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Article ; Online: A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs.

English, Kieran / Kwan, Rain / Holz, Lauren E / McGuffog, Claire / Krol, Jelte M M / Kempe, Daryan / Kaisho, Tsuneyasu / Heath, William R / Lisowski, Leszek / Biro, Maté / McCaughan, Geoffrey W / Bowen, David G / Bertolino, Patrick

Nature communications

2024 Volume 15, Issue 1, Page(s) 1261

Abstract: ... While ... ...

Abstract	While CD4
MeSH term(s)	Antigens ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Dendritic Cells/immunology ; Liver/immunology ; Humans ; Lymphoid Tissue/immunology
Chemical Substances	Antigens
Language	English
Publishing date	2024-02-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45612-5
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Article ; Online: The liver contains distinct interconnected networks of CX3CR1

English, Kieran / Tan, Sioh Yang / Kwan, Rain / Holz, Lauren E / Sierro, Frederic / McGuffog, Claire / Kaisho, Tsuneyasu / Heath, William R / MacDonald, Kelli Pa / McCaughan, Geoffrey W / Bowen, David G / Bertolino, Patrick

Immunology and cell biology

2022 Volume 100, Issue 6, Page(s) 394–408

Abstract: Portal tracts are key intrahepatic structures where leukocytes accumulate during immune responses. They contain the blood inflow, which includes portal blood from the gut, and lymphatic and biliary outflow of the liver, and as such represent a key ... ...

Abstract	Portal tracts are key intrahepatic structures where leukocytes accumulate during immune responses. They contain the blood inflow, which includes portal blood from the gut, and lymphatic and biliary outflow of the liver, and as such represent a key interface for potential pathogen entry to the liver. Myeloid cells residing in the interstitium of the portal tract might play an important role in the surveillance or prevention of pathogen dissemination; however, the exact composition and localization of this population has not been explored fully. Our in-depth characterization of portal tract myeloid cells revealed that in addition to T lymphocytes, portal tracts contain a heterogeneous population of MHCII
MeSH term(s)	Dendritic Cells ; Liver ; Macrophages
Language	English
Publishing date	2022-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12559
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Article ; Online: Antigen-specific T cells fully conserve antitumour function following cryopreservation.

Galeano Niño, Jorge L / Kwan, Rain Y Q / Weninger, Wolfgang / Biro, Maté

Immunology and cell biology

2016 Volume 94, Issue 4, Page(s) 411–418

Abstract: Immunotherapies based on the autologous adoptive transfer of ex vivo-manipulated T cells are rapidly evolving for the treatment of both metastatic and primary malignancies. However, extended ex vivo culturing reduces the functionality of isolated T cells. ...

Abstract	Immunotherapies based on the autologous adoptive transfer of ex vivo-manipulated T cells are rapidly evolving for the treatment of both metastatic and primary malignancies. However, extended ex vivo culturing reduces the functionality of isolated T cells. Cryopreservation of rapidly expanded T cells for subsequent use throughout an immunotherapeutic regimen is a highly desirable recourse, thus far encumbered by a lack of studies investigating its effects on effector T-cell functionality. Here we directly compare murine tumour-reactive CD8(+) T cells cryopreserved during ex vivo expansion to freshly isolated populations. We show that cryopreservation fully conserves the differentiation potential of effector T cells, secretion of pro-inflammatory cytokines, cytotoxic function and does not impair the three-dimensional scanning motility of T cells or their capacity to infiltrate and reject tumours.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; CD8-Positive T-Lymphocytes/physiology ; Cell Differentiation ; Cells, Cultured ; Cryopreservation ; Cytokines/metabolism ; Feasibility Studies ; Humans ; Immunotherapy, Adoptive ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Neoplasms/immunology ; Neoplasms/therapy
Chemical Substances	Antigens, Neoplasm ; Cytokines
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1038/icb.2015.105
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Article ; Online: Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Kouri, Naomi / Frankenhauser, Isabelle / Peng, Zhongwei / Labuzan, Sydney A / Boon, Baayla D C / Moloney, Christina M / Pottier, Cyril / Wickland, Daniel P / Caetano-Anolles, Kelsey / Corriveau-Lecavalier, Nick / Tranovich, Jessica F / Wood, Ashley C / Hinkle, Kelly M / Lincoln, Sarah J / Spychalla, A J / Senjem, Matthew L / Przybelski, Scott A / Engelberg-Cook, Erica / Schwarz, Christopher G /

