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1.
Nat Immunol ; 21(3): 321-330, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32066949

RESUMEN

Differentiation of CD4+ T cells into either follicular helper T (TFH) or type 1 helper T (TH1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4+ T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove TFH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into TH1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4+ T cell differentiation and might instruct vaccine design strategies.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interferón Tipo I/metabolismo , Inmunidad Adaptativa , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/clasificación , Diferenciación Celular/inmunología , Femenino , Interleucina-6/biosíntesis , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/patogenicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis Espacio-Temporal , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología , Virus de la Estomatitis Vesicular Indiana/patogenicidad , Virus de la Estomatitis Vesicular New Jersey/inmunología , Virus de la Estomatitis Vesicular New Jersey/patogenicidad
2.
Eur J Immunol ; 53(12): e2350529, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37741290

RESUMEN

TDC are hematopoietic cells that combine dendritic cell (DC) and conventional T-cell markers and functional properties. They were identified in secondary lymphoid organs (SLOs) of naïve mice as cells expressing CD11c, major histocompatibility molecules (MHC)-II, and the T-cell receptor (TCR). Despite thorough characterization, a physiological role for TDC remains to be determined. Unfortunately, using CD11c as a marker for TDC has the caveat of its upregulation on different cells, including T cells, upon activation. Here, we took advantage of Zbtb46-GFP reporter mice to explore the frequency and localization of TDC in different tissues at steady state and upon viral infection. RNA sequencing analysis confirmed that TDC sorted from Zbtb46-GFP mice have a gene signature that is distinct from conventional T cells and DC. In addition, this reporter model allowed for identification of TDC in situ not only in SLOs but also in the liver and lung of naïve mice. Interestingly, we found that TDC numbers in the SLOs increased upon viral infection, suggesting that TDC might play a role during viral infections. In conclusion, we propose a visualization strategy that might shed light on the physiological role of TDC in several pathological contexts, including infection and cancer.


Asunto(s)
Linfocitos T , Virosis , Ratones , Animales , Células Dendríticas/patología , Antígeno CD11c , Ratones Endogámicos C57BL
3.
Mol Ther ; 30(1): 311-326, 2022 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-34547465

RESUMEN

The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax-a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)-induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.


Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Inmunización/métodos , Modelos Animales , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de ADN/administración & dosificación , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/genética , COVID-19/virología , Femenino , Hurones , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Dominios Proteicos , Ratas Sprague-Dawley
4.
Genome Res ; 29(6): 883-895, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31097473

RESUMEN

Despite increasing insights in genome structure organization, the role of DNA repetitive elements, accounting for more than two thirds of the human genome, remains elusive. Facioscapulohumeral muscular dystrophy (FSHD) is associated with deletion of D4Z4 repeat array below 11 units at 4q35.2. It is known that the deletion alters chromatin structure in cis, leading to gene up-regulation. Here we show a genome-wide role of 4q-D4Z4 array in modulating gene expression via 3D nuclear contacts. We have developed an integrated strategy of 4q-D4Z4-specific 4C-seq and chromatin segmentation analyses, showing that 4q-D4Z4 3D interactome and chromatin states of interacting genes are impaired in FSHD1 condition; in particular, genes that have lost the 4q-D4Z4 interaction and with a more active chromatin state are enriched for muscle atrophy transcriptional signature. Expression level of these genes is restored by the interaction with an ectopic 4q-D4Z4 array, suggesting that the repeat directly modulates the transcription of contacted targets. Of note, the up-regulation of atrophic genes is a common feature of several FSHD1 and FSHD2 patients, indicating that we have identified a core set of deregulated genes involved in FSHD pathophysiology.


Asunto(s)
Cromatina/genética , Cromosomas Humanos Par 4 , Distrofia Muscular Facioescapulohumeral/genética , Secuencias Repetidas en Tándem , Transcripción Genética , Biomarcadores , Células Cultivadas , Ensamble y Desensamble de Cromatina/genética , Expresión Génica Ectópica , Epistasis Genética , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Proteínas Musculares/genética , Distrofia Muscular Facioescapulohumeral/diagnóstico , Proteínas Ligasas SKP Cullina F-box/genética
5.
Nat Commun ; 15(1): 7366, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39191730

RESUMEN

The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.


