Recent studies have offered a glimpse into the sophisticated mechanisms by which inflammasomes respond to danger and promote secretion of interleukin (IL)-1β and IL-18. Activation of caspases 1 and ...11 in canonical and noncanonical inflammasomes, respectively, also protects against infection by triggering pyroptosis, a proinflammatory and lytic mode of cell death. The therapeutic potential of inhibiting these proinflammatory caspases in infectious and autoimmune diseases is raised by the successful deployment of anti-IL-1 therapies to control autoinflammatory diseases associated with aberrant inflammasome signaling. This Review summarizes recent insights into inflammasome biology and discusses the questions that remain in the field.
Vishva Dixit and colleagues offer a broad perspective on the increasing diversity of inflammasome complexes, the mechanisms controlling their activity, and diseases that can emerge from uncontrolled inflammasome activity.
Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system ...（UPS）. Similar to kinases, com- ponents of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neuro- degeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategoies to targoet the UPS.
Dying cells fan the flames of inflammation Newton, Kim; Dixit, Vishva M; Kayagaki, Nobuhiko
Science (American Association for the Advancement of Science),
2021-Nov-26, 2021-11-26, 20211126, Letnik:
374, Številka:
6571
Journal Article
Recenzirano
Inflammatory processes that recruit leukocytes to injured or infected tissues are crucial for tissue repair and the elimination of pathogens. However, excessive or chronic inflammation promotes ...tissue damage and disease, as in arthritis, atherosclerosis, inflammatory bowel disease, and COVID-19. Intracellular constituents released from dying cells are among the stimuli that trigger proinflammatory gene expression programs in innate immune cells. We explore how programmed cell death mechanisms—apoptosis, necroptosis, and pyroptosis—may contribute to inflammatory disease. We discuss inhibition of cell death as a potential therapeutic strategy, focusing on the targets RIPK1 (receptor interacting serine/threonine kinase 1), NLRP3 (NLR family pyrin domain containing 3), and GSDMD (gasdermin D) as important mediators of lytic cell death. We also consider the potential benefits of limiting membrane rupture rather than cell death by targeting NINJ1.
Fiery Cell Death: Pyroptosis in the Central Nervous System McKenzie, Brienne A.; Dixit, Vishva M.; Power, Christopher
Trends in neurosciences (Regular ed.),
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
43, Številka:
1
Journal Article
Recenzirano
Pyroptosis (‘fiery death’) is an inflammatory type of regulated cell death (RCD), which occurs downstream of inflammasome activation. Pyroptosis is mediated directly by the recently identified family ...of pore-forming proteins known as gasdermins, the best characterized of which is gasdermin D (GSDMD). Recent investigations implicate pyroptosis in the pathogenesis of multiple neurological diseases. In this review, we discuss molecular mechanisms that drive pyroptosis, evidence for pyroptosis within the CNS, and emerging therapeutic strategies for its inhibition in the context of neurological disease.
Pyroptosis (‘fiery death’) is a lytic and highly inflammatory regulated cell death program, recently found to be driven by members of the gasdermin family, most notably gasdermin D (GSDMD).GSDMD is a pore-forming executioner protein that is proteolytically cleaved and activated by proinflammatory caspases (caspase-1/4/5/11). These caspases are localized on inflammasomes, large cytosolic protein complexes that serve as platforms upon which activated proinflammatory caspases cleave and activate their protein substrates.Cleaved GSDMD oligomerizes and forms pores in the plasma membrane, leading to disruption of local osmotic potential, formation of pyroptotic bodies, and eventual membrane rupture.During neuroinflammation and neurodegeneration, inflammasome activation and pyroptosis are initiated by acute perturbations in homeostasis (e.g., mitochondrial dysfunction, ion flux) as well as danger signals in the microenvironment (e.g., extracellular ATP, aberrant protein aggregates, double-stranded DNA, microbial molecules) that are present in the injured or diseased CNS.Pyroptosis occurs in multiple CNS cell types under pathological conditions (e.g., multiple sclerosis, Alzheimer’s disease, and stroke), leading to both neuroinflammation and neurodegeneration through multiple mechanisms.Targeting pyroptosis therapeutically shows promise in multiple preclinical models of neurological injury and disease.