Kwan, Rain S / Lesser, Elizabeth R / Crook, Julia E / Carter, Rickey E / Ross, Owen A / Lachner, Christian / Ertekin-Taner, Nilüfer / Ferman, Tanis J / Fields, Julie A / Machulda, Mary M / Ramanan, Vijay K / Nguyen, Aivi T / Reichard, R Ross / Jones, David T / Graff-Radford, Jonathan / Boeve, Bradley F / Knopman, David S / Petersen, Ronald C / Jack, Clifford R / Kantarci, Kejal / Day, Gregory S / Duara, Ranjan / Graff-Radford, Neill R / Dickson, Dennis W / Lowe, Val J / Vemuri, Prashanthi / Murray, Melissa E

JAMA neurology

2024

Abstract: Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement.!# ...

Abstract	Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, setting, and participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main outcomes and measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2024.0784
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Article ; Online: Partial loss of actin nucleator actin-related protein 2/3 activity triggers blebbing in primary T lymphocytes.

Obeidy, Peyman / Ju, Lining A / Oehlers, Stefan H / Zulkhernain, Nursafwana S / Lee, Quintin / Galeano Niño, Jorge L / Kwan, Rain Yq / Tikoo, Shweta / Cavanagh, Lois L / Mrass, Paulus / Cook, Adam Jl / Jackson, Shaun P / Biro, Maté / Roediger, Ben / Sixt, Michael / Weninger, Wolfgang

Immunology and cell biology

2019 Volume 98, Issue 2, Page(s) 93–113

Abstract: T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin-related ... ...

Abstract	T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin-related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F-actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3-knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon-like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three-dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3-dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actin-Related Protein 2-3 Complex/genetics ; Actin-Related Protein 2-3 Complex/metabolism ; Actin-Related Protein 3/genetics ; Actin-Related Protein 3/metabolism ; Actins/metabolism ; Animals ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Cell Survival/genetics ; Down-Regulation ; Gene Knockdown Techniques ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; RNA, Small Interfering ; Single-Cell Analysis ; T-Lymphocytes, Cytotoxic/cytology ; T-Lymphocytes, Cytotoxic/metabolism ; Zebrafish
Chemical Substances	Actin-Related Protein 2-3 Complex ; Actin-Related Protein 3 ; Actins ; RNA, Small Interfering
Language	English
Publishing date	2019-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12304
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Article ; Online: RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes.

International journal of cancer

2019 Volume 144, Issue 12, Page(s) 3070–3085

Abstract: Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying ... ...

Abstract	Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Movement/physiology ; Clustered Regularly Interspaced Short Palindromic Repeats ; Culture Media, Conditioned ; Exosomes/genetics ; Exosomes/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma, Experimental/genetics ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Melanosomes/genetics ; Melanosomes/metabolism ; Mice ; Neoplasm Invasiveness ; Nevus/genetics ; Nevus/metabolism ; Proteomics ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Spheroids, Cellular ; rab27 GTP-Binding Proteins/biosynthesis ; rab27 GTP-Binding Proteins/genetics ; rab27 GTP-Binding Proteins/metabolism
Chemical Substances	Culture Media, Conditioned ; rab27 GTP-Binding Proteins ; RAB27A protein, human (EC 3.6.1.-.)
Language	English
Publishing date	2019-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.32064
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Article ; Online: Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.