Asunto(s)
Linfocitos T CD8-positivos , Histona Demetilasas , Inmunoterapia Adoptiva , Ratones Endogámicos C57BL , Animales , Histona Demetilasas/metabolismo , Histona Demetilasas/antagonistas & inhibidores , Inmunoterapia Adoptiva/métodos , Ratones , Femenino , Linfocitos T CD8-positivos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Línea Celular Tumoral , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Humanos , Melanoma/inmunología , Melanoma/terapia
6.
J Exp Med ; 220(11)2023 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-37703004

RESUMEN

T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Mechanistically, adoptive transfer experiments using WT and Rinl-KO naïve CD4+ T cells unraveled T cell-intrinsic GEF-dependent functions of Rinl. Further, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore, connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first time the importance of endocytic processes for Tfh differentiation.


Asunto(s)
Antígenos CD28 , Factores de Intercambio de Guanina Nucleótido , Humanos , Animales , Ratones , Transducción de Señal , Diferenciación Celular , Traslado Adoptivo
7.
Vaccines (Basel) ; 11(10)2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37896949

RESUMEN

The vaccination campaign against SARS-CoV-2 relies on the world-wide availability of effective vaccines, with a potential need of 20 billion vaccine doses to fully vaccinate the world population. To reach this goal, the manufacturing and logistic processes should be affordable to all countries, irrespective of economical and climatic conditions. Outer membrane vesicles (OMVs) are bacterial-derived vesicles that can be engineered to incorporate heterologous antigens. Given the inherent adjuvanticity, such modified OMVs can be used as vaccines to induce potent immune responses against the associated proteins. Here, we show that OMVs engineered to incorporate peptides derived from the receptor binding motif (RBM) of the spike protein from SARS-CoV-2 elicit an effective immune response in vaccinated mice, resulting in the production of neutralizing antibodies (nAbs) with a titre higher than 1:300. The immunity induced by the vaccine is sufficient to protect the animals from intranasal challenge with SARS-CoV-2, preventing both virus replication in the lungs and the pathology associated with virus infection. Furthermore, we show that OMVs can be effectively decorated with the RBM of the Omicron BA.1 variant and that such engineered OMVs induce nAbs against Omicron BA.1 and BA.5, as measured using the pseudovirus neutralization infectivity assay. Importantly, we show that the RBM438-509 ancestral-OMVs elicited antibodies which efficiently neutralize in vitro both the homologous ancestral strain, the Omicron BA.1 and BA.5 variants with a neutralization titre ranging from 1:100 to 1:1500, suggesting its potential use as a vaccine targeting diverse SARS-CoV-2 variants. Altogether, given the convenience associated with the ease of engineering, production and distribution, our results demonstrate that OMV-based SARS-CoV-2 vaccines can be a crucial addition to the vaccines currently available.

8.
Res Sq ; 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37292970

RESUMEN

The vaccination campaign against SARS-CoV-2 relies on the world-wide availability of effective vaccines, with a potential need of 20 billion vaccine doses to fully vaccinate the world population. To reach this goal, the manufacturing and logistic processes should be affordable to all countries, irrespectively of economical and climatic conditions. Outer membrane vesicles (OMV) are bacterial-derived vesicles that can be engineered to incorporate heterologous antigens. Given the inherent adjuvanticity, such modified OMV can be used as vaccine to induce potent immune responses against the associated protein. Here we show that OMVs engineered to incorporate peptides derived from the receptor binding motif (RBM) of the spike protein from SARS-CoV-2 elicit an effective immune response in vaccinated mice, resulting in the production of neutralizing antibodies (nAbs). The immunity induced by the vaccine is sufficient to protect the animals from intranasal challenge with SARS-CoV-2, preventing both virus replication in the lungs and the pathology associated with virus infection. Furthermore, we show that OMVs can be effectively decorated with the RBM of the Omicron BA.1 variant and that such engineered OMVs induced nAbs against Omicron BA.1 and BA.5, as judged by pseudovirus infectivity assay. Importantly, we show that the RBM438-509 ancestral-OMVs elicited antibodies which efficiently neutralized in vitro both the homologous ancestral strain, the Omicron BA.1 and BA.5 variants, suggesting its potential use as a pan SARS-CoV-2 vaccine. Altogether, given the convenience associated with ease of engineering, production and distribution, our results demonstrate that OMV-based SARS-CoV-2 vaccines can be a crucial addition to the vaccines currently available.

