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Little is known regarding T cell translational regulation. We demonstrate that T follicular helper (TFH) cells use a previously unknown mechanism of selective messenger RNA (mRNA) translation for their differentiation, role in B cell maturation, and in autoimmune pathogenesis. We show that TFH cells have much higher levels of translation factor eIF4E than non-TFH CD4 + T cells, which is essential for translation of TFH cell fate-specification mRNAs. Genome-wide translation studies indicate that modest down-regulation of eIF4E activity by a small-molecule inhibitor or short hairpin RN impairs TFH cell development and function. In mice, down-regulation of eIF4E activity specifically reduces TFH cells among T helper subtypes, germinal centers, B cell recruitment, and antibody production. In experimental autoimmune encephalomyelitis, eIF4E activity down-regulation blocks TFH cell participation in disease pathogenesis while promoting rapid remission and spinal cord remyelination. TFH cell development and its role in autoimmune pathogenesis involve selective mRNA translation that is highly druggable.

Bacterial pathogen identification, which is critical for human health, has historically relied on culturing organisms from clinical specimens. More recently, the application of machine learning (ML) to whole-genome sequences (WGSs) has facilitated pathogen identification. However, relying solely on genetic information to identify emerging or new pathogens is fundamentally constrained, especially if novel virulence factors exist. In addition, even WGSs with ML pipelines are unable to discern phenotypes associated with cryptic genetic loci linked to virulence. Here, we set out to determine if ML using phenotypic hallmarks of pathogenesis could assess potential pathogenic threat without using any sequence-based analysis. This approach successfully classified potential pathogenetic threat associated with previously machine-observed and unobserved bacteria with 99% and 85% accuracy, respectively. This work establishes a phenotype-based pipeline for potential pathogenic threat assessment, which we term PathEngine, and offers strategies for the identification of bacterial pathogens.

Purpose The functional composition and diversity of the gut microbiome (estrobolome) may affect breast cancer risk by modulation of systemic sex hormones. Gut bacteria with β-glucuronidase enzymatic activity may deconjugate estrogens, leading to increased estrogen reabsorption into the circulation thereby increasing breast cancer risk. We investigated the relationship between the gut bacterial microbiome and endogenous estrogens and related sex hormones in women with hormone receptor-positive breast cancer compared to healthy control women. Methods In this prospective case-control study, postmenopausal women (n = 46) with newly diagnosed stage I-III estrogen and/or progesterone receptor-positive breast cancer were compared with healthy postmenopausal female controls (n = 22). Bacterial composition of the gut microbiome was analyzed by 16S rRNA gene sequencing from fecal specimens. Plasma and urine sex hormones were quantified using high-performance liquid chromatography/mass spectrometry. Results We found evidence that some β-glucuronidase positive bacteria were enriched in the breast cancer patients compared to healthy controls, whereas abundances of some β-glucuronidase negative bacteria were reduced. There was also a wide distribution of prevalence of β-glucuronidase positive taxa in both the breast cancer subjects and healthy controls, as well as higher probability of breast cancer subjects having higher average β-glucuronidase levels. Significant differences were found in endogenous progesterone levels between the breast cancer patients and healthy controls. Conclusion This pilot study showed differences in the gut microbiome and endogenous progesterone levels among postmenopausal women with hormone receptor-positive breast cancer compared with healthy controls. These interesting findings may have implications for breast cancer risk and prevention and warrant further exploration.