Tuberculosis causes ∼1.5 million deaths every year, thus remaining a leading cause of death from infectious diseases in the world. A growing body of evidence demonstrates that type I IFN plays a detrimental role in tuberculosis pathogenesis, likely by interfering with IFN-γ–dependent immunity. In this article, we reveal a novel mechanism by which type I IFN may confer protection against Mycobacterium tuberculosis infection in the absence of IFN-γ signaling. We show that production of type I IFN by M. tuberculosis–infected macrophages induced NO synthase 2 and inhibited arginase 1 gene expression. In vivo, absence of both type I and type II IFN receptors led to strikingly increased levels of arginase 1 gene expression and protein activity in infected lungs, characteristic of alternatively activated macrophages. This correlated with increased lung bacterial burden and pathology and decreased survival compared with mice deficient in either receptor. Increased expression of other genes associated with alternatively activated macrophages, as well as increased expression of Th2-associated cytokines and decreased TNF expression, were also observed. Thus, in the absence of IFN-γ signaling, type I IFN suppressed the switching of macrophages from a more protective classically activated phenotype to a more permissive alternatively activated phenotype. Together, our data support a model in which suppression of alternative macrophage activation by type I IFN during M. tuberculosis infection, in the absence of IFN-γ signaling, contributes to host protection.

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy.

Summary The Niemann-Pick type C is a rare metabolic disease with a severe neurodegenerative phenotype characterized by an accumulation of high amounts of lipids (cholesterol and sphingolipids) in the late endosomal/lysosomal network. It is caused by loss-of-function point mutations in either NPC1 or NPC2, which seem to mediate proper intracellular lipid transport through endocytic pathway. In this study, we show that yeast cells lacking Ncr1p, an orthologue of mammalian NPC1, exhibited a higher sensitivity to hydrogen peroxide and a shortened chronological lifespan. These phenotypes were associated with increased levels of oxidative stress markers, decreased levels of antioxidant defenses and mitochondrial dysfunctions. Moreover, we report that Ncr1p deficient cells displayed high levels of long chain bases (LCB), and that Sch9p-phospho-T570 and Sch9p levels increased in ncr1Δ cells through a mechanism regulated by Pkh1p, a LCB-activated protein kinase. Notably, deletion of PKH1 or SCH9 suppressed ncr1Δ phenotypes but downregulation of de novo sphingolipid biosynthesis had no protective effect, suggesting that LCBs accumulation may result from an increased turnover of complex sphingolipids. These results suggest that sphingolipid signaling through Pkh1p-Sch9p mediate mitochondrial dysfunction, oxidative stress sensitivity and shortened chronological lifespan in the yeast model of Niemann-Pick type C disease.

A large variation in the severity of disease symptoms is one of the key open questions in COVID-19 pandemics. The fact that only a small subset of people infected with SARS-CoV-2 develop severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the IgG glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of inter-individual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine (GlcNAc) in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing. To our knowledge, this is the first study exploring IgG N-glycome variability in COVID-19 severity.

Nicotinamide adenine dinucleotide (NAD ?) is a vital molecule found in all living cells. NAD ? intracellular levels are dictated by its synthesis, using the de novo and/or salvage pathway, and through its catabolic use as co-enzyme or co-substrate. The regulation of NAD ? metabolism has proven to be an adequate drug target for several diseases, including cancer, neurodegenerative or inflammatory diseases. Increasing interest has been given to NAD ? metabolism during innate and adaptive immune responses suggesting that its modulation could also be relevant during host-pathogen interactions. While the maintenance of NAD ? homeostatic levels assures an adequate environment for host cell survival and proliferation, fluctuations in NAD ? or biosynthetic precursors bioavailability have been described during host-pathogen interactions, which will interfere with pathogen persistence or clearance. Here, we review the double-edged sword of NAD ? metabolism during host-pathogen interactions emphasizing its potential for treatment of infectious diseases. Keywords Nicotinamide adenine dinucleotide (NAD ?) Á Host-pathogen interaction Á NAD ? /NADH ratio Á NADPH Á Sirtuins Á L-tryptophan Nicotinamide adenine dinucleotide (NAD ?) was initially discovered by Sir Arthur Harden as a 'cozymase' for yeast fermentation over 100 years ago. The succeeding work contributed to the identification of NAD ? as a player in hundreds of biochemical reactions through its role in redox reactions. NAD ? is either consumed as a co-substrate by NAD ?-consuming enzymes or used as an electron carrier in redox reactions. Yet, the intracellular NAD ? /NADH ratio is key to the maintenance of an adequate metabolic status and cell survival. Growing evidences indicate that NAD ? biosynthetic pathways and metabolism are playing a major role in hostpathogen interactions. In this review, we overview these mechanisms highlighting the role of NAD ? metabolism as an attractive therapeutic target for microbe infections. NAD 1 biosynthesis: where the tale begins NAD 1 biosynthesis in mammalian cells The biosynthesis of NAD ? in mammals occurs through two different pathways: the de novo and the salvage pathways (Fig. 1). The de novo pathway begins with the uptake and conversion of dietary L-tryptophan in N-formylkynurenine, which is mediated by the rate-limiting indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3

Continental Portugal has an extensive Atlantic Ocean coastline; however little is known about the diversity of its marine cyanobacteria, with only a few reports published. Cyanobacteria are a prolific source of bioactive compounds with promising therapeutic applications. Previously, several cyanobacterial strains (Subsections I-IV) were isolated from the Portuguese Atlantic coast and characterized using a polyphasic approach. Preliminary screening indicated that these cyanobacteria lacked the genes for proteins involved in the production of conventional cyanotoxins. However, it was previously shown that extracts of marine Synechocystis and Synechococcus were toxic to invertebrates, with crude extracts causing stronger effects than partially purified ones. To further evaluate the potential of our temperate region Portuguese isolates to produce bioactive compounds, a PCR screening for the presence of genes encoding non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), targeting the adenylation (A) and ketosynthase (KS) domains respectively, was performed. DNA fragments were obtained for more than 80% of the strains tested, and the results revealed that PKS genes are more ubiquitous than NRPS genes. The sequences obtained were used in an in silico prediction of the PKS and NRPS systems. RT-PCR analyses revealed that these genes are transcribed under routine laboratory conditions in several selected strains. Furthermore, LC-MS analysis coupled with molecular networking, a mass spectrometric tool that clusters metabolites with similar MS/MS fragmentation patterns, was used to search for novel or otherwise interesting metabolites revealing an untapped chemodiversity.

Similar efficacy with omalizumab in chronic idiopathic/spontaneous urticaria despite different background therapy.

The fate of infected macrophages is a critical aspect of immunity to mycobacteria. By depriving the pathogen of its intracellular niche, apoptotic death of the infected macrophage has been shown to be an important mechanism to control bacterial growth. Here, we show that IL-17 inhibits apoptosis of Mycobacterium bovis BCG- or Mycobacterium tuberculosis-infected macrophages thus hampering their ability to control bacterial growth. Mechanistically, we show that IL-17 inhibits p53, and impacts on the intrinsic apoptotic pathway, by increasing the Bcl2 and decreasing Bax expression, decreasing cytochrome c release from the mitochondria, and inhibiting caspase-3 activation. The same effect of IL-17 was observed in infected macrophages upon blockade of p53 nuclear translocation. These results reveal a previously unappreciated role for the IL-17/p53 axis in the regulation of mycobacteria-induced apoptosis and can have important implications in a broad spectrum of diseases where apoptosis of the infected cell is an important host defense mechanism.