9.
Ital J Pediatr ; 48(1): 205, 2022 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-36581899

RESUMEN

BACKGROUND: Congenital syphilis (CS) depends on the placental transmission of Treponema pallidum (TP) spirochetes from an infected mother to fetus during pregnancy. It shows a wide clinical variability with cutaneous and visceral manifestations, including stillbirths, neonatal death, and asymptomatic cases. Preterm infants with CS may have more severe features of disease than the term ones, due to the combined pathogenic effect of both CS and prematurity. CASE PRESENTATION: We report on a female preterm (32+6 weeks of gestation) newborn showing most of the typical CS manifestations, in addition to gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth restriction. The mother resulted positive at the syphilis screening test of the first trimester of pregnancy, but she did not undergo any treatment. At birth, our newborn was VDRL positive (antibody titer four times higher compared to the mother), and she was treated with intravenous benzathine benzylpenicillin G for 10 days (50,000 IU/Kg three times per day). Poor tolerance to enteral nutrition (abdominal distension, increased biliary type gastric secretions) was observed. A barium enema X-Ray identified a colon stenosis within the descending tract. However, the poor general conditions due to a concurrent fungal sepsis did not allow to perform any surgical procedure, and a conservative approach with total parenteral nutrition was started. The following evolution was marked by difficulties in enteral feeding including refusal of food and vomiting, to which also contributed the neurological abnormalities related to a perinatal asphyxia, and the affective deprivation for the physical absence of the mother during hospitalization. At 5 months of age, after the introduction of an amino acid-based formula (Neocate LCP Nutricia ®), an improvement of enteral feeding was observed, with no further and significantly decreased episodes of abdominal distension and vomiting respectively, and regular stool emission. A psychological support offered to the family allowed a more stable bond between the mother and her baby, thus providing a significant additional benefit to food tolerance and growth. She was discharged at 5 months of age, and included in a multidisciplinary follow-up. She at present shows global growth delay, and normal development apart from mildly increased tone of lower limbs. CONCLUSIONS: Our report highlights less common clinical CS manifestations like gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth delay. Moreover, it underlines how prematurity may worsen the clinical evolution of such congenital infection, due to the additional pathogenic effect of possible associated diseases and/or conditions like sepsis, hypoxic/ischemic injury, or use of drugs. CS may be observed also in high-income countries, with high rates of antenatal screening and availability of prenatal treatment. A multidisciplinary network must be guaranteed to the affected subjects, to ensure adequate care and improve the quality of life for patients and their families.


Asunto(s)
Enfermedades Gastrointestinales , Enfermedades del Recién Nacido , Sepsis , Sífilis Congénita , Lactante , Recién Nacido , Humanos , Femenino , Embarazo , Sífilis Congénita/complicaciones , Sífilis Congénita/diagnóstico , Sífilis Congénita/terapia , Recien Nacido Prematuro , Calidad de Vida , Constricción Patológica , Placenta , Vómitos
10.
Sci Immunol ; 7(67): eabl9929, 2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-34812647

RESUMEN

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model's usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2­infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.


Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/fisiopatología , Modelos Animales de Enfermedad , Encefalitis Viral/prevención & control , Queratina-18/genética , Rociadores Nasales , SARS-CoV-2/fisiología , Administración por Inhalación , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/inmunología , COVID-19/virología , Encefalitis Viral/mortalidad , Células Epiteliales/metabolismo , Femenino , Humanos , Queratina-18/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Transcriptoma , Replicación Viral
11.
Viral Immunol ; 33(4): 327-333, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32027238

RESUMEN

Inflammatory monocytes play important functions in antiviral immune responses, including release of inflammatory cytokines and antigen presentation to T lymphocytes. Depending on the pathological context, these functions might translate into beneficial or detrimental effects in the resolution of the disease. Recent literature has highlighted a role for inflammatory monocytes also in direct suppression of B cell responses. In this review, we will briefly discuss research showing the relationship between inflammatory monocytes and B lymphocytes, its functional consequences on antiviral antibody responses, and possible implications in the design of future vaccination strategies.


Asunto(s)
Anticuerpos Antivirales/inmunología , Tolerancia Inmunológica , Inflamación/inmunología , Monocitos/inmunología , Virosis/inmunología , Animales , Formación de Anticuerpos , Linfocitos B/inmunología , Ratones , Óxido Nítrico , Linfocitos T/inmunología
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