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#innateimmunity

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Public
David Gregory

New study! Learning about inflammation by studying the differences between mammals – a toot-orial.

doi.org/10.1186/s10020-024-010

When the body meets an infectious microbe or similar challenge it activates an inflammatory cascade. Inflammation helps eliminate the microbe, but, if it gets of control, it can be dangerous or even fatal.

We like to assume that inflammation is basically the same for all animals. And this is usually true in cell culture, but in vivo …

1/

BioMed CentralMolecular profiles of blood from numerous species that differ in sensitivity to acute inflammation - Molecular MedicineVertebrates differ over 100,000-fold in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation. This may inform better selection of species for pre-clinical models and could lead to new therapeutic strategies that mimic mechanisms in inflammation-resilient species to limit inflammation without causing immunosuppression.
Public
Thiago Carvalho

'Thus, here we asked whether B. bassiana could damage the Drosophila brain via Toll-1, Wek and Sarm. We show that exposure to B. bassiana reduced fly lifespan and impaired locomotion. B. bassiana entered the brain and induced the up-regulation of AMPs, as well as wek and sarm, within the brain. Exposure to B. bassiana caused neuronal and glial loss in the adult Drosophilabrain. Importantly, RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana induced cell loss.'
#Immunology #InnateImmunity
#Preprint
biorxiv.org/content/10.1101/20

bioRxiv · Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brainFungi evolve within the host, ensuring their own nutrition and reproduction, at the expense of host health. They intervene in hosts’ brain function, to alter host behaviour and induce neurodegeneration. In humans, fungal infections are emerging as drivers of neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. Fungi trigger an innate immune response mediated by the Toll-1/TLR receptor, the adaptor MyD88 and the transcription factor Dif/NFκB, that induce the expression of antimicrobial peptides (AMPs). However, in the nervous system, Toll-1/TLR could also drive an alternative pathway involving the adaptor Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. The entomopathogenic fungus Beauveria bassiana is well-known to activate Toll-1 signalling in innate immunity in Drosophila . In fruit-flies, the adaptor Wek links Toll-1 to Sarm. Thus, here we asked whether B. bassiana could damage the Drosophila brain via Toll-1, Wek and Sarm. We show that exposure to B. bassiana reduced fly lifespan and impaired locomotion. B. bassiana entered the brain and induced the up-regulation of AMPs, as well as wek and sarm, within the brain. Exposure to B. bassiana caused neuronal and glial loss in the adult Drosophila brain. Importantly, RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause dopaminergic neuron loss in the absence of infection. These data show that B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. We conclude that pathogens can benefit from an innate immunity receptor to damage the host brain. A similar activation of Sarm downstream of TLRs in response to fungal infections could underlie psychiatric and neurodegenerative diseases in humans. ### Competing Interest Statement The authors have declared no competing interest.
Public
Thiago Carvalho

'Stimulator of IFN genes (STING) is a critical component of the innate immune system, playing an essential role in defending against DNA virus infections. However, the mechanisms governing basal STING regulation remain poorly understood. In this study, we demonstrate that the basal level of STING is critically maintained by hypoxia-inducible factor 1 (HIF-1)α through transcription.'
#Immunology #InnateImmunity
journals.aai.org/jimmunol/arti

Public
Thiago Carvalho

'Here we studied the endogenous TLR pathways in human and mouse macrophages. We provide evidence that myddosomes are dynamic and long-lived entities, numbering in the dozens within individual cells. We demonstrate that the complex cellular responses of the entire TLR pathway are coordinated and executed from within these structures.'
#Immunology #InnateImmunity
nature.com/articles/s41586-024

NatureMolecular definition of the endogenous Toll-like receptor signalling pathways - NatureMyddosomes, in which MyD88 forms barrel-like scaffold structures for effector protein recruitment and activation, contain proteins that act at all stages and regulate all effector responses of the TLR signalling pathways.
Public
Thiago Carvalho

'Distinct patterns emerge when comparing sustained and transient infections. Transiently infected participants have a robust type of antiviral defence response termed a type I interferon (IFN-I) response in the nasal mucosal tissue shortly after viral exposure (day 1 after infection), potentially contributing to viral removal. By contrast, participants who had sustained infection showed delayed (only starting on day 5 after infection) mucosal IFN-I responses, as well as delays in immune-cell infiltration into the nasopharynx, indicating an impaired innate antiviral response at the site of initial viral inoculation and replication.'
#Covid #Covid19 #Immunology #Virology #InnateImmunity

nature.com/articles/d41586-024

www.nature.comFirst encounter with SARS-CoV-2: immune portraits of COVID susceptibilityControlled human infection with SARS-CoV-2 to track defence responses.
Public
Thiago Carvalho