Devi, Sapna / Kuligowski, Michael P / Kwan, Rain Y Q / Westein, Erik / Jackson, Shaun P / Kitching, A Richard / Hickey, Michael J

The American journal of pathology

2010 Volume 177, Issue 3, Page(s) 1131–1142

Abstract: Recruitment of leukocytes to glomeruli is fundamental to the pathogenesis of many forms of glomerulonephritis. In a model of glomerulonephritis induced by in situ immune complex deposition, we previously observed that, in addition to leukocytes, ... ...

Abstract	Recruitment of leukocytes to glomeruli is fundamental to the pathogenesis of many forms of glomerulonephritis. In a model of glomerulonephritis induced by in situ immune complex deposition, we previously observed that, in addition to leukocytes, platelets accumulate in glomerular capillaries, where they contribute to leukocyte recruitment. However, the mechanisms of platelet recruitment and the role of platelet-expressed P-selectin in leukocyte recruitment require further investigation. We used intravital microscopy to examine the mechanisms of platelet and leukocyte recruitment to glomeruli of mice following administration of an antibody against the glomerular basement membrane (anti-GBM antibody). Platelet recruitment was initiated within five minutes of administration of anti-GBM antibody. This was unaltered by inhibition of platelet GPIbalpha but was prevented by the absence of platelet GPVI. Fibrinogen was deposited in glomerular capillaries via a partially intercellular adhesion molecule 1 (ICAM-1)-dependent mechanism, and inhibition of alpha(IIb)beta(3), fibrinogen and ICAM-1 inhibited platelet recruitment. Notably, neutrophil depletion also reduced platelet accumulation, indicating a cooperative interaction underlying recruitment of platelets and neutrophils. Finally, using bone marrow chimeras to restrict expression of P-selectin to platelets or endothelial cells, platelet but not endothelial P-selectin was required for glomerular leukocyte recruitment. Together these data indicate that platelet recruitment in this model is dependent on the combined actions of GPVI and the alpha(IIb)beta(3)/fibrinogen/ICAM-1 pathway and that platelet P-selectin is crucial for subsequent leukocyte recruitment.
MeSH term(s)	Analysis of Variance ; Animals ; Autoantibodies/immunology ; Autoantibodies/metabolism ; Blood Platelets/immunology ; Blood Platelets/metabolism ; Immunohistochemistry ; Kidney Glomerulus/immunology ; Kidney Glomerulus/metabolism ; Leukocytes/immunology ; Leukocytes/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neutrophil Activation/physiology ; P-Selectin/immunology ; P-Selectin/metabolism ; Platelet Activation/physiology ; Platelet Membrane Glycoproteins/immunology ; Platelet Membrane Glycoproteins/metabolism ; Signal Transduction/physiology
Chemical Substances	Autoantibodies ; P-Selectin ; Platelet Membrane Glycoproteins ; antiglomerular basement membrane antibody ; platelet membrane glycoprotein VI
Language	English
Publishing date	2010-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.2353/ajpath.2010.091143
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Article: Interferon gamma is recognised by importin alpha/beta: enhanced nuclear localising and transactivation activities of an interferon gamma mimetic.

Fulcher, Alex J / Ahmed, Chulbul M I / Noon-Song, Ezra N / Kwan, Rain Y Q / Subramaniam, Prem S / Johnson, Howard M / Jans, David A

FEBS letters

2008 Volume 582, Issue 11, Page(s) 1569–1574

Abstract: Interferon (IFN) gamma's ability to localise in the nucleus and function in gene activation has been known for some time, although the role of the conventional nuclear transporting importin molecules is unclear. Here, we demonstrate for the first time ... ...