High levels of reactive oxygen species (ROS) are observed in chronic human diseases such as neurodegeneration, Crohn's disease, and cancer. In addition to the presence of oxidative stress, these ...diseases are also characterized by deregulated inflammatory responses, including but not limited to proinflammatory cytokine production. New work exploring the mechanisms linking ROS and inflammation find that ROS derived from mitochondria act as signal-transducing molecules that provoke the up-regulation of inflammatory cytokine subsets via distinct molecular pathways.
Inflammation is triggered when innate immune cells detect infection or tissue injury. Surveillance mechanisms involve pattern recognition receptors (PRRs) on the cell surface and in the cytoplasm. ...Most PRRs respond to pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) by triggering activation of NF-κB, AP1, CREB, c/EBP, and IRF transcription factors. Induction of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the recruitment and activation of leukocytes, which are critical for eliminating foreign particles and host debris. A subset of PRRs activates the protease caspase-1, which causes maturation of the cytokines IL1β and IL18. Cell adhesion molecules and chemokines facilitate leukocyte extravasation from the circulation to the affected site, the chemokines stimulating G-protein-coupled receptors (GPCRs). Binding initiates signals that regulate leukocyte motility and effector functions. Other triggers of inflammation include allergens, which form antibody complexes that stimulate Fc receptors on mast cells. Although the role of inflammation is to resolve infection and injury, increasing evidence indicates that chronic inflammation is a risk factor for cancer.
The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can ...activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through 'repurposing' drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SARS-CoV-2 infection results in highly heterogeneous outcomes, from cure without symptoms to acute respiratory distress and death. Empirical evidence points to the prominent roles of innate immune ...and CD8 T-cell responses in determining the outcomes. However, how these immune arms act in concert to elicit the outcomes remains unclear. Here, we developed a mathematical model of within-host SARS-CoV-2 infection that incorporates the essential features of the innate immune and CD8 T-cell responses. Remarkably, by varying the strengths and timings of the two immune arms, the model recapitulated the entire spectrum of outcomes realized. Furthermore, model predictions offered plausible explanations of several confounding clinical observations, including the occurrence of multiple peaks in viral load, viral recrudescence after symptom loss, and prolonged viral positivity. We applied the model to analyze published datasets of longitudinal viral load measurements from patients exhibiting diverse outcomes. The model provided excellent fits to the data. The best-fit parameter estimates indicated a nearly 80-fold stronger innate immune response and an over 200-fold more sensitive CD8 T-cell response in patients with mild compared to severe infection. These estimates provide quantitative insights into the likely origins of the dramatic inter-patient variability in the outcomes of SARS-CoV-2 infection. The insights have implications for interventions aimed at preventing severe disease and for understanding the differences between viral variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transmission bottlenecks introduce selection pressures on HIV-1 that vary with the mode of transmission. Recent studies on small cohorts have suggested that stronger selection pressures lead to ...fitter transmitted/founder (T/F) strains. Manifestations of this selection bias at the population level have remained elusive. Here, we analysed early CD4 cell count measurements reported from ∼340,000 infected heterosexual individuals (HET) and men-who-have-sex-with-men (MSM), across geographies, ethnicities and calendar years. The reduction in CD4 counts early in infection is reflective of the virulence of T/F strains. MSM and HET use predominant modes of transmission, namely, anal and penile-vaginal, with among the largest differences in the selection pressures at transmission across modes. Further, in most geographies, the groups show little inter-mixing, allowing for the differential selection bias to be sustained and amplified. We found that the early reduction in CD4 counts was consistently greater in HET than MSM (P<0.05). To account for inherent variations in baseline CD4 counts, we constructed a metric to quantify the extent of progression to AIDS as the ratio of the reduction in measured CD4 counts from baseline and the reduction associated with AIDS. We found that this progression corresponding to the early CD4 measurements was ∼68% for MSM and ∼87% for HET on average (P<10-4; Cohen's d, ds = 0.36), reflecting the more severe disease caused by T/F strains in HET than MSM at the population level. Interestingly, the set-point viral load was not different between the groups (ds<0.12), suggesting that MSM were more tolerant and not more resistant to their T/F strains than HET. This difference remained when we controlled for confounding factors using multivariable regression. We concluded that the different selection pressures at transmission have resulted in more virulent T/F strains in HET than MSM. These findings have implications for our understanding of HIV-1 pathogenesis, evolution, and epidemiology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like ...receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.
PDF
