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Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/[alpha]-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via [sup.13]C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS- activated macrophages. We also found that type I IFN-driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages. Our findings have identified the autocrine type I IFN pathway as being responsible for the inhibition of IDH in LPS-stimulated macrophages., Introduction Macrophages activated with LPS (so-called M1 macrophages) have a TCA cycle that is altered at 2 distinct steps, leading to the accumulation of citrate, succinate, and itaconate (1). The [...]

Background: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection. Case: We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension. Methods: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro. Results: WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease. Conclusion: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae coinfection is a major cause of influenza-associated mortality; however, the mechanisms underlying pathogenesis or protection remain unclear. Using a clinically relevant mouse model, we identify immune-mediated damage early during coinfection as a new mechanism causing susceptibility. Coinfected CCR2−/− mice lacking monocytes and monocyte-derived cells control bacterial invasion better, show reduced epithelial damage and are overall more resistant than wild-type controls. In influenza-infected wild-type lungs, monocytes and monocyte-derived cells are the major cell populations expressing the apoptosis-inducing ligand TRAIL. Accordingly, anti-TRAIL treatment reduces bacterial load and protects against coinfection if administered during viral infection, but not following bacterial exposure. Post-influenza bacterial outgrowth induces a strong proinflammatory cytokine response and massive inflammatory cell infiltrate. Depletion of neutrophils or blockade of TNF-α facilitate bacterial outgrowth, leading to increased mortality, demonstrating that these factors aid bacterial control. We conclude that inflammatory monocytes recruited early, during the viral phase of coinfection, induce TRAIL-mediated lung damage, which facilitates bacterial invasion, while TNF-α and neutrophil responses help control subsequent bacterial outgrowth. We thus identify novel determinants of protection versus pathology in influenza- Streptococcus pneumoniae coinfection. [ABSTRACT FROM AUTHOR]

Type I and type III interferons (IFN α β and IFN λ ) are key antiviral cytokines. In addition, IFN α β is increasingly recognised as potentially disease-promoting in infection. We explored the roles of these IFN families in influenza infection and as anti-influenza treatment. When comparing influenza-infected 129 to C57BL/6 mouse strains, we found increased lung damage, morbidity and mortality, yet higher levels of IFN α β , in 129 mice than in the more resistant C57BL/6 mice. IFN α β receptor deficiency in 129 mice decreased morbidity and lung damage, and ameliorated immune-mediated tissue damage, indicating that IFN α β levels are a host determinant of influenza severity. In contrast, the respiratory epithelial anti-influenza response was unaffected by IFN α β receptor deficiency, as IFN λ replaced IFN α β in these cells. Lack of IFN α β signalling reduced expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes, and depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protected infected 129 mice. Therefore, excessive IFN α β signalling in response to acute influenza infection may explain morbidity. Our results suggest that humans with propensity to strong IFN α β signalling may be at risk of severe influenza. We assessed the implications of our results for influenza treatment, using C57BL/6 mice with a functional Mx1 allele. Treatment with either IFN α 4 or IFN λ 2 prior to infection blocked influenza replication and protected against host morbidity and mortality. In contrast, outcome of IFN treatment during influenza infection was divergent. Results of IFN therapy will be presented and discussed in the context of treatment options for influenza in humans. [ABSTRACT FROM AUTHOR]

Rationale: One of the immunopathological features of allergic inflammation is the infiltration of helper T type 2 (Th2) cells to the site of disease. Activation of innate pattern recognition receptors such as Toll-like receptors (TLRs) plays a critical role in helper T type 1 cell differentiation, yet their contribution to the generation of Th2 responses to clinically relevant aeroallergens remains poorly defined., Objectives: To determine the requirement for TLR2, TLR4, and the Toll/IL-1 receptor domain adaptor protein MyD88 in a murine model of allergic asthma., Methods: Wild-type and factor-deficient ((-/-)) mice were sensitized intranasally to the common allergen house dust mite (HDM) and challenged 2 weeks later on four consecutive days. Measurements of allergic airway inflammation, T-cell cytokine production, and airway hyperreactivity were performed 24 hours later., Measurements and Main Results: Mice deficient in MyD88 were protected from the cardinal features of allergic asthma, including granulocytic inflammation, Th2 cytokine production and airway hyperreactivity. Although HDM activated NF-kappaB in TLR2- or TLR4-expressing HEK cells, only in TLR4(-/-) mice was the magnitude of allergic airway inflammation and hyperreactivity attenuated. The diminished Th2 response present in MyD88(-/-) and TLR4(-/-) mice was associated with fewer OX40 ligand-expressing myeloid dendritic cells in the draining lymph nodes during allergic sensitization. Finally, HDM-specific IL-17 production and airway neutrophilia were attenuated in MyD88(-/-) but not TLR4(-/-) mice., Conclusions: Together, these data suggest that Th2- and Th17-mediated inflammation generated on inhalational HDM exposure is differentially regulated by the presence of microbial products and the activation of distinct MyD88-dependent pattern recognition receptors.