| 1. |
- Chan, Yi-Hao, et al.
(författare)
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SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
- 2024
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 221:9
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Tidskriftsartikel (refereegranskat)abstract
- Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
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| 2. |
- Churqui, Marianela Patzi, 1987, et al.
(författare)
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Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2
- 2018
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Ingår i: Journal of Ethnopharmacology. - : Elsevier BV. - 0378-8741 .- 1872-7573. ; 210, s. 192-197
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Tidskriftsartikel (refereegranskat)abstract
- Ethnopharmacological relevance Equisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. Aim of the study To assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. Materials and Methods Equisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. Results Equisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. Conclusions These studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Müll. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides. © 2017 Elsevier Ireland Ltd
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| 3. |
- Krzyzowska, Malgorzata, et al.
(författare)
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Fas/FasL Contributes to HSV-1 Brain Infection and Neuroinflammation
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The Fas/FasL pathway plays a key role in immune homeostasis and immune surveillance. In the central nervous system (CNS) Fas/FasL is involved in axonal outgrowth and adult neurogenesis. However, little is known about the role of the Fas/FasL pathway in herpes encephalitis. In this study, we used a neuropathogenic clinical strain of herpes simplex virus type 1 (HSV-1) to explore infection-induced inflammation and immune responses in the mouse brain and the role of Fas/FasL in antiviral CNS immunity. HSV-1 CNS infection induced the infiltration of Fas- FasL-bearing monocytes and T cells in the brain and also to an up-regulation of Fas and FasL expression on resident astrocytes and microglia within infected sites. Upon infection, Fas- and FasL-deficient mice (lpr and gld) were partially protected from encephalitis with a decreased morbidity and mortality compared to WT mice. Fas/FasL deficiency promoted cell-mediated immunity within the CNS. Fas receptor stimulation abrogated HSV-1 induced activation and inflammatory reactions in microglia from WT mice, while lack of Fas or FasL led to a more pronounced activation of monocytes and microglia and also to an enhanced differentiation of these cells into a pro-inflammatory M1 phenotype. Furthermore, the specific immune system was more efficient in Fas- and FasL-deficient mice with significantly higher numbers of infiltrating HSV-1-specific cytotoxic T cells in the brain. Our data indicate that the Fas/FasL pathway leads to excessive neuroinflammation during HSV-1 infection, which is associated with a diminished anti-viral response and an excessive neuroinflammation.
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| 4. |
- Krzyzowska, Malgorzata, et al.
(författare)
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Tofacitinib treatment in primary herpes simplex encephalitis interferes with anti-viral response.
- 2022
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:9, s. 1545-1553
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Tidskriftsartikel (refereegranskat)abstract
- Tofacitinib, a Janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Herpes simplex virus type 1 (HSV-1) may cause encephalitis during primary infection or following reactivation from a latent state. Long-term tofacitinib treatment may increase the risk of this life-threatening condition. The aim of this study was to investigate the effect of tofacitinib on HSV-1 primary infection using a mouse model. Mice pre-treated with tofacitinib were intranasally infected with a clinical strain of HSV-1 and monitored for infection severity and anti-viral response. Tofacitinib treatment of HSV-1 primary infection resulted in increased viral loads and worsened clinical outcome. Furthermore, tofacitinib promoted M2 anti-inflammatory phenotype of microglia and infiltrating monocytes as well as inhibited production of inflammatory and antiviral cytokines by macrophages in vitro. Our findings show that treatment with tofacitinib increases severity of HSE in mice, by impairing anti-viral response induced by monocytes and microglia.
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| 5. |
- Lind, Liza, 1984, et al.
