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BACKGROUND: Impaired interferon response and allergic sensitization may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity as critical producers of type I interferons. pDCs also express the high-affinity IgE receptor through which type I interferon production may be negatively regulated. Whether antiviral function of pDCs is associated with recurrent episodes of wheeze in young children is not well understood. OBJECTIVE: We sought to evaluate the phenotype and function of circulating pDCs in children with a longitudinally defined wheezing phenotype. METHODS: We performed multiparameter flow cytometry on PBMCs from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDCs from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. RESULTS: We observed a significant depletion of circulating pDCs in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the FcεRI on their pDCs. Based on transcriptomic analysis, pDCs from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a nonrecurrent wheezing phenotype. CONCLUSIONS: Our data suggest that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of high-affinity IgE receptor is increased and their function as major interferon producers is impaired during acute exacerbations of wheeze.
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Asma , Interferón Tipo I , Niño , Humanos , Preescolar , Receptores de IgE , Ruidos Respiratorios , Interferón Tipo I/metabolismo , Células DendríticasRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1149107.].
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Zika virus (ZIKV) became a public health concern when it re-emerged in 2015 owing to its ability to cause congenital deformities in the fetus and neurological complications in adults. Despite extensive data on protection, the interplay of protective and pathogenic adaptive immune responses toward ZIKV infection remains poorly understood. In this study, using a T-cellâdeficient mouse model that retains persistent ZIKV viral titers in the blood and organs, we show that the adoptive transfer of CD8+ T cells led to a significant reduction in viral load. This mouse model reveals that ZIKV can induce grossly visible auricular dermatitis and blepharitis, mediated by ZIKV-specific CD8+ T cells. Single-cell RNA sequencing of these causative CD8+ T cells from the ears shows an overactivated and elevated cytotoxic signature in mice with severe symptoms. Our results strongly suggest a role for CD8+ T-cellâassociated pathologies after ZIKV infection in CD4+ T-cellâimmunodeficient patients.
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Blefaritis , Dermatitis , Infección por el Virus Zika , Virus Zika , Ratones , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Modelos Animales de EnfermedadRESUMEN
Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
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Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Linaje de la Célula , Histiocitosis de Células de Langerhans/metabolismo , Histiocitosis de Células de Langerhans/patología , Diferenciación Celular , Monocitos/metabolismoRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that have become dominant as the pandemic progresses bear the ORF8 mutation together with multiple spike mutations. A 382-nucleotide deletion (Δ382) in the ORF7b and ORF8 regions has been associated with milder disease phenotype and less systemic inflammation in COVID-19 patients. However, its impact on host immunity against SARS-CoV-2 remains undefined. Here, RNA-sequencing was performed to elucidate whole blood transcriptomic profiles and identify contrasting immune signatures between patients infected with either wildtype or Δ382 SARS-CoV-2 variant. Interestingly, the immune landscape of Δ382 SARS-CoV-2 infected patients featured an increased adaptive immune response, evidenced by enrichment of genes related to T cell functionality, a more robust SARS-CoV-2-specific T cell immunity, as well as a more rapid antibody response. At the molecular level, eukaryotic initiation factor 2 signaling was found to be upregulated in patients bearing Δ382, and its associated genes were correlated with systemic levels of T cell-associated and pro-inflammatory cytokines. This study provides more in-depth insight into the host-pathogen interactions of ORF8 with great promise as a therapeutic target to combat SARS-CoV-2 infection.
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Inmunidad Adaptativa/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Citocinas/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/inmunología , Mutación/inmunología , Pandemias/prevención & control , Linfocitos T/inmunologíaRESUMEN
More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia1. P. vivax preferentially invades reticulocytes (immature red blood cells)2-4. Previous work has identified 11 parasite proteins involved in reticulocyte invasion, including erythrocyte binding protein 2 (ref. 5) and the reticulocyte-binding proteins (PvRBPs)6-10. PvRBP2b binds to the transferrin receptor CD71 (ref. 11), which is selectively expressed on immature reticulocytes12. Here, we identified CD98 heavy chain (CD98), a heteromeric amino acid transporter from the SLC3 family (also known as SLCA2), as a reticulocyte-specific receptor for the PvRBP2a parasite ligand using mass spectrometry, flow cytometry, biochemical and parasite invasion assays. We characterized the expression level of CD98 at the surface of immature reticulocytes (CD71+) and identified an interaction between CD98 and PvRBP2a expressed at the merozoite surface. Our results identify CD98 as an additional host membrane protein, besides CD71, that is directly associated with P. vivax reticulocyte tropism. These findings highlight the potential of using PvRBP2a as a vaccine target against P. vivax malaria.
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Eritrocitos/parasitología , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Malaria Vivax/metabolismo , Plasmodium vivax/metabolismo , Antígenos CD , Antígenos de Protozoos/genética , Antígenos de Protozoos/metabolismo , Eritrocitos/metabolismo , Cadena Pesada de la Proteína-1 Reguladora de Fusión/genética , Interacciones Huésped-Parásitos , Humanos , Malaria Vivax/sangre , Malaria Vivax/genética , Plasmodium vivax/genética , Unión Proteica , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Transferrina , Reticulocitos/metabolismo , Reticulocitos/parasitologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies.