'Here we examine the contribution of Mitogen Activated Protein Kinase (MAPK) signaling on IFNλ-mediated antiviral activity. We find that extracellular-signal-regulated kinase 5 (ERK5), a poorly characterized member of the conventional MAPK family, potentiates the antiviral efficacy of IFNλ.'
#Preprint #Immunology #InnateImmunity #Interferon

biorxiv.org/content/10.1101/20

bioRxiv · ERK5 Signaling is Required for Type III IFN-mediated Mucosal Antiviral ResponsesType III interferons (IFNλ) are innate immune cytokines that limit viral replication and coordinate tissue repair through the induction of interferon stimulated genes (ISGs). This response must be tightly regulated to avoid excessive responses that result in the disruption of tissue barrier integrity or inefficient responses that allow for pathogen escape. Here we examine the contribution of Mitogen Activated Protein Kinase (MAPK) signaling on IFNλ-mediated antiviral activity. We find that extracellular-signal-regulated kinase 5 (ERK5), a poorly characterized member of the conventional MAPK family, potentiates the antiviral efficacy of IFNλ. Chemical inhibition and genetic targeting of ERK5 during IFNλ treatment of cells results in a decrease in ISG induction and impaired control of viral infections. This decrease in IFNλ antiviral efficacy in the absence of ERK5 kinase activity corresponded to lowered STAT1 phosphorylation, revealing a noncanonical role for ERK5 in STAT1 activation downstream of IFNλ. In contrast, type I IFN antiviral signaling is largely resistant to ERK5 modulation. Altogether, we identify ERK5 as a potentiator of STAT1 activation, ISG expression, and antiviral activity following type III IFN stimulation. ### Competing Interest Statement The authors have declared no competing interest.
Public
ℵ₀ 🏳️‍⚧️🏴‍☠️

nature.com/articles/s41579-022

Long COVID: major findings, mechanisms and recommendations

sciencedirect.com/science/arti

Impact of peripheral mitochondrial DNA level on immune response after COVID-19 vaccination

ncbi.nlm.nih.gov/pmc/articles/
Common mitochondrial haplogroups as modifiers of the onset-age for critical COVID-19

NatureLong COVID: major findings, mechanisms and recommendations - Nature Reviews MicrobiologyLong COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.
#COVID19#LongCovid#mitochondria
Public
Thiago Carvalho

"In the present study, we show that adult Drosophila melanogaster fed high-sugar diets became more susceptible to infection by the Gram-negative bacteria Providencia rettgeri and Serratia marcescens, although diet had no significant effect on infection by Gram-positive bacteria Enterococcus faecalis or Lactococcus lactis."
#Preprint #Immunity #Metabolism #InnateImmunity #Drosophila

biorxiv.org/content/10.1101/20

bioRxiv · High sugar diets can increase susceptibility to bacterial infection in Drosophila melanogasterOvernutrition with dietary sugar can worsen infection outcomes in diverse organisms including insects and humans, generally through unknown mechanisms. In the present study, we show that adult Drosophila melanogaster fed high-sugar diets became more susceptible to infection by the Gram-negative bacteria Providencia rettgeri and Serratia marcescens, although diet had no significant effect on infection by Gram-positive bacteria Enterococcus faecalis or Lactococcus lactis. We found that P. rettgeri and S. marcescens proliferate more rapidly in D. melanogaster fed a high-sugar diet, resulting in increased probability of host death. D. melanogaster become hyperglycemic on the high-sugar diet, and we find evidence that the extra carbon availability may promote S. marcescens growth within the host. However, we found no evidence that increased carbon availability directly supports greater P. rettgeri growth. D. melanogaster on both diets fully induce transcription of antimicrobial peptide (AMP) genes in response to infection, but D. melanogaster provided with high-sugar diets show reduced production of AMP protein. Thus, overnutrition with dietary sugar may impair host immunity at the level of AMP translation. Our results demonstrate that dietary sugar can shape infection dynamics by impacting both host and pathogen, depending on the nutritional requirements of the pathogen and by altering the physiological capacity of the host to sustain an immune response. Author Summary Diet has critical impact on the quality of immune defense, and high-sugar diets increase susceptibility to bacterial infection in many animals. Yet it is unknown which aspects of host and pathogen physiology are impacted by diet to influence infection dynamics. Here we show that high-sugar diets increase susceptibility to some, but not all, bacterial infections in Drosophila . We find that feeding on high sugar diet impairs the host immune response by reducing the level of antimicrobial peptides produced. The expression of genes encoding these peptides is not affected, so we infer that protein translation is impaired. We further show that flies on high-sugar diets are hyperglycemic, and that some pathogens may use the excess sugar in the host to promote growth during the infection. Thus, our study demonstrates that dietary impacts on infection outcome arise through physiological effects on both the host and pathogen. ### Competing Interest Statement The authors have declared no competing interest.
Public *
halama_immuno

