Publications by authors named "Thirumala-Devi Kanneganti"

286 Publications

It's just a phase: NLRP6 phase separations drive signaling.

Cell Res 2021 Nov 26. Epub 2021 Nov 26.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1038/s41422-021-00594-7DOI Listing
November 2021

Fungal cell wall components modulate our immune system.

Cell Surf 2021 Dec 6;7:100067. Epub 2021 Nov 6.

Univ Angers, Univ Brest, GEIHP, SFR ICAT, F-49000 Angers, France.

Invasive fungal infections remain highly problematic for human health. Collectively, they account for more than 1 million deaths a year in addition to more than 100 million mucosal infections and 1 billion skin infections. To be able to make progress it is important to understand the pathobiology of fungal interactions with the immune system. Here, we highlight new advancements pointing out the pivotal role of fungal cell wall components (β-glucan, mannan, galactosaminogalactan and melanin) in modulating host immunity and discuss how these open new opportunities for the development of immunomodulatory strategies to combat deadly fungal infectious diseases.
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http://dx.doi.org/10.1016/j.tcsw.2021.100067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603304PMC
December 2021

Integrated stress response restricts macrophage necroptosis.

Life Sci Alliance 2022 Jan 11;5(1). Epub 2021 Nov 11.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA

The integrated stress response (ISR) regulates cellular homeostasis and cell survival following exposure to stressors. Cell death processes such as apoptosis and pyroptosis are known to be modulated by stress responses, but the role of the ISR in necroptosis is poorly understood. Necroptosis is an inflammatory, lytic form of cell death driven by the RIPK3-MLKL signaling axis. Here, we show that macrophages that have induced the ISR are protected from subsequent necroptosis. Consistent with a reduction in necroptosis, phosphorylation of RIPK1, RIPK3, and MLKL is reduced in macrophages pre-treated with ISR-inducing agents that are challenged with necroptosis-inducing triggers. The stress granule component DDX3X, which is involved in ISR-mediated regulation of pyroptosis, is not required for protecting ISR-treated cells from necroptosis. Disruption of stress granule assembly or knockdown of restored necroptosis in pre-stressed cells. Together, these findings identify a critical role for the ISR in limiting necroptosis in macrophages.
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http://dx.doi.org/10.26508/lsa.202101260DOI Listing
January 2022

Caspase-6 promotes activation of the caspase-11-NLRP3 inflammasome during gram-negative bacterial infections.

J Biol Chem 2021 Nov 2:101379. Epub 2021 Nov 2.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Electronic address:

The innate immune system acts as the first line of defense against infection. One key component of the innate immune response to gram-negative bacterial infections is inflammasome activation. The caspase-11 (CASP11)-NLRP3 inflammasome is activated by cytosolic lipopolysaccharide (LPS), a gram-negative bacterial cell wall component, to trigger pyroptosis and host defense during infection. Although several cellular signaling pathways have been shown to regulate CASP11-NLRP3 inflammasome activation in response to LPS, the upstream molecules regulating CASP11 activation during infection with live pathogens remain unclear. Here we report that the understudied caspase-6 (CASP6) contributes to the activation of the CASP11-NLRP3 inflammasome in response to infections with gram-negative bacteria. We found using in vitro cellular systems with bone marrow-derived macrophages and 293T cells that CASP6 can directly process CASP11 by cleaving at Asp59 and Asp285, the CASP11 auto-cleavage sites, which could contribute to the activation of CASP11 during gram-negative bacteria infection. Thus, loss of CASP6 led to impaired CASP11-NLRP3 inflammasome activation in response to gram-negative bacteria. These results demonstrate that CASP6 regulates activation of the CASP11-NLRP3 inflammasome to control inflammatory cytokine production during gram-negative bacterial infections.
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http://dx.doi.org/10.1016/j.jbc.2021.101379DOI Listing
November 2021

The IFN-inducible GTPase IRGB10 regulates viral replication and inflammasome activation during influenza A virus infection in mice.

Eur J Immunol 2021 Oct 25. Epub 2021 Oct 25.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

The upregulation of interferon (IFN)-inducible GTPases in response to pathogenic insults is vital to host defense against many bacterial, fungal, and viral pathogens. Several IFN-inducible GTPases play key roles in mediating inflammasome activation and providing host protection after bacterial or fungal infections, though their role in inflammasome activation after viral infection is less clear. Among the IFN-inducible GTPases, the expression of immunity-related GTPases (IRGs) varies widely across species for unknown reasons. Here, we report that IRGB10, but not IRGM1, IRGM2, or IRGM3, is required for NLRP3 inflammasome activation in response to influenza A virus (IAV) infection in mice. While IRGB10 functions to release inflammasome ligands in the context of bacterial and fungal infections, we found that IRGB10 facilitates endosomal maturation and nuclear translocation of IAV, thereby regulating viral replication. Corresponding with our in vitro results, we found that Irgb10 mice were more resistant to IAV-induced mortality than WT mice. The results of our study demonstrate a detrimental role of IRGB10 in host immunity in response to IAV and a novel function of IRGB10, but not IRGMs, in promoting viral translocation into the nucleus.
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http://dx.doi.org/10.1002/eji.202149305DOI Listing
October 2021

ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis.

Cell Rep 2021 Oct;37(3):109858

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1's interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1LysM mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.
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http://dx.doi.org/10.1016/j.celrep.2021.109858DOI Listing
October 2021

NLRP3 inflammasome activation triggers gasdermin D-independent inflammation.

Sci Immunol 2021 Oct 22;6(64):eabj3859. Epub 2021 Oct 22.

Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciimmunol.abj3859DOI Listing
October 2021

Cutting Edge: Caspase-8 Is a Linchpin in Caspase-3 and Gasdermin D Activation to Control Cell Death, Cytokine Release, and Host Defense during Influenza A Virus Infection.

J Immunol 2021 11 18;207(10):2411-2416. Epub 2021 Oct 18.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN; and

Programmed cell death (PCD) is essential for the innate immune response, which serves as the first line of defense against pathogens. Caspases regulate PCD, immune responses, and homeostasis. Caspase-8 specifically plays multifaceted roles in PCD pathways including pyroptosis, apoptosis, and necroptosis. However, because caspase-8-deficient mice are embryonically lethal, little is known about how caspase-8 coordinates different PCD pathways under physiological conditions. Here, we report an anti-inflammatory role of caspase-8 during influenza A virus infection. We generated viable mice carrying an uncleavable version of caspase-8 ( ). We demonstrated that caspase-8 autoprocessing was responsible for activating caspase-3, thereby suppressing gasdermin D-mediated pyroptosis and inflammatory cytokine release. We also found that apoptotic and pyroptotic pathways were activated at the same time during influenza A virus infection, which enabled the cell-intrinsic anti-inflammatory function of the caspase-8-caspase-3 axis. Our findings provide new insight into the immunological consequences of caspase-8-coordinated PCD cross-talk under physiological conditions.
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http://dx.doi.org/10.4049/jimmunol.2100757DOI Listing
November 2021

Programming inflammatory cell death for therapy.

Pharmacol Ther 2021 Oct 4:108010. Epub 2021 Oct 4.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of homeostasis. However, excess activation of PCD pathways has proven to be detrimental and can drive disease. Additionally, resistance to PCD can also contribute to disease development. Modulation of PCD, therefore, has great therapeutic potential in a wide range of diseases, including infectious, neurodegenerative, autoinflammatory, and metabolic diseases and cancer. Nevertheless, manipulation of cell death and inflammation for therapeutic intervention is a delicate process, highly specific to the context of the disease of interest, making the selection of the appropriate target molecule crucially important. Several PCD pathways are associated with innate immunity, including pyroptosis, apoptosis, necroptosis, and PANoptosis, which is defined as an inflammatory PCD pathway with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. All of these PCD pathways are regulated by upstream sensors and signaling cascades that assemble multimeric complexes to serve as activation platforms for downstream molecules; these sensors and signaling molecules provide attractive target points for therapeutic intervention. Here, we discuss the molecular mechanisms of innate immune-mediated cell death in health and disease, with a particular focus on the molecules putatively involved in the formation of the PANoptosome and the induction of inflammatory cell death. Further, we discuss the implications and feasibility of targeting these molecules to improve disease outcomes, as well as current clinical approaches.
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http://dx.doi.org/10.1016/j.pharmthera.2021.108010DOI Listing
October 2021

PANoptosis in Viral Infection: The Missing Puzzle Piece in the Cell Death Field.

J Mol Biol 2021 Sep 16:167249. Epub 2021 Sep 16.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

In the past decade, emerging viral outbreaks like SARS-CoV-2, Zika and Ebola have presented major challenges to the global health system. Viruses are unique pathogens in that they fully rely on the host cell to complete their lifecycle and potentiate disease. Therefore, programmed cell death (PCD), a key component of the host innate immune response, is an effective strategy for the host cell to curb viral spread. The most well-established PCD pathways, pyroptosis, apoptosis and necroptosis, can be activated in response to viruses. Recently, extensive crosstalk between PCD pathways has been identified, and there is evidence that molecules from all three PCD pathways can be activated during virus infection. These findings have led to the emergence of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. While PCD is important to eliminate infected cells, many viruses are equipped to hijack host PCD pathways to benefit their own propagation and subvert host defense, and PCD can also lead to the production of inflammatory cytokines and inflammation. Therefore, PANoptosis induced by viral infection contributes to either host defense or viral pathogenesis in context-specific ways. In this review, we will discuss the multi-faceted roles of PCD pathways in controlling viral infections.
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http://dx.doi.org/10.1016/j.jmb.2021.167249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444475PMC
September 2021

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways.

Comput Struct Biotechnol J 2021 3;19:4641-4657. Epub 2021 Aug 3.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.
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http://dx.doi.org/10.1016/j.csbj.2021.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405902PMC
August 2021

AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence.

Nature 2021 09 1;597(7876):415-419. Epub 2021 Sep 1.

Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.

Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells. There are several inflammasome sensors that each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively). During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors. Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases.
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http://dx.doi.org/10.1038/s41586-021-03875-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603942PMC
September 2021

Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth.

Immunohorizons 2021 07 21;5(7):568-580. Epub 2021 Jul 21.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN

Resistance to cell death is a hallmark of cancer. Immunotherapy, particularly immune checkpoint blockade therapy, drives immune-mediated cell death and has greatly improved treatment outcomes for some patients with cancer, but it often fails clinically. Its success relies on the cytokines and cytotoxic functions of effector immune cells to bypass the resistance to cell death and eliminate cancer cells. However, the specific cytokines capable of inducing cell death in tumors and the mechanisms that connect cytokines to cell death across cancer cell types remain unknown. In this study, we analyzed expression of several cytokines that are modulated in tumors and found correlations between cytokine expression and mortality. Of several cytokines tested for their ability to kill cancer cells, only TNF-α and IFN-γ together were able to induce cell death in 13 distinct human cancer cell lines derived from colon and lung cancer, melanoma, and leukemia. Further evaluation of the specific programmed cell death pathways activated by TNF-α and IFN-γ in these cancer lines identified PANoptosis, a form of inflammatory cell death that was previously shown to be activated by contemporaneous engagement of components from pyroptosis, apoptosis, and/or necroptosis. Specifically, TNF-α and IFN-γ triggered activation of gasdermin D, gasdermin E, caspase-8, caspase-3, caspase-7, and MLKL. Furthermore, the intratumoral administration of TNF-α and IFN-γ suppressed the growth of transplanted xenograft tumors in an NSG mouse model. Overall, this study shows that PANoptosis, induced by synergism of TNF-α and IFN-γ, is an important mechanism to kill cancer cells and suppress tumor growth that could be therapeutically targeted.
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http://dx.doi.org/10.4049/immunohorizons.2100059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522052PMC
July 2021

The 'cytokine storm': molecular mechanisms and therapeutic prospects.

Trends Immunol 2021 08 1;42(8):681-705. Epub 2021 Jul 1.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address:

Cytokine storm syndrome (CSS) has generally been described as a collection of clinical manifestations resulting from an overactivated immune system. Cytokine storms (CSs) are associated with various pathologies, as observed in infectious diseases, certain acquired or inherited immunodeficiencies and autoinflammatory diseases, or following therapeutic interventions. Despite the role of CS in tissue damage and multiorgan failure, a systematic understanding of its underlying molecular mechanisms is lacking. Recent studies demonstrate a positive feedback loop between cytokine release and cell death pathways; certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, leading to further cytokine secretion. Here, we discuss recent progress in innate immunity and inflammatory cell death, providing insights into the cellular and molecular mechanisms of CSs and therapeutics that might quell ensuing life-threatening effects.
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http://dx.doi.org/10.1016/j.it.2021.06.001DOI Listing
August 2021

Hierarchical Cell Death Program Disrupts the Intracellular Niche Required for Burkholderia thailandensis Pathogenesis.

mBio 2021 06 22;12(3):e0105921. Epub 2021 Jun 22.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

infections can result in serious diseases with high mortality, such as melioidosis, and they are difficult to treat with antibiotics. Innate immunity is critical for cell-autonomous clearance of intracellular pathogens like by regulating programmed cell death. Inflammasome-dependent inflammatory cytokine release and cell death contribute to host protection against Burkholderia pseudomallei and Burkholderia thailandensis; however, the contribution of apoptosis and necroptosis to protection is not known. Here, we found that bone marrow-derived macrophages (BMDMs) lacking key components of pyroptosis died via apoptosis during infection. BMDMs lacking molecules required for pyroptosis, apoptosis, and necroptosis (PANoptosis), however, were significantly resistant to B. thailandensisinduced cell death until later stages of infection. Consequently, PANoptosis-deficient BMDMs failed to limit B. thailandensisinduced cell-cell fusion, which permits increased intercellular spread and replication compared to wild-type or pyroptosis-deficient BMDMs. Respiratory B. thailandensis infection resulted in higher mortality in PANoptosis-deficient mice than in pyroptosis-deficient mice, indicating that, in the absence of pyroptosis, apoptosis is essential for efficient control of infection . Together, these findings suggest both pyroptosis and apoptosis are necessary for host-mediated control of infection. infections result in a high degree of mortality when left untreated; therefore, understanding the host immune response required to control infection is critical. In this study, we found a hierarchical cell death program utilized by infected cells to disrupt the intracellular niche of Burkholderia thailandensis, which limits bacterial intercellular spread, host cell-cell fusion, and bacterial replication. In macrophages, combined loss of key PANoptosis components results in extensive B. thailandensis infection-induced cell-cell fusion, bacterial replication, and increased cell death at later stages of infection compared with both wild-type (WT) and pyroptosis-deficient cells. During respiratory infection, mortality was increased in PANoptosis-deficient mice compared to pyroptosis-deficient mice, identifying an essential role for multiple cell death pathways in controlling B. thailandensis infection. These findings advance our understanding of the physiological role of programmed cell death in controlling infection.
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http://dx.doi.org/10.1128/mBio.01059-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262894PMC
June 2021

TLR and IKK Complex-Mediated Innate Immune Signaling Inhibits Stress Granule Assembly.

J Immunol 2021 Jun 18. Epub 2021 Jun 18.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN

Cellular stress can induce cytoplasmic ribonucleoprotein complexes called stress granules that allow the cells to survive. Stress granules are also central to cellular responses to infections, in which they can act as platforms for viral sending or modulate innate immune signaling through pattern recognition receptors. However, the effect of innate immune signaling on stress granules is poorly understood. In this study, we report that prior induction of innate immune signaling through TLRs inhibited stress granule assembly in a TLR ligand dose-dependent manner in murine bone marrow-derived macrophages. Time course analysis suggests that TLR stimulation can reverse stress granule assembly even after it has begun. Additionally, both MYD88- and TRIF-mediated TLR signaling inhibited stress granule assembly in response to endoplasmic reticulum stress in bone marrow-derived macrophages and the chemotherapeutic drug oxaliplatin in murine B16 melanoma cells. This inhibition was not due to a decrease in expression of the critical stress granule proteins G3BP1 and DDX3X and was independent of IRAK1/4, JNK, ERK and P38 kinase activity but dependent on IKK complex kinase activity. Overall, we have identified the TLR-IKK complex signaling axis as a regulator of stress granule assembly-disassembly dynamics, highlighting cross-talk between processes that are critical in health and disease.
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http://dx.doi.org/10.4049/jimmunol.2100115DOI Listing
June 2021

Rising to the challenge of COVID-19: Working on SARS-CoV-2 during the pandemic.

Mol Cell 2021 06;81(11):2261-2265

COVID-19 altered our lives and pushed scientific research to operate at breakneck speed, leading to significant breakthroughs in record time. We asked experts in the field about the challenges they faced in transitioning, rapidly but safely, to working on the virus while navigating the shutdown. Their voices converge on the importance of teamwork, forging new collaborations, and working toward a shared goal.
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http://dx.doi.org/10.1016/j.molcel.2021.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173667PMC
June 2021

CovidExpress: an interactive portal for intuitive investigation on SARS-CoV-2 related transcriptomes.

bioRxiv 2021 Aug 5. Epub 2021 Aug 5.

Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans could cause coronavirus disease 2019 (COVID-19). Since its first discovery in Dec 2019, SARS-CoV-2 has become a global pandemic and caused 3.3 million direct/indirect deaths (2021 May). Amongst the scientific community's response to COVID-19, data sharing has emerged as an essential aspect of the combat against SARS-CoV-2. Despite the ever-growing studies about SARS-CoV-2 and COVID-19, to date, only a few databases were curated to enable access to gene expression data. Furthermore, these databases curated only a small set of data and do not provide easy access for investigators without computational skills to perform analyses. To fill this gap and advance open-access to the growing gene expression data on this deadly virus, we collected about 1,500 human bulk RNA-seq datasets from publicly available resources, developed a database and visualization tool, named CovidExpress (https://stjudecab.github.io/covidexpress). This open access database will allow research investigators to examine the gene expression in various tissues, cell lines, and their response to SARS-CoV-2 under different experimental conditions, accelerating the understanding of the etiology of this disease to inform the drug and vaccine development. Our integrative analysis of this big dataset highlights a set of commonly regulated genes in SARS-CoV-2 infected lung and Rhinovirus infected nasal tissues, including OASL that were under-studied in COVID-19 related reports. Our results also suggested a potential FURIN positive feedback loop that might explain the evolutional advantage of SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.05.14.444026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168395PMC
August 2021

TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines.

Nat Immunol 2021 07 7;22(7):829-838. Epub 2021 May 7.

Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.

The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including SARS-CoV-2, is driven by hyperactive cytokine release, or a cytokine storm. The innate sensors that activate production of proinflammatory cytokines and chemokines during COVID-19 remain poorly characterized. In the present study, we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and Myd88 were required for β-coronavirus-induced inflammatory responses, and TLR2-dependent signaling induced the production of proinflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. In addition, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of β-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1038/s41590-021-00937-xDOI Listing
July 2021

Intestinal tête-à-tête: helminths blunt immunity against flaviviruses.

Cell Res 2021 Jul;31(7):723-724

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

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http://dx.doi.org/10.1038/s41422-021-00505-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249402PMC
July 2021

DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response.

J Biol Chem 2021 Jan-Jun;296:100579. Epub 2021 Mar 23.

Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, USA. Electronic address:

Viruses and hosts have coevolved for millions of years, leading to the development of complex host-pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule-mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection.
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http://dx.doi.org/10.1016/j.jbc.2021.100579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081917PMC
August 2021

Role of inflammasomes/pyroptosis and PANoptosis during fungal infection.

PLoS Pathog 2021 03 18;17(3):e1009358. Epub 2021 Mar 18.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

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http://dx.doi.org/10.1371/journal.ppat.1009358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971547PMC
March 2021

NLRP3 inflammasome in cancer and metabolic diseases.

Nat Immunol 2021 05 11;22(5):550-559. Epub 2021 Mar 11.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.
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http://dx.doi.org/10.1038/s41590-021-00886-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132572PMC
May 2021

Sepsis take-out: Inhibiting bacterial deliveries.

Immunity 2021 03;54(3):399-401

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Electronic address:

Sepsis remains a deadly disease with limited treatment options. In this issue of Immunity, Tang et al. propose that heparin provides protection during gram-negative sepsis by dampening harmful CASP11-dependent signaling through inhibition of HMGB1- and heparanase-mediated cytosolic delivery of LPS.
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http://dx.doi.org/10.1016/j.immuni.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132570PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

A MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma.

Cancer Res 2021 05 22;81(9):2358-2372. Epub 2021 Feb 22.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are generally associated with tumor-promoting immunosuppressive functions in solid tumors. Here, we examined the transcriptional landscape of adaptor molecules downstream of Toll-like receptors in human cancers and found that higher expression of correlated with tumor progression. In murine melanoma, MyD88, but not Trif, was essential for tumor progression, angiogenesis, and maintaining the immunosuppressive phenotype of TAMs. In addition, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/IL1 receptor (IL1R) axis regulated programmed cell death (PD)-1 expression on TAMs by promoting recruitment of NF-κBp65 to the promoter. Furthermore, a combinatorial immunotherapy approach combining the MyD88 inhibitor with anti-PD-1 blockade elicited strong antitumor effects. Thus, the MyD88/IL1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression. SIGNIFICANCE: These findings indicate that MyD88 regulates TAM-immunosuppressive activity, suggesting that macrophage-mediated immunotherapy combining MYD88 inhibitors with PD-1 blockade could result in better treatment outcomes in a wide variety of cancers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2358/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3510DOI Listing
May 2021

Metabolic regulation of pyroptotic cell death expands the therapeutic landscape for treating inflammatory disease.

Signal Transduct Target Ther 2021 01 29;6(1):37. Epub 2021 Jan 29.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1038/s41392-021-00467-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846556PMC
January 2021

Advances in Understanding Activation and Function of the NLRC4 Inflammasome.

Int J Mol Sci 2021 Jan 21;22(3). Epub 2021 Jan 21.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1-mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro-IL-1β and pro-IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.
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http://dx.doi.org/10.3390/ijms22031048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864484PMC
January 2021

Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins.

Nat Commun 2021 01 21;12(1):496. Epub 2021 Jan 21.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Chronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferon-stimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. We show that mice deficient in IFN signaling components including IFN alpha and beta receptor 1 (IFNAR1), interferon regulatory factor 1 (IRF1), IRF9, and STAT1 each have reduced bone density and increased osteoclastogenesis compared to wild type mice. The IFN-inducible guanylate-binding proteins (GBPs) on mouse chromosome 3 (GBP1, GBP2, GBP3, GBP5, GBP7) are required to negatively regulate age-associated bone loss and osteoclastogenesis. Mechanistically, GBP2 and GBP5 both negatively regulate in vitro osteoclast differentiation, and loss of GBP5, but not GBP2, results in greater age-associated bone loss in mice. Moreover, mice deficient in GBP5 or chromosome 3 GBPs have greater LPS-mediated inflammatory bone loss compared to wild type mice. Overall, we find that GBP5 contributes to restricting age-associated and inflammation-induced bone loss by negatively regulating osteoclastogenesis.
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http://dx.doi.org/10.1038/s41467-020-20807-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820603PMC
January 2021
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