Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT‐mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host‐directed therapy.

SUMMARY: The rapid spread of the Zika virus (ZIKV) in the Americas and its potential association with thousands of suspected cases of microcephaly in Brazil and higher rates of Guillain-Barré syndrome meet the conditions for a Public Health Emergency of International Concern, as stated by the World Health Organization in February 2016. Two months later, the Centers for Disease Control and Prevention (CDC) announced that the current available evidence supports the existence of a causal relationship between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Microcephaly can be caused by several factors, and its clinical course and prognosis are difficult to predict. Other pathogens with proven teratogenicity have been identified long before the current ZIKV epidemic. Despite the growing number of cases with maternal signs of infection and/or presence of ZIKV in tissues of affected newborns or fetuses, it is currently difficult to assess the magnitude of increase of microcephaly prevalence in Brazil, as well as the role of other factors in the development of congenital neurological conditions. Meanwhile, health agencies and medical organizations have issued cautious guidelines advising health care practitioners and expectant couples traveling to, returning from, or living in affected areas. Analogous to dengue virus (DENV) epidemics, ZIKV has the potential to become endemic in all countries infested by Aedes mosquitoes, while new mutations could impact viral replication in humans, leading to increased virulence and consequently heightened chances of viral transmission to additional naive mosquito vectors. Studies are urgently needed to answer the questions surrounding ZIKV and its role in congenital neurological conditions.

During blood‐stage Plasmodium infection, large‐scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)‐infected C57BL/6 mice, CD4⁺ T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8⁺ T cells. Expression analysis revealed that the transcriptional signature of CD4⁺ T cells from PbA‐infected mice was dominated by type I IFN (IFN‐I) and IFN‐γ‐signalling pathway‐related genes. A role for IFN‐I during blood‐stage Plasmodium infection had yet to be established. Here, we observed IFN‐α protein production in the spleen of PbA‐infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN‐I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN‐I substantially inhibited CD4⁺ T‐bet⁺ T‐cell‐derived IFN‐γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN‐I signalled predominantly via radio‐sensitive, haematopoietic cells, but did not suppress CD4⁺ T cells via direct signalling to this cell type. Finally, we found that IFN‐I suppressed IFN‐γ production, and hampered efficient control of parasitaemia in mice infected with non‐lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood‐stage Plasmodium infection that suppresses CD4⁺ T‐cell‐mediated parasite control.

Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4⁺ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ–producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8^– cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8^– splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN–inducing pathogens.

Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus . Transcription and production of the proinflammatory cytokine interleukin-1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-γ-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not β-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen-associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin. IMPORTANCE Invasive aspergillosis and allergic aspergillosis are increasing health care problems. Patients get infected by inhalation of the airborne spores of Aspergillus fumigatus . A profound knowledge of how Aspergillus and its cell wall components are recognized by the host cell and which type of immune response it induces is necessary to develop target-specific treatment options with less severe side effects than the treatment options to date. There is controversy in the literature about the receptor for chitin in human cells. We identified the Fc-γ receptor and Syk/PI3K pathway via which chitin can induce anti-inflammatory immune responses by inducing IL-1 receptor antagonist in the presence of human immunoglobulins but also proinflammatory responses in the presence of bacterial components. This explains why Aspergillus does not induce strong inflammation just by inhalation and rather fulfills an immune-dampening function. While in a lung coinfected with bacteria, Aspergillus augments immune responses by shifting toward a proinflammatory reaction.

Invasive aspergillosis (IA) is a severe infection that can occur in severely immunocompromised patients. Efficient immune recognition ofAspergillusis crucial to protect against infection, and previous studies suggested a role for NOD2 in this process. However, thorough investigation of the impact of NOD2 on susceptibility to aspergillosis is lacking. Common genetic variations inNOD2has been associated with Crohn’s disease and here we investigated the influence of these genetic variations on the anti-Aspergillushost response. A NOD2polymorphism reduced the risk of IA after hematopoietic stem-cell transplantation. Mechanistically, absence of NOD2 in monocytes and macrophages increases phagocytosis leading to enhanced fungal killing, conversely, NOD2 activation reduces the antifungal potential of these cells. Crucially,Nod2deficiency results in resistance toAspergillusinfection in anin vivomodel of pulmonary aspergillosis. Collectively, our data demonstrate that genetic deficiency ofNOD2plays a protective role duringAspergillusinfection.