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Biomarcadores/sangre , Células Dendríticas/inmunología , Inflamación/sangre , Inflamación/inmunología , Leucocitos Mononucleares/inmunología , Fagocitos/inmunología , Antígenos CD/sangre , Antígenos CD/inmunología , Células Cultivadas , Citometría de Flujo/métodos , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Monocitos/inmunología , Fenotipo , Análisis de la Célula IndividualRESUMEN
Cerebral malaria (CM) is one the major complications occurring during malaria infection. The mechanisms leading to this syndrome are still not completely understood. Although it is clear that parasite sequestration is the key initiation factor, the downstream pathological processes are still highly debated. The experimental cerebral malaria (ECM) model, in which susceptible mice are infected with Plasmodium berghei ANKA, has led to the identification of CD8(+) T cells as the major mediator of ECM death. In this review, we discuss the recent advances and future developments in the understanding of the role of CD8(+) T cells in CM.
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Linfocitos T CD8-positivos/inmunología , Interacciones Huésped-Parásitos/inmunología , Malaria Cerebral/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Movimiento Celular , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Epítopos de Linfocito T/química , Epítopos de Linfocito T/inmunología , Matriz Extracelular/inmunología , Humanos , Inmunomodulación , Malaria Cerebral/parasitología , Fenotipo , Plasmodium/inmunologíaRESUMEN
Malaria is responsible for over 500 million clinical cases and over 500000 deaths annually. Fatalities arise from a range of overlapping syndromes, such as cerebral malaria, whose pathogenesis is still incompletely understood. In a new study, Coban and colleagues provide new clues on the involvement of the olfactory bulb during experimental cerebral malaria in mice that open the way to testable hypotheses and potentially earlier intervention in humans.
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Malaria Cerebral/parasitología , Bulbo Olfatorio/parasitología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Plasmodium berghei/fisiologíaRESUMEN
Hepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and expensive to implement in clinical trials. Moreover, it raises safety concerns related to insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients with persistent infection. To develop a more practical and safer approach to cell therapy of HCC, we used electroporation of mRNA encoding anti-HBV TCR. Approximately 80% of CD8(+) T cells expressed functional HBV TCR 24 hours postelectroporation, an expression efficiency much higher than that obtained by retroviral transduction (~18%). Antigen-specific cytokine production of electroporated T cells was efficient within 72-hour period, after which the redirected T cells lost their HBV-specific function. Despite this transient functionality, the TCR-electroporated T cells efficiently prevented tumor seeding and suppressed the growth of established tumors in a xenograft model of HCC. Finally, we established a method for large-scale TCR mRNA electroporation that yielded large numbers of highly functional clinical-grade anti-HBV T cells. This method represents a practical approach to cell therapy of HCC and its inherently self-limiting toxicity suggests potential for application in other HBV-related pathologies.Molecular Therapy-Nucleic Acids (2013) 2, e114; doi:10.1038/mtna.2013.43; published online 13 August 2013.
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Cerebral malaria is the most severe pathology caused by the malaria parasite, Plasmodium falciparum. The pathogenic mechanisms leading to cerebral malaria are still poorly defined as studies have been hampered by limited accessibility to human tissues. Nevertheless, histopathology of post-mortem human tissues and mouse models of cerebral malaria have indicated involvement of the blood-brain barrier in cerebral malaria. In contrast to viruses and bacteria, malaria parasites do not infiltrate and infect the brain parenchyma. Instead, rupture of the blood-brain barrier occurs and may lead to hemorrhages resulting in neurological alterations. Here, we review the most recent findings from human studies and mouse models on the interactions of malaria parasites and the blood-brain barrier, shedding light on the pathogenesis of cerebral malaria, which may provide directions for possible interventions.
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Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/parasitología , Interacciones Huésped-Patógeno , Malaria Cerebral/patología , Malaria Cerebral/parasitología , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
BACKGROUND: Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA-induced pathologies, which mechanisms are poorly understood. METHODS AND FINDINGS: Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8(+) T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6-12 days post-infection, at a time when mice develop ECM. Other cells types like CD4(+) T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs. CONCLUSIONS: CD8(+) T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues.
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Linfocitos T CD8-positivos/inmunología , Eritrocitos/parasitología , Interferón gamma/metabolismo , Malaria Cerebral/inmunología , Malaria Cerebral/parasitología , Especificidad de Órganos/inmunología , Animales , Biomasa , Encéfalo/inmunología , Encéfalo/parasitología , Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Eritrocitos/inmunología , Femenino , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos C57BL , Células Mieloides/inmunología , Plasmodium berghei/fisiología , Factores de TiempoRESUMEN
Microscopic examination of Giemsa-stained thin blood smears remains the gold standard method used to quantify and stage malaria parasites. However, this technique is tedious, and requires trained microscopists. We have developed a fast and simple flow cytometry method to quantify and stage, various malaria parasites in red blood cells in whole blood or in vitro cultured Plasmodium falciparum. The parasites were stained with dihydroethidium and Hoechst 33342 or SYBR Green I and leukocytes were identified with an antibody against CD45. Depending on the DNA stains used, samples were analyzed using different models of flow cytometers. This protocol, which does not require any washing steps, allows infected red blood cells to be distinguished from leukocytes, as well as allowing non-infected reticulocytes and normocytes to be identified. It also allows assessing the proportion of parasites at different developmental stages. Lastly, we demonstrate how this technique can be applied to antimalarial drug testing.