Characterization of Gut Microbiota-Derived Bacterial Strains With Neuroprotective Properties.

Neurodegenerative diseases are disabling, incurable, and progressive conditions characterized by neuronal loss and decreased cognitive function. Changes in gut microbiome composition have been linked to a number of neurodegenerative diseases, indicating a role for the gut-brain axis. Here, we show how specific gut-derived bacterial strains can modulate neuroinflammatory and neurodegenerative processes through the production of specific metabolites and discuss the potential therapeutic implications for neurodegenerative disorders.

HIV-1 Promotes the Degradation of Components of the Type 1 IFN JAK/STAT Pathway and Blocks Anti-viral ISG Induction.

Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components.

Control of HIV infection by IFN-α: implications for latency and a cure.

Viral infections, including HIV, trigger the production of type I interferons (IFNs), which in turn, activate a signalling cascade that ultimately culminates with the expression of anti-viral proteins. Mounting evidence suggests that type I IFNs, in particular IFN-α, play a pivotal role in limiting acute HIV infection. Highly active anti-retroviral treatment reduces viral load and increases life expectancy in HIV positive patients; however, it fails to fully eliminate latent HIV reservoirs.

Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.

Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes.

Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-α responses.

TNF-α is a proinflammatory cytokine, dramatically elevated during pathogenic infection and often responsible for inflammation-induced disease pathology. SOCS proteins are inhibitors of cytokine signaling and regulators of inflammation. In this study, we found that both SOCS1 and SOCS3 were transiently induced by TNF-α and negatively regulate its NF-κB-mediated signal transduction.

TRIF-mediated TLR3 and TLR4 signaling is negatively regulated by ADAM15.

TLRs are a group of pattern-recognition receptors that play a crucial role in danger recognition and induction of the innate immune response against bacterial and viral infections. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-κB and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling.

14-3-3ε and 14-3-3σ inhibit Toll-like receptor (TLR)-mediated proinflammatory cytokine induction.

Toll-like receptors (TLRs) are a group of pattern recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential.

The microtubule-associated protein doublecortin-like regulates the transport of the glucocorticoid receptor in neuronal progenitor cells.

In neuronal cells, activated glucocorticoid receptor (GR) translocates to the nucleus guided by the cytoskeleton. However, the detailed mechanisms underlying GR translocation remain unclear. Using gain and loss of function studies, we report here for the first time that the microtubule-associated protein doublecortin-like (DCL) controls GR translocation to the nucleus.

Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.

The vesicle-associated membrane protein-associated proteins (VAPs) VAPA and VAPB interact with lipid-binding proteins carrying a short motif containing two phenylalanines in an acidic tract (FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum (ER). A genetic mutation (P56S) in the conserved major sperm protein homology domain of VAPB has been linked to motor-neuron degeneration in affected amyotrophic lateral sclerosis (ALS) patients. We report that in the CNS, VAPB is abundant in motor neurons and that the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAP in mutant aggregates.