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Infection-induced membrane ruffling initiates danger and immune signaling via the mechanosensor PIEZO1
Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Puhar)ORCID-id: 0000-0002-1653-9639
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). (Puhar)ORCID-id: 0000-0002-0971-4910
Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Puhar)ORCID-id: 0000-0003-3171-9379
Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Puhar)ORCID-id: 0000-0002-0984-6286
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2022 (Engelska)Ingår i: Cell Reports, E-ISSN 2211-1247, Vol. 40, nr 6, artikel-id 111173Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Microorganisms are generally sensed by receptors recognizing microbial molecules, which evoke changes in cellular activities and gene expression. Bacterial pathogens induce secretion of the danger signal ATP as an early alert response of intestinal epithelial cells, initiating overt inflammation. However, what triggers ATP secretion during infection is unclear. Here we show that the inherently mechanosensitive plasma membrane channel PIEZO1 acts as a sensor for bacterial entry. PIEZO1 is mechanically activated by invasion-induced membrane ruffles upstream of Ca2+ influx and ATP secretion. Mimicking mechanical stimuli of pathogen uptake with sterile beads equally elicits ATP secretion. Chemical or genetic PIEZO1 inactivation inhibits mechanically induced ATP secretion. Moreover, chemical or mechanical PIEZO1 activation evokes gene expression in immune and barrier pathways. Thus, mechanosensation of invasion-induced plasma membrane distortion initiates immune signaling upon infection, independently of detection of microbial molecules. Hence, PIEZO1-dependent detection of infection is driven by physical signals instead of chemical ligands.

Ort, förlag, år, upplaga, sidor
Elsevier, 2022. Vol. 40, nr 6, artikel-id 111173
Nyckelord [en]
mechanosensing, immune detection, danger signals, invasive pathogens, Shigella, Listeria, plasma membrane ruffles, PIEZO1, extracellular ATP, intestinal epithelial cells
Nationell ämneskategori
Cell- och molekylärbiologi Immunologi inom det medicinska området Mikrobiologi inom det medicinska området
Forskningsämne
infektionssjukdomar
Identifikatorer
URN: urn:nbn:se:umu:diva-198648DOI: 10.1016/j.celrep.2022.111173ISI: 000881382400003Scopus ID: 2-s2.0-85135700972OAI: oai:DiVA.org:umu-198648DiVA, id: diva2:1687514
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, KAW 2015.0225Kempestiftelserna, JCK-1528Kempestiftelserna, SMK-1859Kempestiftelserna, JCK-2031.3Vetenskapsrådet, 2016-06598Carl Tryggers stiftelse för vetenskaplig forskning , CTS 18-65Kempestiftelserna, SMK-1860Kempestiftelserna, SMK-1532.2Svenska Sällskapet för Medicinsk Forskning (SSMF), PD20-0022Tillgänglig från: 2022-08-15 Skapad: 2022-08-15 Senast uppdaterad: 2024-01-17Bibliografiskt granskad
Ingår i avhandling
1. Role of extracellular ATP in immune mechanisms against infections
Öppna denna publikation i ny flik eller fönster >>Role of extracellular ATP in immune mechanisms against infections
2022 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Roll av extracellulär ATP i immunmekanismer mot infektioner
Abstract [en]

Inflammation is driven either by infection with pathogens or sterile stimuli, such as tissue damage or autoimmune diseases. Upon tissue damage, ATP is released passively from the dead or compromised cells. During stress, ATP can be secreted from the cells. Extracellular ATP (eATP) acts as an endogenous danger signal. An increase in eATP is sensed by cell surface purinergic receptors and regulates the onset and resolution of inflammation. Extracellular ATP is an important inflammatory mediator during sterile inflammation. On the other hand, the role of eATP is poorly studied during infection, both bacterial and viral. In this thesis, I present the molecular mechanisms underlying ATP secretion during bacterial infections and the role of eATP in human hantaviral infections.

During infection with certain enteropathogenic Gram-negative bacteria, intestinal epithelial cells secrete ATP via connexin hemichannels as an alert signal to activate the immune system, which triggers acute inflammation in the gut. However, neither what triggers ATP secretion nor the molecular mechanisms of ATP secretion were known. Pharmacological, genetic, and microscopy-based evidence shows that during invasive bacterial infections, the plasma membrane ruffles act as mechanical immune stimuli and activate the inherently mechanosensitive plasma membrane channel PIEZO1. Mechanically activated PIEZO1 leads to the influx of Ca2+ ions and concurrent ATP secretion. In addition, PIEZO1 also activates protective transcriptional responses. Thus, PIEZO1 acts as a sensor for invasive infection using mechanical stimuli, unlike the so-far-described immune sensors of infection, which all recognize microbial components by chemical interaction.

During human hantavirus infection, the humoral immune responses are poorly studied. Our collaborators found that atypical B cells, which do not have the surface marker CD27, show increased frequency in a cohort of hantavirus-infected patients. CD27 shedding in murine lymphocytes had been previously linked to eATP-dependent activation of a purinergic receptor7. To test whether ATP levels in the circulation of hantavirus-infected patients are elevated, an approach to perform same-day eATP quantifications in human plasma was developed. This assay was used to establish the normal eATP concentration in plasma in a cohort of healthy volunteers and to show that eATP levels are elevated in the acute and convalescent stages of hantavirus infection. Further, the addition of ATP to isolated human B cells recapitulated the observed CD27 shedding via a metallomatrix proteinase-8-dependent (MMP8) mechanism. Together, these projects provide evidence for the importance of eATP in bacterial and viral infectious diseases.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2022. s. 44
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2216
Nyckelord
Extracellular ATP, invasive bacteria, Shigella, Listeria, plasma membrane ruffle, PIEZO1, infection, immune response, Hanta virus
Nationell ämneskategori
Mikrobiologi inom det medicinska området Infektionsmedicin
Forskningsämne
molekylär cellbiologi
Identifikatorer
urn:nbn:se:umu:diva-200913 (URN)978-91-7855-932-9 (ISBN)978-91-7855-933-6 (ISBN)
Disputation
2022-12-02, Atrium Betula, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2022-11-11 Skapad: 2022-11-09 Senast uppdaterad: 2023-10-05Bibliografiskt granskad

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Tadala, LalithaDannborg, MirjamCervantes-Rivera, RamónSharma, AtinWanders, AlkwinCisneros, David A.Puhar, Andrea

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Tadala, LalithaLangenbach, DorotheeDannborg, MirjamCervantes-Rivera, RamónSharma, AtinVieth, KevinWanders, AlkwinCisneros, David A.Puhar, Andrea
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Molekylär Infektionsmedicin, Sverige (MIMS)Umeå Centre for Microbial Research (UCMR)Institutionen för molekylärbiologi (Medicinska fakulteten)Patologi
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