Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the “sepsis syndrome,” a widespread and uncontrolled inflammatory response. Though it is well ...recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection.
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► TRIF is essential for NLRP3 inflammasome activation by EHEC and C. rodentium ► TRIF signaling via type I interferon couples caspase-11 induction and autoactivation ► The TRIF-IFN-caspase-11 axis licenses NLRP3 inflammasome activation ► Caspase-11 activation licenses NLRP3 activation by Gram-negative, but not -positive, bacteria
TRIF is as an integral component of NLRP3 inflammasome activation during Gram-negative bacterial infection, highlighting the central role of TLRs as master regulators of the NLRP3 inflammasome and providing new targets for therapeutic intervention in septic shock.
Animal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the ...transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection.
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•HLH-30 is a key regulator of the C. elegans transcriptional response to infection•HLH-30 induces autophagy and antimicrobial genes required for tolerance of infection•TFEB, a murine homolog of HLH-30, is activated during infection in macrophages•TFEB is required for proper induction of several cytokines and chemokines
Transcriptional regulators that control host responses to infection are crucially important to the outcome of host-microbe interactions. Visvikis et al. show an evolutionarily-conserved role for the transcription factor TFEB in the induction of the host response to infection in nematodes and in mammalian macrophages.
A fundamental question regarding any immune system is how it can discriminate between pathogens and non-pathogens. Here, we discuss how this discrimination can be mediated by a surveillance system ...distinct from pattern-recognition receptors that recognize conserved microbial patterns. It can be based instead on the ability of the host to sense perturbations in host cells induced by bacterial toxins or 'effectors' that are encoded by pathogenic microorganisms. Such 'effector-triggered immunity' was previously demonstrated mainly in plants, but recent data confirm that animals can also use this strategy.
High-fat (HF) diet-induced obesity and insulin insensitivity are associated with inflammation, particularly in white adipose tissue (WAT). However, insulin insensitivity is apparent within days of HF ...feeding when gains in adiposity and changes in markers of inflammation are relatively minor. To investigate further the effects of HF diet, C57Bl/6J mice were fed either a low (LF) or HF diet for 3 days to 16 weeks, or fed the HF-diet matched to the caloric intake of the LF diet (PF) for 3 days or 1 week, with the time course of glucose tolerance and inflammatory gene expression measured in liver, muscle and WAT. HF fed mice gained adiposity and liver lipid steadily over 16 weeks, but developed glucose intolerance, assessed by intraperitoneal glucose tolerance tests (IPGTT), in two phases. The first phase, after 3 days, resulted in a 50% increase in area under the curve (AUC) for HF and PF mice, which improved to 30% after 1 week and remained stable until 12 weeks. Between 12 and 16 weeks the difference in AUC increased to 60%, when gene markers of inflammation appeared in WAT and muscle but not in liver. Plasma proteomics were used to reveal an acute phase response at day 3. Data from PF mice reveals that glucose intolerance and the acute phase response are the result of the HF composition of the diet and increased caloric intake respectively. Thus, the initial increase in glucose intolerance due to a HF diet occurs concurrently with an acute phase response but these effects are caused by different properties of the diet. The second increase in glucose intolerance occurs between 12-16 weeks of HF diet and is correlated with WAT and muscle inflammation. Between these times glucose tolerance remains stable and markers of inflammation are undetectable.
Summary Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor ...degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov , number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio HR 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 17% in the fulvestrant group vs 24 10% in the anastrozole group) and hot flushes (26 11% in the fulvestrant group vs 24 10% in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. Funding AstraZeneca.
Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of ...the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.
Phagocytosis, the engulfment of material by cells, is a highly conserved process that arose before the development of multicellularity. Phagocytes have a key role in embryogenesis and also guard the ...portals of potential pathogen entry. They discriminate between diverse particles through the array of receptors expressed on their surface. In higher species, arguably the most sophisticated function of phagocytes is the processing and presentation of antigens derived from internalized material to stimulate lymphocytes and long-lived specific immunity. Central to these processes is the generation of a phagosome, the organelle that forms around internalized material. As we discuss in this Review, over the past two decades important insights into phagocytosis have been gleaned from studies in the model organism Drosophila melanogaster.
In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-beta triggers a protracted sterile inflammatory response. ...Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.
Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly ...understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an
Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.
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► The bacterial effector CNF1 is sufficient to drive a protective immune response ► CNF1 modification of Rac2 triggers antimicrobial peptide response ► Activation of Rac2 triggers an immune response via the IMD signaling pathway ► Human Rac2 induces immune activation through Rip1 and Rip2
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