#innateimmunity in action: #immunotherapy against #breastcancer with TLR3 ligand and interferon alpha. Only six patients in this #trial , but biopsy analyses show improved #inmuneinfiltration with #TILs and is linked to clinical observations. #interferon #cytokines #immunology #macrophages @chfloudas
jitc.bmj.com/content/11/11/e00

Journal for ImmunoTherapy of Cancer · Systemic infusion of TLR3-ligand and IFN-α in patients with breast cancer reprograms local tumor microenvironments for selective CTL influxBackground Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts the effectiveness of cancer immunotherapies. The ability of toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory T cell (Treg)-attractants) in the TME, but not in healthy tissues, observed in our preclinical studies, suggested that their systemic application can reprogram local TMEs. Methods Six evaluable patients (33–69 years) with metastatic triple-negative breast cancer received six doses of systemic chemokine-modulating (CKM) regimen composed of TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m2; intravenous) and COX2 inhibitor (celecoxib; 2×200 mg; oral) over 2 weeks. The predetermined primary endpoint was the intratumoral change in the expression of CTL marker, CD8α, in the post-CKM versus pre-CKM tumor biopsies. Patients received follow-up pembrolizumab (200 mg, intravenously, every 3 weeks), starting 3–8 days after completion of CKM. Results Post-CKM biopsies showed selectively increased CTL markers CD8α (average 10.2-fold, median 5.5-fold, p=0.034) and granzyme B (GZMB; 6.1-fold, median 5.8-fold, p=0.02), but not FOXP3 (Treg marker) relative to HPRT1 expression, resulting in the increases in average CD8α/FOXP3 ratio and GZMB/FOXP3 ratio. CKM increased intratumoral CTL-attractants CCL5 and CXCL10, but not Treg-attractants CCL22 or CXCL12. In contrast, CD8+ T cells and their CXCR3+ subset showed transient decreases in blood. One clinical response (breast tumor autoamputation) and three stable diseases were observed. The patient with clinical response remains disease free, with a follow-up of 46 months as of data cut-off. Conclusions Short-term systemic CKM selectively increases CTL numbers and CTL/Treg ratios in the TME, while transiently decreasing CTL numbers in the blood. Transient effects of CKM suggest that its simultaneous application with checkpoint blockade and other forms of immunotherapy may be needed for optimal outcomes. All data relevant to the study are included in the article or uploaded as supplementary information.
Public *
halama_immuno

Interleukin-1 is involved in #inflammation but the role in #cancer is not so clear...and here is a new insight for #pancreaticcancer : a loop between tumour cells and interleukin-1β-expressing #tumor associated #macrophages is supporting the tumor, this being brought on by a synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF), also opening the door for translational interventions #immunotherapy #innateimmunity #Immunology @cyrilpedia @gpollara

nature.com/articles/s41586-023

NatureIL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer - NatureSingle-cell and spatial gene expression analyses of pancreatic ductal adenocarcinoma uncover a population of interleukin-1β-expressing macrophages that drive inflammatory reprogramming of neighboring tumour cells leading to disease progression and poor prognosis for patients.
Public
Thiago Carvalho

Now I cant stop singing "more than a spike gene" to the tune of the BeeGees (protein didnt fit the meter).

'We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors.'
#Covid #Covid19 #SarsCov2 #Interferon #Virology #Immunology #InnateImmunity

sciencedirect.com/science/arti

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