Cooperation of the Ebola Virus Proteins VP40 and GP1,2 with BST2 To Activate NF-κB Independently of Virus-Like Particle Trapping.

BST2 is a host protein with dual functions in response to viral infections: it traps newly assembled enveloped virions at the plasma membrane in infected cells, and it induces NF-κB activity, especially in the context of retroviral assembly. In this study, we examined whether Ebola virus proteins affect BST2-mediated induction of NF-κB. We found that the Ebola virus matrix protein, VP40, and envelope glycoprotein, GP, each cooperate with BST2 to induce NF-κB activity, with maximal activity when all three proteins are expressed. Unlike human immunodeficiency virus type 1 Vpu protein, which antagonizes both virion entrapment and the activation of NF-κB by BST2, Ebola virus GP does not inhibit NF-κB signaling even while it antagonizes the entrapment of virus-like particles. GP from Reston ebolavirus, a nonpathogenic species in humans, showed a phenotype similar to that of GP from Zaire ebolavirus, a highly pathogenic species, in terms of both the activation of NF-κB and the antagonism of virion entrapment. Although Ebola virus VP40 and GP both activate NF-κB independently of BST2, VP40 is the more potent activator. Activation of NF-κB by the Ebola virus proteins either alone or together with BST2 requires the canonical NF-κB signaling pathway. Mechanistically, the maximal NF-κB activation by GP, VP40, and BST2 together requires the ectodomain cysteines needed for BST2 dimerization, the putative BST2 tetramerization residue L70, and Y6 of a potential hemi-ITAM motif in BST2's cytoplasmic domain. BST2 with a glycosylphosphatidylinositol (GPI) anchor signal deletion, which is not expressed at the plasma membrane and is unable to entrap virions, activated NF-κB in concert with the Ebola virus proteins at least as effectively as wild-type BST2. Signaling by the GPI anchor mutant also depended on Y6 of BST2. Overall, our data show that activation of NF-κB by BST2 is independent of virion entrapment in the case of Ebola virus. Nonetheless, BST2 may induce or amplify proinflammatory signaling during Ebola virus infection, potentially contributing to the dysregulated cytokine response that is a hallmark of Ebola virus disease.IMPORTANCE Understanding how the host responds to viral infections informs the development of therapeutics and vaccines. We asked how proinflammatory signaling by the host protein BST2/tetherin, which is mediated by the transcription factor NF-κB, responds to Ebola virus proteins. Although the Ebola virus envelope glycoprotein (GP1,2) antagonizes the trapping of newly formed virions at the plasma membrane by BST2, we found that it does not inhibit BST2's ability to induce NF-κB activity. This distinguishes GP1,2 from the HIV-1 protein Vpu, the prototype BST2 antagonist, which inhibits both virion entrapment and the induction of NF-κB activity. Ebola virus GP1,2, the Ebola virus matrix protein VP40, and BST2 are at least additive with respect to the induction of NF-κB activity. The effects of these proteins converge on an intracellular signaling pathway that depends on a protein modification termed neddylation. Better mechanistic understanding of these phenomena could provide targets for therapies that modulate the inflammatory response during Ebola virus disease.

Intersection of Polycystic Ovary Syndrome and the Gut Microbiome.

The etiology of polycystic ovary syndrome (PCOS) remains unclear, although studies indicate that both genetic and environmental factors contribute to the syndrome. In 2012, Tremellen and Pearce proposed the idea that dysbiosis of the intestinal (gut) microbiome is a causative factor of metabolic and reproductive manifestations of PCOS. In the past 5 years, studies in both humans and rodent models have demonstrated that changes in the taxonomic composition of gut bacteria are associated with PCOS. Studies have also clearly shown that these changes in gut microbiota are associated with PCOS as opposed to obesity, since these changes are observed in women with PCOS that are both of a normal weight or obese, as well as in adolescent girls with PCOS and obesity compared with body mass index- and age-matched females without the disorder. Additionally, studies in both women with PCOS and rodent models of PCOS demonstrated that hyperandrogenism is associated with gut microbial dysbiosis, indicating that androgens may modulate the gut microbial community in females. One study reported that the fecal microbiome transplantation of stool from women with PCOS or exposure to certain bacteria resulted in a PCOS-like phenotype in mice, while other studies showed that exposure to a healthy gut microbiome, pre/probiotics, or specific gut metabolites resulted in protection from developing PCOS-like traits in mice. Altogether, these results suggest that dysbiosis of the gut microbiome may be sufficient to develop PCOS-like symptoms and that modulation of the gut microbiome may be a potential therapeutic target for PCOS.