Abstract	Interferon (IFN) gamma's ability to localise in the nucleus and function in gene activation has been known for some time, although the role of the conventional nuclear transporting importin molecules is unclear. Here, we demonstrate for the first time the direct recognition of IFNgamma and an IFNgamma mimetic peptide by IMPalpha and the IMPalpha/beta heterodimer, where the IFNgamma mimetic shows higher affinity. Significantly, this correlates well both with in vivo ability to target green fluorescent protein to the nucleus in transfected cells as determined by quantitative confocal laser scanning microscopy, as well as GAS promoter activity of a luciferase reporter. This has important implications for IFNgamma's anti-viral action, and the potential use of the IFNgamma mimetic in antiviral therapies.
MeSH term(s)	Amino Acid Sequence ; Animals ; Biomimetic Materials/metabolism ; COS Cells ; Cell Nucleus/metabolism ; Chlorocebus aethiops ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Molecular Sequence Data ; Nuclear Localization Signals/metabolism ; Peptides ; Promoter Regions, Genetic ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Transcriptional Activation ; alpha Karyopherins/metabolism ; beta Karyopherins/metabolism
Chemical Substances	Nuclear Localization Signals ; Peptides ; Recombinant Fusion Proteins ; alpha Karyopherins ; beta Karyopherins ; Green Fluorescent Proteins (147336-22-9) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2008-04-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2008.03.054
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Article ; Online: Antimyeloperoxidase antibodies rapidly induce alpha-4-integrin-dependent glomerular neutrophil adhesion.

Kuligowski, Michael P / Kwan, Rain Y Q / Lo, Cecilia / Wong, Cyndi / James, Will G / Bourges, Dorothee / Ooi, Joshua D / Abeynaike, Latasha D / Hall, Pam / Kitching, A Richard / Hickey, Michael J

Blood

2009 Volume 113, Issue 25, Page(s) 6485–6494

Abstract: Patients with antineutrophil cytoplasmic antibodies (ANCAs) frequently develop severe vasculitis and glomerulonephritis. Although ANCAs, particularly antimyeloperoxidase (anti-MPO), have been shown to promote leukocyte adhesion in postcapillary venules, ... ...

Abstract	Patients with antineutrophil cytoplasmic antibodies (ANCAs) frequently develop severe vasculitis and glomerulonephritis. Although ANCAs, particularly antimyeloperoxidase (anti-MPO), have been shown to promote leukocyte adhesion in postcapillary venules, their ability to promote adhesion in the glomerular vasculature is less clear. We used intravital microscopy to examine glomerular leukocyte adhesion induced by anti-MPO. In mice pretreated with LPS, 50 microg anti-MPO induced LFA-1-dependent adhesion in glomeruli. In concert with this finding, in mice pretreated with LPS, more than 80% of circulating neutrophils bound anti-MPO within 5 minutes of intravenous administration. However, even in the absence of LPS, more than 40% of circulating neutrophils bound anti-MPO in vivo, a response not seen in MPO(-/-) mice. In addition, a higher dose of anti-MPO (200 microg) induced robust glomerular leukocyte adhesion in the absence of LPS. The latter response was beta2-integrin independent, instead requiring the alpha4-integrin, which was up-regulated on neutrophils in response to anti-MPO. These data indicate that anti-MPO antibodies bind to circulating neutrophils, and can induce glomerular leukocyte adhesion via multiple pathways. Lower doses induce adhesion only after an infection-related stimulus, whereas higher doses are capable of inducing responses in the absence of an additional inflammatory stimulus, via alternative adhesion mechanisms.
MeSH term(s)	Animals ; Antibodies, Antineutrophil Cytoplasmic/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antigen-Antibody Reactions ; CD18 Antigens/immunology ; CD18 Antigens/physiology ; Cell Adhesion/immunology ; Endotoxemia/immunology ; Endotoxins/pharmacology ; Endotoxins/toxicity ; Hydronephrosis/immunology ; Hydronephrosis/pathology ; Immunization ; Integrin alpha4/metabolism ; Integrin alpha4/physiology ; Kidney Glomerulus/blood supply ; Kidney Glomerulus/pathology ; Lymphocyte Function-Associated Antigen-1/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes/enzymology ; Monocytes/immunology ; Neutrophils/enzymology ; Neutrophils/immunology ; P-Selectin/immunology ; Peroxidase/deficiency ; Peroxidase/immunology ; Vascular Cell Adhesion Molecule-1/metabolism
Chemical Substances	Antibodies, Antineutrophil Cytoplasmic ; Antibodies, Monoclonal ; CD18 Antigens ; Endotoxins ; Lymphocyte Function-Associated Antigen-1 ; P-Selectin ; Vascular Cell Adhesion Molecule-1 ; Integrin alpha4 (143198-26-9) ; endotoxin, Escherichia coli (67924-63-4) ; Peroxidase (EC 1.11.1.7)
Language	English
Publishing date	2009-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2008-12-192617
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Article ; Online: Molecular and cellular basis of microvascular perfusion deficits induced by Clostridium perfringens and Clostridium septicum.

