specificity of 98.1% for the diagnosis of definite LNB and the test exhibited a diagnostic odds ratio of 1525.3. Elevated CSF CXCL13 levels were also detected in three controls with viral meningitis (enterovirus n = 1, varicella-zoster virus n = 2) while other CNS affections such as idiopathic facial palsy did not lead to CXCL13 elevation. Of the 41 patients with possible LNB, 27% had CXCL13 values above the cut-off of 55 pg/ml (median 16.7 pg/ml).ConclusionsCSF CXCL13 is highly elevated in children during early LNB as previously shown in adults. CXCL13 is a highly sensitive and specific marker that helps to differentiate LNB from other CNS affections in children.

We report a case of transverse myelitis as a complication of acute cytomegalovirus (CMV) infection in immunocompetent patients; and review the literature on the entity. Primary CMV infection was documented by CMV antigenemia and high serum titers of CMV IgM and IgG antibodies. Cerebrospinal fluid (CSF) pleocytosis indicated central nervous system inflammation; CSF polymerase chain reaction (PCR) for CMV, however, was negative. The results of magnetic resonance imaging of the myelon were normal. Although CMV-associated transverse myelitis has been well described in HIV-positive individuals, but is very rare in immunocompetent individuals. It remains unclear whether the neuronal damage is immune mediated or due to a cytotoxic effect of viral infection. The outcome is mainly favorable.

Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific Gpr137 isoforms differently activating the Wnt pathway. In humans, ESRP1 is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of ESRP1-dependent GPR137 isoforms is altered in CRC and expression of a specific GPR137 isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology.

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