(författare)
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CD8(+) T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3
- 2021
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Ingår i: Journal of Neurovirology. - : Springer Science and Business Media LLC. - 1355-0284 .- 1538-2443. ; 27, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 2 (HSV-2) is a neurotropic virus that can cause meningitis, an inflammation of the meninges in the central nervous system. T cells are key players in viral clearance, and these cells migrate from peripheral blood into the central nervous system upon infection. Several factors contribute to T cell migration, including the expression of chemokines in the inflamed tissue that attract T cells through their expression of chemokine receptors. Here we investigated CD8(+) T cell profile in the spinal cord in a mouse model of herpes simplex virus type 2 neuroinflammation. Mice were infected with HSV-2 and sacrificed when showing signs of neuroinflammation. Cells and/or tissue from spinal cord, spleen, and blood were analyzed for expression of activation markers, chemokine receptors, and chemokines. High numbers of CD8(+) T cells were present in the spinal cord following genital HSV-2-infection. CD8(+) T cells were highly activated and HSV-2 glycoprotein B -specific effector cells, some of which showed signs of recent degranulation. They also expressed high levels of many chemokine receptors, in particular CCR2, CCR4, CCR5, and CXCR3. Investigating corresponding receptor ligands in spinal cord tissue revealed markedly increased expression of the cognate ligands CCL2, CCL5, CCL8, CCL12, and CXCL10. This study shows that during herpesvirus neuroinflammation anti-viral CD8(+) T cells accumulate in the CNS. CD8(+) T cells in the CNS also express chemotactic receptors cognate to the chemotactic gradients in the spinal cord. This indicates that anti-viral CD8(+) T cells may migrate to infected areas in the spinal cord during herpesvirus neuroinflammation in response to chemotactic gradients.
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| 6. |
- Lindqvist, Madelene, 1982, et al.
(författare)
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The mucosal adjuvant effect of alpha-galactosylceramide for induction of protective immunity to sexually transmitted viral infection.
- 2009
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:10, s. 6435-43
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Tidskriftsartikel (refereegranskat)abstract
- Development of mucosal adjuvants to generate immunity in the female genital tract may have important implications for the development of vaccines to counter sexually transmitted infections. alpha-Galactosylceramide (alpha-GalCer) is presented by CD1d molecule on APCs to invariant Valpha14(+) NKT (iNKT) cells, which upon activation rapidly produce large amounts of immunomodulatory cytokines, leading to activation of a variety of innate and adaptive immune cells. Here, we assessed whether alpha-GalCer could act as a mucosal adjuvant for induction of protective immunity against genital herpes. We found that intranasal immunization with HSV-2 glycoprotein D (gD) in combination with alpha-GalCer elicits strong systemic gD-specific IgG Ab response as well as lymphoproliferative response with a mixed Th1/Th2 cytokine profile in the spleen, mediastinal lymph nodes, and genital lymph nodes. Importantly, such an immunization scheme conferred complete protection against an otherwise lethal vaginal HSV-2 challenge. We could also show that intravaginal immunization with gD plus alpha-GalCer generates potent gD-specific lymphoproliferative and IFN-gamma responses in the genital lymph nodes and spleen. Furthermore, the vaginally immunized mice developed a strong systemic and mucosal IgG Ab response and protection against vaginal HSV-2 challenge. The mucosal adjuvant effect of alpha-GalCer was found to be mediated via CD1d molecule and appeared to be independent of the usage of the adaptor molecule MyD88. To our knowledge, this is the first report on the mucosal adjuvant effect of alpha-GalCer for induction of protective immunity against a sexually transmitted pathogen.
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| 7. |
- Lindqvist, Madelene, 1982, et al.
(författare)
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Unraveling molecular signatures of immunostimulatory adjuvants in the female genital tract through systems biology
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Sexually transmitted infections (STIs) unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs.
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| 8. |
- Lingman Framme, Jenny, 1977, et al.
(författare)
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Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs
- 2022
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Ingår i: Journal of Clinical Immunology. - : Springer. - 0271-9142 .- 1573-2592. ; 42, s. 618-633
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Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.
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| 9. |
- Lundberg, Vanja, et al.
(författare)
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Thymic exosomes promote the final maturation of thymocytes
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4(+)CD25(-) cells into mature thymocytes with S1P(1)(+)Qa2(+) and CCR7(+)Qa2(+) phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4(+)CD25(+)FoxP3(+) thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC's is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.
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| 10. |
- Odqvist, Lina, et al.
(författare)
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Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 78:10, s. 1363-1370
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
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