RESUMEN
Transcription factor RBPJ is the central component in Notch signal transduction and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSSs), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed across different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness.
Asunto(s)
Elementos de Facilitación Genéticos , Receptores Notch , Animales , Humanos , Ratones , Sitios de Unión , Cromatina/metabolismo , Cromatina/genética , Secuenciación de Inmunoprecipitación de Cromatina , Regulación de la Expresión Génica , Genómica/métodos , Aprendizaje Automático , Regiones Promotoras Genéticas , Unión Proteica , Receptores Notch/metabolismo , Receptores Notch/genética , Transducción de Señal/genética , Sitio de Iniciación de la TranscripciónRESUMEN
Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. Due to the limited data available, the World Health Organization (WHO) considers public health risk to the general population to be low. The present study investigated the genetic variation and molecular evolution of E11 genomes collected from May to December 2023. Whole genome sequencing (WGS) was performed for 16 E11 strains. Phylogenetic analysis on WG showed how all Italian strains belonged to genogroup D5, similarly to other E11 strains recently reported in France and Germany all together aggregated into separate clusters. A cluster-specific recombination pattern was also identified using phylogenetic analysis of different genome regions. Echovirus 6 was identified as the major recombinant virus in 3Cpro and 3Dpol regions. The molecular clock analysis revealed that the recombination event probably occurred in June 2018 (95% HPD interval: Jan 2016-Jan 2020). Shannon entropy analyses, within P1 region, showed how 11 amino acids exhibited relatively high entropy. Five of them were exposed on the canyon region which is responsible for receptor binding with the neonatal Fc receptor. The present study showed the recombinant origin of a new lineage of E11 associated with severe neonatal infections.
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Infecciones por Echovirus , Enterovirus Humano B , Genoma Viral , Genotipo , Filogenia , Recombinación Genética , Humanos , Recién Nacido , Genoma Viral/genética , Enterovirus Humano B/genética , Enterovirus Humano B/clasificación , Enterovirus Humano B/aislamiento & purificación , Infecciones por Echovirus/virología , Infecciones por Echovirus/epidemiología , Variación Genética , Secuenciación Completa del Genoma , Evolución Molecular , Italia/epidemiologíaRESUMEN
Signal transduction pathways often involve transcription factors that promote activation of defined target gene sets. The transcription factor RBPJ is the central player in Notch signaling and either forms an activator complex with the Notch intracellular domain (NICD) or a repressor complex with corepressors like KYOT2/FHL1. The balance between these two antagonizing RBPJ-complexes depends on the activation state of the Notch receptor regulated by cell-to-cell interaction, ligand binding and proteolytic cleavage events. Here, we depleted RBPJ in mature T-cells lacking active Notch signaling and performed RNA-Seq, ChIP-Seq and ATAC-seq analyses. RBPJ depletion leads to upregulation of many Notch target genes. Ectopic expression of NICD1 activates several Notch target genes and enhances RBPJ occupancy. Based on gene expression changes and RBPJ occupancy we define four different clusters, either RBPJ- and/or Notch-regulated genes. Importantly, we identify early (Hes1 and Hey1) and late Notch-responsive genes (IL2ra). Similarly, to RBPJ depletion, interfering with transcriptional repression by squelching with cofactor KYOT2/FHL1, leads to upregulation of Notch target genes. Taken together, RBPJ is not only an essential part of the Notch co-activator complex but also functions as a repressor in a Notch-independent manner.