Hickey, Michael J / Kwan, Rain Y Q / Awad, Milena M / Kennedy, Catherine L / Young, Lauren F / Hall, Pam / Cordner, Leanne M / Lyras, Dena / Emmins, John J / Rood, Julian I

PLoS pathogens

2008 Volume 4, Issue 4, Page(s) e1000045

Abstract: Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens alpha-toxin has been shown capable of inducing these changes, but its potential synergy ... ...

Abstract	Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens alpha-toxin has been shown capable of inducing these changes, but its potential synergy with perfringolysin O (theta-toxin) is less well understood. Similarly, Clostridium septicum is a highly virulent causative agent of spontaneous gas gangrene, but its effect on the microcirculation has not been examined. Therefore, the aim of this study was to use intravital microscopy to examine the effects of C. perfringens and C. septicum on the functional microcirculation, coupled with the use of isogenic toxin mutants to elucidate the role of particular toxins in the resultant microvascular perfusion deficits. This study represents the first time this integrated approach has been used in the analysis of the pathological response to clostridial toxins. Culture supernatants from wild-type C. perfringens induced extensive cell death within 30 min, as assessed by in vivo uptake of propidium iodide. Furthermore, significant reductions in capillary perfusion were observed within 60 min. Depletion of either platelets or neutrophils reduced the alteration in perfusion, consistent with a role for these blood-borne cells in obstructing perfusion. In addition, mutation of either the alpha-toxin or perfringolysin O structural genes attenuated the reduction in perfusion, a process that was reversed by genetic complementation. C. septicum also induced a marked reduction in perfusion, with the degree of microvascular compromise correlating with the level of the C. septicum alpha-toxin. Together, these data indicate that as a result of its ability to produce alpha-toxin and perfringolysin O, C. perfringens rapidly induces irreversible cellular injury and a marked reduction in microvascular perfusion. Since C. septicum induces a similar reduction in microvascular perfusion, it is postulated that this function is central to the pathogenesis of clostridial myonecrosis, irrespective of the causative bacterium.
MeSH term(s)	Animals ; Bacterial Toxins/genetics ; Bacterial Toxins/metabolism ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Cell Death/drug effects ; Clostridium perfringens/pathogenicity ; Clostridium perfringens/physiology ; Clostridium septicum/pathogenicity ; Clostridium septicum/physiology ; Gas Gangrene/microbiology ; Gas Gangrene/physiopathology ; Gene Expression Regulation, Fungal/drug effects ; Hemolysin Proteins/genetics ; Hemolysin Proteins/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Microcirculation/drug effects ; Microscopy, Video ; Muscle, Skeletal/blood supply ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/pathology ; Mutagenesis, Insertional ; Perfusion ; Regional Blood Flow/drug effects ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
Chemical Substances	Bacterial Toxins ; Calcium-Binding Proteins ; Hemolysin Proteins ; Clostridium perfringens theta-toxin (71329-60-7) ; Type C Phospholipases (EC 3.1.4.-) ; alpha toxin, Clostridium perfringens (EC 3.1.4.3)
Language	English
Publishing date	2008-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1000045
Database	MEDical Literature Analysis and Retrieval System OnLINE

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