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- Ezzat, Kariem, et al.
(författare)
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The viral protein corona directs viral pathogenesis and amyloid aggregation
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta-peptide (A beta(42)), a major constituent of amyloid plaques in Alzheimer's disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.
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| 2. |
- Cuapio, Angelica, et al.
(författare)
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NK cell frequencies, function and correlates to vaccine outcome in BNT162b2 mRNA anti-SARS-CoV-2 vaccinated healthy and immunocompromised individuals
- 2022
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Ingår i: Molecular Medicine. - : BioMed Central (BMC). - 1076-1551 .- 1528-3658. ; 28:1
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive immune responses have been studied extensively in the course of mRNA vaccination against COVID-19. Considerably fewer studies have assessed the effects on innate immune cells. Here, we characterized NK cells in healthy individuals and immunocompromised patients in the course of an anti-SARS-CoV-2 BNT162b2 mRNA prospective, open-label clinical vaccine trial. See trial registration description in notes. Results revealed preserved NK cell numbers, frequencies, subsets, phenotypes, and function as assessed through consecutive peripheral blood samplings at 0, 10, 21, and 35 days following vaccination. A positive correlation was observed between the frequency of NKG2C+ NK cells at baseline (Day 0) and anti-SARS-CoV-2 Ab titers following BNT162b2 mRNA vaccination at Day 35. The present results provide basic insights in regards to NK cells in the context of mRNA vaccination, and have relevance for future mRNA-based vaccinations against COVID-19, other viral infections, and cancer.Trial registration: The current study is based on clinical material from the COVAXID open-label, non-randomized prospective clinical trial registered at EudraCT and clinicaltrials.gov (no. 2021–000175-37). Description: https://clinicaltrials.gov/ct2/show/NCT04780659?term=2021-000175-37&draw=2&rank=1.
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| 3. |
- Healy, Katie, et al.
(författare)
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Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions
- 2021
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Ingår i: JHEP Reports. - : Elsevier BV. - 2589-5559. ; 3:4
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Virus-specific T cell dysfunction is a common feature of HBV-related hepatocellular carcinoma (HBV-HCC). Conventional T (ConT) cells can be redirected towards viral antigens in HBV-HCC when they express an HBV-specific receptor; however, their efficacy can be impaired by liver-specific physical and metabolic features. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the liver and can elicit potent intrahepatic effector functions. Here, we engineered ConT and MAIT cells to kill HBV expressing hepatoma cells and compared their functional properties. Methods: Donor-matched ConT and MAIT cells were engineered to express an HBV-specific T cell receptor (TCR). Cytotoxicity and hepatocyte homing potential were investigated using flow cytometry, real-time killing assays, and confocal microscopy in 2D and 3D HBV-HCC cell models. Major histocompatibility complex (MHC) class I-related molecule (MR1)-dependent and MR1-independent activation was evaluated in an Escherichia coli THP-1 cell model and by IL-12/IL-18 stimulation, respectively. Results: HBV TCR-MAIT cells demonstrated polyfunctional properties (CD107a, interferon [IFN] γ, tumour necrosis factor [TNF], and IL-17A) with strong HBV target sensitivity and liver-homing chemokine receptor expression when compared with HBV TCR-ConT cells. TCR-mediated lysis of hepatoma cells was comparable between the cell types and augmented in the presence of inflammation. Coculturing with HBV+ target cells in a 3D microdevice mimicking aspects of the liver microenvironment demonstrated that TCR-MAIT cells migrate readily towards hepatoma targets. Expression of an ectopic TCR did not affect the ability of the MAIT cells to be activated via MR1-presented bacterial antigens or IL-12/IL-18 stimulation. Conclusions: HBV TCR-MAIT cells demonstrate anti-HBV functions without losing their endogenous antimicrobial mechanisms or hepatotropic features. Our results support future exploitations of MAIT cells for liver-directed immunotherapies. Lay summary: Chronic HBV infection is a leading cause of liver cancer. T cell receptor (TCR)-engineered T cells are patients’ immune cells that have been modified to recognise virus-infected and/or cancer cells. Herein, we evaluated whether mucosal-associated invariant T cells, a large population of unconventional T cells in the liver, could recognise and kill HBV infected hepatocytes when engineered with an HBV-specific TCR. We show that their effector functions may exceed those of conventional T cells currently used in the clinic, including antimicrobial properties and chemokine receptor profiles better suited for targeting liver tumours.
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| 4. |
- Sobkowiak, Michał J
(författare)
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Invariant T cell subsets in immune defense of oral mucosa and skin
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Innate-like T lymphocytes such as mucosa-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells recognize antigens presented by MR1 and CD1d molecules, respectively. As MR1 presents microbial riboflavin metabolite antigens, and CD1d presents endogenous or microbial glycolipid antigens, MAIT cells and iNKT cells survey the non-protein fraction of the potential antigenic universe. Both these cell types respond in an innate-like fashion without the need for priming and clonal expansion, and are thus rapidly available to help protect the host from viral and bacterial infections. This thesis is focused primarily on the role of the innate-like T cell subsets in immune defense of the human oral mucosa and skin, two tissues that together form a large part of the body barrier to the surrounding world of microbes. In paper I, we establish a set of reproducible and adaptable methods to study human MAIT cell activation, cytokine production, proliferation and cytolytic function in response to microbes expressing riboflavin metabolite antigens. These novel and optimized methods establish a framework and open new possibilities to study MAIT cell immunobiology using Escherichia coli as a model antigen. In paper II, we study the lymphocyte population in healthy human buccal mucosa, and establish the presence of MAIT cells at this site. The buccal mucosal MAIT cell population is located both in the epithelium and in the lamina propria and can be divided into a tissue resident CD103+ subset and a tissue non-resident CD103- subset. These two subsets differ in their functional profile both between each other and compared to the circulating peripheral blood MAIT cell population. Interestingly, tissue-resident MAIT cells had a specialized polyfunctional response profile with higher IL-17 levels, and were low in the cytolytic effector molecule perforin. In paper III, we investigate the involvement of oral mucosal MAIT cells in apical periodontitis (AP). MAIT cells were moderately enriched in AP tissue as compared to the surrounding healthy gingival tissue, but with higher representation of the CD4+ MAIT cell subset. When the abundance of MAIT cell TCR transcript was analyzed in relation to AP microbiome data, we could identify bacterial relative abundances that negatively correlated with Vα7.2-Jα33, Cα, and IL-17A transcript expressions in AP, implying that MAIT cells could play a role in this oral disease setting. In paper IV, we investigate the innate immune response to herpes simplex virus 1 (HSV1) in keratinocytes. In response to HSV1 infection keratinocytes rapidly upregulate surface expression of the innate immune activating cytokine IL-15 in a TLR3-dependent manner. Interestingly, the virus actively downregulates the IL-15/IL-15Ra complex in an apparent novel mode of immune evasion. Furthermore, we show that iNKT cells can counteract this viral effect and support the maintenance of IL-15 expression on the surface of infected keratinocytes. In summary, the research covered by this thesis unravels a series of novel aspects of immunity mediated by innate-like T cells at barrier sites of the human body. The findings are of considerable importance for our understanding of immunity against bacterial and viral antigens in the oral mucosa and the skin.
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