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Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas , Receptores Notch , Linfocitos T , Regulación de la Expresión Génica , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Linfocitos T/metabolismoRESUMEN
The Notch pathway transmits signals between neighboring cells to elicit downstream transcriptional programs. Notch is a major regulator of cell fate specification, proliferation, and apoptosis, such that aberrant signaling leads to a pleiotropy of human diseases, including developmental disorders and cancers. The pathway signals through the transcription factor CSL (RBPJ in mammals), which forms an activation complex with the intracellular domain of the Notch receptor and the coactivator Mastermind. CSL can also function as a transcriptional repressor by forming complexes with one of several different corepressor proteins, such as FHL1 or SHARP in mammals and Hairless in Drosophila. Recently, we identified L3MBTL3 as a bona fide RBPJ-binding corepressor that recruits the repressive lysine demethylase LSD1/KDM1A to Notch target genes. Here, we define the RBPJ-interacting domain of L3MBTL3 and report the 2.06 Å crystal structure of the RBPJ-L3MBTL3-DNA complex. The structure reveals that L3MBTL3 interacts with RBPJ via an unusual binding motif compared to other RBPJ binding partners, which we comprehensively analyze with a series of structure-based mutants. We also show that these disruptive mutations affect RBPJ and L3MBTL3 function in cells, providing further insights into Notch mediated transcriptional regulation.
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Proteínas de Unión al ADN , Regulación de la Expresión Génica , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas , Animales , Humanos , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Histona Demetilasas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/metabolismo , Proteínas Musculares/genética , Unión Proteica , Receptores Notch/genética , Receptores Notch/metabolismoRESUMEN
Torque Teno Virus (TTV) is a ubiquitous component of the human virome, not associated with any disease. As its load increases when the immune system is compromised, such as in kidney transplant (KT) recipients, TTV load monitoring has been proposed as a method to assess immunosuppression. In this prospective study, TTV load was measured in plasma and urine samples from 42 KT recipients, immediately before KT and in the first 150 days after it. Data obtained suggest that TTV could be a relevant marker for evaluating immune status and could be used as a guide to predict the onset of infectious complications in the follow-up of KT recipients. Since we observed no differences considering distance from transplantation, while we found a changing trend in days before viral infections, we suggest to consider changes over time in the same subjects, irrespective of time distance from transplantation.
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Biomarcadores , Trasplante de Riñón , Torque teno virus , Carga Viral , Trasplante de Riñón/efectos adversos , Humanos , Biomarcadores/orina , Biomarcadores/sangre , Masculino , Persona de Mediana Edad , Femenino , Adulto , Infecciones por Virus ADN/orina , Infecciones por Virus ADN/sangre , Infecciones por Virus ADN/virología , Estudios Prospectivos , Receptores de Trasplantes , AncianoRESUMEN
Oxylipins are important signalling compounds that are significantly involved in the regulation of the immune system and the resolution of inflammation. Lipid metabolism is strongly activated upon SARS-CoV-2 infection, however the modulating effects of oxylipins induced by different variants remain unexplored. Here, we compare the plasma profiles of thirty-seven oxylipins and four PUFAs in subjects infected with Wild-type, Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. The results suggest that oxidative stress and inflammation resulting from COVID-19 were highly dependent on the SARS-CoV-2 variant, and that the Wild-type elicited the strongest inflammatory storm. The Alpha and Delta variants induced a comparable lipid profile alteration upon infection, which differed significantly from Omicron. The latter variant increased the levels of pro-inflammatory mediators and decreased the levels of omega-3 PUFA in infected patients. We speculate that changes in therapeutics, vaccination, and prior infections may have a role in the alteration of the oxylipin profile besides viral mutations. The results shed new light on the evolution of the inflammatory response in COVID-19.
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COVID-19 , SARS-CoV-2 , Humanos , Oxilipinas , Ácidos Grasos Insaturados , InflamaciónRESUMEN
With numbers of COVID-19 cases having substantially increased at the end of 2022 in China, some countries have started or expanded testing and genomic surveillance of travellers. We report screening results in Italy in late December 2022 of 556 flight passengers in provenance from two Chinese provinces. Among these passengers, 126 (22.7%) tested SARS-CoV-2 positive. Whole genome sequencing of 61 passengers' positive samples revealed Omicron variants, notably sub-lineages BA.5.2.48, BF.7.14 and BQ.1.1, in line with data released from China.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiología , Genómica , China/epidemiología , Italia/epidemiologíaRESUMEN
Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.
