RESUMO
RNA processing is a highly conserved mechanism that serves as a pivotal regulator of gene expression. Alternative processing generates transcripts that can still be translated but lead to potentially nonfunctional proteins. A plethora of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strategically manipulate the host's RNA processing machinery to circumvent antiviral responses. We integrated publicly available omics datasets to systematically analyze isoform-level expression and delineate the nascent peptide landscape of SARS-CoV-2-infected human cells. Our findings explore a suggested but uncharacterized mechanism, whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling, interferon-stimulated (ISGs), class I MHC, and splicing machinery genes, including IRF7, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6 and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs an unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
Assuntos
Processamento Alternativo , COVID-19 , Interferons , Isoformas de Proteínas , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/virologia , COVID-19/genética , COVID-19/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferons/metabolismo , Interferons/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismoRESUMO
Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents Plasmodium falciparum (Pf) malaria but is ineffective against Plasmodium vivax (Pv) disease. Herein, we evaluated the murine immunogenicity of a recombinant PvCSP incorporating prevalent polymorphisms, adjuvanted with Alhydrogel or Poly I:C. Both formulations induced prolonged IgG responses, with IgG1 dominance by the Alhydrogel group and high titers of all IgG isotypes by the Poly I:C counterpart. Poly I:C-adjuvanted vaccination increased splenic plasma cells, terminally-differentiated memory cells (MBCs), and precursors relative to the Alhydrogel-combined immunization. Splenic B-cells from Poly I:C-vaccinated mice revealed an antibody-secreting cell- and MBC-differentiating gene expression profile. Biological processes such as antibody folding and secretion were highlighted by the Poly I:C-adjuvanted vaccination. These findings underscore the potential of Poly I:C to strengthen immune responses against Pv malaria.
Assuntos
Adjuvantes de Vacinas , Hidróxido de Alumínio , Imunogenicidade da Vacina , Vacinas Antimaláricas , Malária Vivax , Plasmodium vivax , Poli I-C , Proteínas de Protozoários , Poli I-C/administração & dosagem , Plasmodium vivax/imunologia , Imunidade Humoral , Imunidade Celular , Proteínas de Protozoários/imunologia , Vacinas Antimaláricas/química , Vacinas Antimaláricas/imunologia , Hidróxido de Alumínio/administração & dosagem , Imunoglobulina G/sangue , Masculino , Animais , Plasmócitos/imunologia , Feminino , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/imunologia , Vacinação , Adjuvantes de Vacinas/administração & dosagem , Malária Vivax/prevenção & controleRESUMO
OBJECTIVE: This study aimed to present a temporal and spatial analysis of the 2018 measles outbreak in Brazil, particularly in the metropolitan city of Manaus in the Amazon region, and further introduce a new tool for spatial analysis. METHODS: We analyzed the geographical data of the residences of over 7,000 individuals with measles in Manaus during 2018 and 2019. