bims-inflin 2024-11-03 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2024‒11‒03
ten papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Priming from within: TLR2 dependent but receptor independent activation of the mammary macrophage inflammasome by Streptococcus uberis.
Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection.
Taking AIM at Influenza: The Role of the AIM2 Inflammasome.
A type VI secretion system in Burkholderia species cenocepacia and orbicola triggers distinct macrophage death pathways independent of the pyrin inflammasome.
Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria.
Caffeic acid inhibits Staphylococcus aureus-induced endometritis through regulating AMPKα/mTOR/HIF-1α signalling pathway.
HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.
Leishmania protein KMP-11 modulates cholesterol transport and membrane fluidity to facilitate host cell invasion.
Advancing Roles and Therapeutic Potentials of Pyroptosis in Host Immune Defenses against Tuberculosis.
Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway.

Front Cell Infect Microbiol. 2024 ;14 1444178

Priming from within: TLR2 dependent but receptor independent activation of the mammary macrophage inflammasome by Streptococcus uberis.

Abbie Hinds, Philip Ward, Nathan Archer, James Leigh.

  Introduction: Streptococcus uberis is a member of the pyogenic cluster of Streptococcus commonly associated with intramammary infection and mastitis in dairy cattle. It is a poorly controlled globally endemic pathogen responsible for a significant cause of the disease worldwide. The ruminant mammary gland provides an atypical body niche in which immune cell surveillance occurs on both sides of the epithelial tissue. S. uberis does not cause disease in non-ruminant species and is an asymptomatic commensal in other body niches. S. uberis exploits the unusual niche of the mammary gland to initiate an innate response from bovine mammary macrophage (BMMO) present in the secretion (milk) in which it can resist the host immune responses. As a result - and unexpectedly - the host inflammatory response is a key step in the pathogenesis of S.uberis, without which colonisation is impaired. In contrast to other bacteria pathogenic to the bovine mammary gland, S. uberis does not elicit innate responses from epithelial tissues; initial recognition of infection is via macrophages within milk.Methods: We dissected the role of the bacterial protein SUB1154 in the inflammasome pathway using ex vivo bovine mammary macrophages isolated from milk, recombinant protein expression, and a panel of inhibitors, agonists, and antagonists. We combine this with reverse-transcription quantitative real-time PCR to investigate the mechanisms underlying SUB1154-mediated priming of the immune response.
Results: Here, we show that SUB1154 is responsible for priming the NLRP3 inflammasome in macrophages found in the mammary gland. Without SUB1154, IL-1β is not produced, and we were able to restore IL-1β responses to a sub1154 deletion S. uberis mutant using recombinant SUB1154. Surprisingly, only by blocking internalisation, or the cytoplasmic TIR domain of TLR2 were we able to block SUB1154-mediated priming.
Discussion: Together, our data unifies several contrasting past studies and provides new mechanistic understanding of potential early interactions between pyogenic streptococci and the host.

Keywords:  NLRP3; Streptococcus; TLR2; inflammasome; mastitis

DOI:  https://doi.org/10.3389/fcimb.2024.1444178
mBio. 2024 Oct 30. e0194524

Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection.

Zicheng Ma, Depeng Liu, Wandi Cao, Lei Guo, Kesen Liu, Juan Bai, Xingyi Li, Ping Jiang, Xing Liu.

  The interaction between Z-DNA binding protein 1 (ZBP1) and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been uncovered in several viral infections. However, the role of this molecular pathway during infection with the alpha-herpesvirus pseudorabies virus (PRV) remains largely elusive. Here, we report that during PRV infection, ZBP1-mediated NLRP3 inflammasome activation is inhibited by the viral tegument protein VP22, thereby facilitating viral infection. Through a combination of RNA sequencing and genetic studies, we demonstrate that PRV VP22 functions as a virus-encoded virulence factor by evading the inhibitory effects of ZBP1 on virus infection. Importantly, the replication and pathogenicity of a recombinant PRV lacking VP22 are significantly increased in ZBP1-deficient cells and mice. Mechanistically, PRV VP22 interacts with ZBP1, impeding the recruitment of receptor-interacting protein kinase 3 and Caspase-8, thereby inhibiting NLRP3 activation. Furthermore, we show that the N-terminal 1-50 amino acid domain of VP22 dominantly destabilizes ZBP1-mediated function. Taken together, these findings identify a functional link between PRV infection and ZBP1-mediated NLRP3 inflammatory response, providing novel insights into the pathogenesis of PRV and other herpesviruses.IMPORTANCE: Z-DNA binding protein 1 (ZBP1) functions as a pivotal innate immune sensor that regulates inflammatory cell death during viral infections. However, its role in pseudorabies virus (PRV) infection remains unknown. Here, we demonstrate that ZBP1 serves as a restrictive factor by triggering the activation of the NLR family pyrin domain-containing 3 inflammasome, a process counteracted by PRV-encoded protein VP22. Furthermore, VP22 interferes with the interaction between ZBP1 and receptor-interacting protein kinase 3/Caspase-8, particularly through its N-terminal 1-50 amino acids. Importantly, deficiency in ZBP1 enhances the replication and virulence of recombinant viruses lacking VP22 or its N-terminal 1-50 amino acids. These findings reveal how PRV escapes ZBP1-mediated inflammatory responses during infection, potentially informing the rational design of therapeutic interventions.

Keywords:  NLRP3 inflammasome; VP22; ZBP1; pseudorabies virus

DOI:  https://doi.org/10.1128/mbio.01945-24
Viruses. 2024 Sep 27. pii: 1535. [Epub ahead of print]16(10):

Taking AIM at Influenza: The Role of the AIM2 Inflammasome.

Dianne W Xu, Michelle D Tate.

  Influenza A viruses (IAV) are dynamic and highly mutable respiratory pathogens that present persistent public health challenges. Inflammasomes, as components of the innate immune system, play a crucial role in the early detection and response to infections. They react to viral pathogens by triggering inflammation to promote immune defences and initiate repair mechanisms. While a strong response is necessary for early viral control, overactivation of inflammasomes can precipitate harmful hyperinflammatory responses, a defining characteristic observed during severe influenza infections. The Absent in Melanoma 2 (AIM2) inflammasome, traditionally recognised for its role as a DNA sensor, has recently been implicated in the response to RNA viruses, like IAV. Paradoxically, AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection. This review synthesises the current understanding of AIM2 inflammasome activation during IAV and explores its clinical implications. Understanding the nuances of AIM2's involvement could unveil novel therapeutic avenues for mitigating severe influenza outcomes.

Keywords:  AIM2 inflammasome; DNA sensing; cytosolic DNA; immunotherapy; inflammation; influenza A virus

DOI:  https://doi.org/10.3390/v16101535
Infect Immun. 2024 Oct 31. e0031624

A type VI secretion system in Burkholderia species cenocepacia and orbicola triggers distinct macrophage death pathways independent of the pyrin inflammasome.

Nicole A Loeven, Clarrisa Dabi, Joseph P Pennington, Arianna D Reuven, Abigail P McGee, Bethany W Mwaura, James B Bliska.

  The Burkholderia cepacia complex contains opportunistic pathogens that cause chronic infections and inflammation in the lungs of people with cystic fibrosis. Two closely related species within this complex are Burkholderia cenocepacia and the recently classified Burkholderia orbicola. B. cenocepacia and B. orbicola encode a type VI secretion system and the effector TecA, which is detected by the pyrin/caspase-1 inflammasome, and triggers macrophage inflammatory death. We previously showed that the pyrin inflammasome was dispensable for lung inflammation in mice infected with B. orbicola AU1054, indicating this species activates an alternative pathway of macrophage inflammatory death. Notably, B. cenocepacia strains J2315 and K56-2 can damage macrophage phagosomes, and K56-2 triggers activation of the caspase-11 inflammasome, which detects cytosolic lipopolysaccharide. Here, we investigated inflammatory cell death in pyrin- (Mefv-/-) or caspase-1/caspase-11- (Casp1/11-/-) deficient mouse macrophages infected with B. cenocepacia J2315 or K56-2 or B. orbicola AU1054 or PC184. Macrophage inflammatory death was measured by cleavage of gasdermin D protein, the release of cytokines IL-1α and IL-1β, and plasma membrane rupture. We found that J2315 and K56-2 are detected by the caspase-11 inflammasome in Mefv-/- macrophages, resulting in IL-1β release. By contrast, inflammasome activation was not detected in Mefv-/- macrophages infected with AU1054 or PC184. Instead, AU1054 triggered an alternative macrophage inflammatory death pathway that required TecA and resulted in plasma membrane rupture and IL-1α release. Structural modeling of TecA orthologs in B. cenocepacia and B. orbicola suggested that amino acid changes in the latter may underlie its ability to trigger a non-inflammasome macrophage death pathway.

Keywords:  Burkholderia; effector functions; inflammasomes; macrophages; pyrin; type VI secretion

DOI:  https://doi.org/10.1128/iai.00316-24
bioRxiv. 2024 Oct 24. pii: 2024.10.22.619707. [Epub ahead of print]

Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria.

Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Essel Charles-Chess, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, John T Harty, John D MacMicking, Samarchith P Kurup.

Plasmodium parasites undergo development and replication within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium . Second, guanylate-binding protein (GBP) 1 disruption of the PV activates caspase-1 inflammasome, inducing pyroptosis to remove the infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium ; their pharmacologic or genetic inhibition led to profound malarial susceptibility, and are essential in vivo . In addition to identifying the IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, this study extends our understanding of how non-immune cells are integral to protective immunity against malaria.

DOI: https://doi.org/10.1101/2024.10.22.619707
J Cell Mol Med. 2024 Oct;28(20): e70175

Caffeic acid inhibits Staphylococcus aureus-induced endometritis through regulating AMPKα/mTOR/HIF-1α signalling pathway.

Lu Cao, Junbao Liu, Cong Ye, Yubo Hu, Rui Qin.

  Endometritis is mostly caused by childbirth or postpartum uterine infection. It is one of the important reasons leading to female infertility. Caffeic acid (CA) and its derivatives are widely found in some foods and traditional Chinese medicine, and have biological activities such as antioxidant, free radical scavenging, anti-inflammatory, and anti-infection. In this study, we aimed to explore the effect of CA on Staphylococcus aureus-induced endometritis. The contents of TNF-α and IL-1β were detected by ELISA in S. aureus-induced endometritis model. Western blot assay was used to detect the expression of AMPKα/mTOR/HIF-1α pathway related proteins and GPX4 expression. In addition, the concentrations of MDA, GSH, and iron were tested by the assay kits. Compared with the model group, CA treatment significantly alleviated S. aureus-induced uterine injury, MPO activity, the contents of inflammatory factors TNF-α and IL-1β, and NF-κB activation. Meanwhile, CA significantly inhibited S. aureus-induced ferroptosis, as confirmed by decreased MDA and iron concentration and up-regulated GPX4 expression and GSH level. Furthermore, CA attenuated S. aureus-induced HIF-1α and phosphorylated mTOR expression and increased phosphorylated AMPK expression. In conclusion, CA inhibits inflammation and ferroptosis by regulating AMPKα/mTOR/HIF-1α signalling pathway to alleviate S. aureus-induced endometritis in mice.

Keywords:   Staphylococcus aureus ; AMPK; endometritis; ferroptosis; inflammation

DOI:  https://doi.org/10.1111/jcmm.70175
Nat Commun. 2024 Oct 30. 15(1): 9394

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.

Hongxing Shen, Oluwagbemiga A Ojo, Haitao Ding, Logan J Mullen, Chuan Xing, M Iqbal Hossain, Abdelrahman Yassin, Vivian Y Shi, Zach Lewis, Ewa Podgorska, Shaida A Andrabi, Maciek R Antoniewicz, James A Bonner, Lewis Zhichang Shi.

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α-/-) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl-/-) increases IFN-γ production. Hypoxic Hif1α-/- T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α-/- mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α-/- T cells and re-sensitizing Hif1α-/- tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.

DOI: https://doi.org/10.1038/s41467-024-53593-8
EMBO Rep. 2024 Oct 31.

Leishmania protein KMP-11 modulates cholesterol transport and membrane fluidity to facilitate host cell invasion.

Achinta Sannigrahi, Souradeepa Ghosh, Supratim Pradhan, Pulak Jana, Junaid Jibran Jawed, Subrata Majumdar, Syamal Roy, Sanat Karmakar, Budhaditya Mukherjee, Krishnananda Chattopadhyay.

  The first step of successful infection by any intracellular pathogen relies on its ability to invade its host cell membrane. However, the detailed structural and molecular understanding underlying lipid membrane modification during pathogenic invasion remains unclear. In this study, we show that a specific Leishmania donovani (LD) protein, KMP-11, forms oligomers that bridge LD and host macrophage (MΦ) membranes. This KMP-11 induced interaction between LD and MΦ depends on the variations in cholesterol (CHOL) and ergosterol (ERG) contents in their respective membranes. These variations are crucial for the subsequent steps of invasion, including (a) the initial attachment, (b) CHOL transport from MΦ to LD, and (c) detachment of LD from the initial point of contact through a liquid ordered (Lo) to liquid disordered (Ld) membrane-phase transition. To validate the importance of KMP-11, we generate KMP-11 depleted LD, which failed to attach and invade host MΦ. Through tryptophan-scanning mutagenesis and synthesized peptides, we develop a generalized mathematical model, which demonstrates that the hydrophobic moment and the symmetry sequence code at the membrane interacting protein domain are key factors in facilitating the membrane phase transition and, consequently, the host cell infection process by Leishmania parasites.

Keywords:  Cholesterol Transport; Host–Pathogen Interaction; Leishmania; Phase-transition; Phospholipid Membranes

DOI:  https://doi.org/10.1038/s44319-024-00302-7
Biomolecules. 2024 Oct 04. pii: 1255. [Epub ahead of print]14(10):

Advancing Roles and Therapeutic Potentials of Pyroptosis in Host Immune Defenses against Tuberculosis.

Jiayi Yang, Yuhe Ma, Jiaqi Yu, Yilin Liu, Jiaojiao Xia, Xinen Kong, Xiaoying Jin, Jiaxiang Li, Siqi Lin, Yongdui Ruan, Fen Yang, Jiang Pi.

  Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a deadly global public health burden. The use of recommended drug combinations in clinic has seen an increasing prevalence of drug-resistant TB, adding to the impediments to global control of TB. Therefore, control of TB and drug-resistant TB has become one of the most pressing issues in global public health, which urges the exploration of potential therapeutic targets in TB and drug-resistant TB. Pyroptosis, a form of programmed cell death characterized by cell swelling and rupture, release of cellular contents and inflammatory responses, has been found to promote pathogen clearance and adopt crucial roles in the control of bacterial infections. It has been demonstrated that Mtb can cause host cell pyroptosis, and these host cells, which are infected by Mtb, can kill Mtb accompanied by pyroptosis, while, at the same time, pyroptosis can also release intracellular Mtb, which may potentially worsen the infection by exacerbating the inflammation. Here, we describe the main pathways of pyroptosis during Mtb infection and summarize the identified effectors of Mtb that regulate pyroptosis to achieve immune evasion. Moreover, we also discuss the potentials of pyroptosis to serve as an anti-TB therapeutic target, with the aim of providing new ideas for the development of TB treatments.

Keywords:  inflammation; pyroptosis; therapeutic; tuberculosis

DOI:  https://doi.org/10.3390/biom14101255
Life Sci. 2024 Oct 24. pii: S0024-3205(24)00763-X. [Epub ahead of print]358 123173

Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway.

Eddie Tam, Erfei Song, Nina Noskovicova, Boris Hinz, Aimin Xu, Gary Sweeney.

  AIMS: Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization.MATERIALS AND METHODS: Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied.
KEY FINDINGS: We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses.
SIGNIFICANCE: Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury.

Keywords:  Atg7; Autophagy; Cell death; Heart; Hypoxia; Reoxygenation

DOI:  https://doi.org/10.1016/j.lfs.2024.123173