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Histona Desacetilasas/metabolismo , Leucemia/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Animales , Línea Celular , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Leucemia/enzimología , Lisina/metabolismo , Ratones , Mutación , Péptidos Cíclicos/farmacología , Estabilidad Proteica , Receptor Notch1/química , Receptor Notch1/genéticaRESUMEN
The Delta variant of concern of severe acute respiratory syndrome coronavirus 2 is dominant worldwide. We report a case cluster caused by Delta sublineage B.1.617.2 harboring the mutation E484K in Italy during July 11-July 29, 2021. This mutation appears to affect immune response and vaccine efficacy; monitoring its appearance is urgent.
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COVID-19 , SARS-CoV-2 , Humanos , Italia/epidemiología , MutaciónRESUMEN
Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. Upon ligand binding, the Notch intracellular domain (NOTCH ICD) translocates into the nucleus and forms a complex with the transcription factor RBPJ (also known as CBF1 or CSL) to activate expression of Notch target genes. In the absence of a Notch signal, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 (also known as MBT1) as a novel RBPJ interactor. L3MBTL3 competes with NOTCH ICD for binding to RBPJ In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and the histone demethylase KDM1A (also known as LSD1) to the enhancers of Notch target genes, leading to H3K4me2 demethylation and to transcriptional repression. Importantly, in vivo analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ and L3MBTL3 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Histona Demetilasas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Neuroglía/metabolismo , Receptores Notch/genética , Animales , Evolución Biológica , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Línea Celular Tumoral , Secuencia Conservada , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Histona Demetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Neuroglía/citología , Unión Proteica , Dominios Proteicos , Receptores Notch/metabolismo , Transcripción Genética , Técnicas del Sistema de Dos HíbridosRESUMEN
A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation.
Asunto(s)
Regulación de la Expresión Génica , Histonas/genética , Receptores Notch/genética , Transducción de Señal/genética , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Células HEK293 , Células HeLa , Histonas/metabolismo , Humanos , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Lisina Acetiltransferasa 5/genética , Lisina Acetiltransferasa 5/metabolismo , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismoRESUMEN
The transcriptional shift from repression to activation of target genes is crucial for the fidelity of Notch responses through incompletely understood mechanisms that likely involve chromatin-based control. To activate silenced genes, repressive chromatin marks are removed and active marks must be acquired. Histone H3 lysine-4 (H3K4) demethylases are key chromatin modifiers that establish the repressive chromatin state at Notch target genes. However, the counteracting histone methyltransferase required for the active chromatin state remained elusive. Here, we show that the RBP-J interacting factor SHARP is not only able to interact with the NCoR corepressor complex, but also with the H3K4 methyltransferase KMT2D coactivator complex. KMT2D and NCoR compete for the C-terminal SPOC-domain of SHARP. We reveal that the SPOC-domain exclusively binds to phosphorylated NCoR. The balance between NCoR and KMT2D binding is shifted upon mutating the phosphorylation sites of NCoR or upon inhibition of the NCoR kinase CK2ß. Furthermore, we show that the homologs of SHARP and KMT2D in Drosophila also physically interact and control Notch-mediated functions in vivo Together, our findings reveal how signaling can fine-tune a committed chromatin state by phosphorylation of a pivotal chromatin-modifier.
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Cromatina/metabolismo , Proteínas Co-Represoras/metabolismo , Regulación de la Expresión Génica , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismo , Transcripción Genética , Animales , Quinasa de la Caseína II/metabolismo , Línea Celular , Línea Celular Tumoral , Proteínas de Unión al ADN , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Código de Histonas , N-Metiltransferasa de Histona-Lisina , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Proteínas Nucleares/química , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Proteínas de Unión al ARN , Xenopus laevisAsunto(s)
COVID-19/patología , SARS-CoV-2 , Tiroiditis Autoinmune/patología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Genoma Viral/genética , Humanos , Italia , Persona de Mediana Edad , Perú , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología , Organización Mundial de la SaludRESUMEN
Quantification of Torquetenovirus (TTV) viremia is becoming important for evaluating the status of the immune system in solid organ transplant recipients, monitoring the appearance of post-transplant complications, and controlling the efficacy of maintenance immunosuppressive therapy. Thus, diagnostic approaches able to scale up TTV quantification are needed. Here, we report on the development and validation of a real-time PCR assay for TTV quantification on the Hologic Panther Fusion® System by utilizing its open-access channel. The manual real-time PCR previously developed in our laboratories was optimized to detect TTV DNA on the Hologic Panther Fusion® System. The assay was validated using clinical samples. The automated TTV assay has a limit of detection of 1.6 log copies per ml of serum. Using 112 samples previously tested via manual real-time PCR, the concordance in TTV detection was 93% between the assays. When the TTV levels were compared, the overall agreement between the methods, as assessed using Passing-Bablok linear regression and Bland-Altman analyses, was excellent. In summary, we validated a highly sensitive and accurate method for the diagnostic use of TTV quantification on a fully automated Hologic Panther Fusion® System. This will greatly improve the turnaround time for TTV testing and better support the laboratory diagnosis of this new viral biomarker.
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Infecciones por Virus ADN , Reacción en Cadena en Tiempo Real de la Polimerasa , Carga Viral , Viremia , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Viremia/diagnóstico , Viremia/virología , Humanos , Carga Viral/métodos , Infecciones por Virus ADN/diagnóstico , Infecciones por Virus ADN/virología , Sensibilidad y Especificidad , Torque teno virus/genética , Torque teno virus/aislamiento & purificación , ADN Viral/genética , ADN Viral/sangre , Límite de Detección , Reproducibilidad de los Resultados , Automatización de Laboratorios/métodosRESUMEN
Carbapenem resistance is a serious public health threat, causing numerous deaths annually primarily due to healthcare-associated infections. To face this menace, surveillance programs in high-risk patients are becoming a widespread practice. Here we report the performance of the combined use of a recently approved commercial multiplex real-time PCR assay (REALQUALITY Carba-Screen kit) with conventional phenotypic screening. In this three-month study, 479 rectal swabs from 309 patients across high-risk units were evaluated by combining the two approaches. Although the molecular assay showed a higher positivity rate than phenotypic screening (7.1% vs. 5%), it should be noted that the molecular method alone would have missed eight carbapenem-resistant isolates, while using only phenotypic screening would not have detected sixteen isolates. This demonstrates the complementary strengths of each method. Our study confirms the need for a combined approach to maximize the possible clinical impact of this kind of screening, ensuring a more comprehensive detection of resistant strains.
RESUMEN
Background: The eco-climatic crisis has been defined by the World Health Organization as the "single biggest health threat facing humanity," influencing both the emergence of zoonoses and the spread of vector-borne and water-borne diseases. The aim of this survey was to explore knowledge, eco-anxiety and attitudes toward the ecological and climate crisis among young Italian doctors and medical students. Methods: A cross-sectional, multicenter survey was conducted from November 2022 to June 2023, by administering an anonymous questionnaire to Italian doctors and students of medicine. Endpoint of the study was a Knowledge, Attitudes and Practices (KAP) score on ecological and climate crisis (0-20 points). Association between variables and KAP score was assessed by Kruskal-Wallis' or Spearman's test, as appropriate, and significant variables were included into ordinal regression model and reported as adjusted odds ratio (aOR) with their 95% confidence intervals (CI). Results: Both KAP and eco-anxiety scores showed acceptable levels of consistency with Cronbach's alpha. A total of 605 medical doctors and students living in 19 Italian regions were included in the study. Median age [Q1-Q3] was 27.6 [24.1-31.3] and females were 352 (58.2%). Despite showing good attitudes toward climate action, knowledge gap were found, with 42.5% (n = 257) of the respondents not knowing the temperature limits set by the Paris Agreements and 45.5% (n = 275) believing that climate change is caused by sunspots. Fears suggestive for eco-anxiety were common. At multivariable ordinal regression, high levels of eco-anxiety (aOR 1.29, p = 0.001) and low trust in government action (aOR 1.96, p = 0.003) were associated with a higher KAP score. Only one Italian medical school offered an educational module on climate change. Conclusion: Young Italian doctors and medical students are concerned about the climate crisis but show poor knowledge of these topics. The Italian academic system should urgently respond to this need.
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Cambio Climático , Conocimientos, Actitudes y Práctica en Salud , Médicos , Estudiantes de Medicina , Humanos , Italia , Femenino , Masculino , Estudios Transversales , Estudiantes de Medicina/estadística & datos numéricos , Estudiantes de Medicina/psicología , Encuestas y Cuestionarios , Adulto , Médicos/estadística & datos numéricos , Médicos/psicología , Enfermedades Transmisibles/epidemiología , Adulto JovenRESUMEN
The broad family of viruses known as anelloviruses (AV) infects both humans and numerous animal species. They have a tiny, covalently closed single-stranded DNA genome and the astonishing capacity to infect a very high percentage of healthy and ill people with chronic infections that could last a lifetime. AV, and particularly the prototype Torquetenovirus, have established a successful interaction with the host's immune system and the rate at which they replicate is a gauge to measure overall immune function, even though many aspects of their life cycle and pathogenesis are still poorly understood.
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This multicenter observational study included 171 COVID-19 adult patients hospitalized in the ICUs of nine hospitals in Lombardy (Northern Italy) from December, 1st 2021, to February, 9th 2022. During the study period, the Delta/Omicron variant ratio of cases decreased with a delay of two weeks in ICU patients compared to that in the community; a higher proportion of COVID-19 unvaccinated patients was infected by Delta than by Omicron whereas a higher rate of COVID-19 boosted patients was Omicron-infected. A higher number of comorbidities and a higher comorbidity score in ICU critically COVID-19 inpatients was positively associated with the Omicron infection as well in vaccinated individuals. Although people infected by Omicron have a lower risk of severe disease than those infected by Delta variant, the outcome, including the risk of ICU admission and the need for mechanical ventilation due to infection by Omicron versus Delta, remains uncertain. The continuous monitoring of the circulating SARS-CoV-2 variants remains a milestone to counteract this pandemic.
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COVID-19 , SARS-CoV-2 , Adulto , Humanos , COVID-19/epidemiología , Pacientes Internos , Unidades de Cuidados Intensivos , Italia/epidemiologíaRESUMEN
The Delta variant of concern (VOC) of SARS-CoV-2 has become dominant worldwide. In this article, we report a cluster caused by B.1.617.2 harboring the additional mutation of concern (MOC) F490S. We observed that 5 fully vaccinated subjects aged between 47 and 84 years were infected with this variant. The immune escape mutation F490S, first identified in the Lambda VOI, appears to impair vaccine efficacy and is rapidly increasing in prevalence worldwide.
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COVID-19 , SARS-CoV-2 , Anciano , Anciano de 80 o más Años , COVID-19/epidemiología , Vacunas contra la COVID-19 , Humanos , Persona de Mediana Edad , Mutación , SARS-CoV-2/genéticaRESUMEN
Given the ongoing COVID19 pandemic, the decline in serological response since dose 2, and the upcoming flu season, COVID19 vaccines will increasingly be administered in combination with vaccines against seasonal pathogens. It is of interest to confirm that concurrent vaccination against influenzavirus has no negative impact on serological response to SARS CoV-2. Anti-Spike IgG and Anti-Receptor Binding Domain (RBD) Neutralizing Antibodies (NAb) in serum was assessed in 64 immunocompetent healthcare workers (HCW) before and 14 days post the third dose of BNT162b2 vaccine (Comirnaty®, Pfizer/BioNTech) or BNT162b2 plus quadrivalent flu vaccine (Vaxigript Tetra ®Sanofi Pasteur) on the same day. We report here safety and efficacy of combined BNT162b2 and flu vaccine in 64 healthcare workers at a single institution. No differences were found in adverse events or anti-Spike antibody levels.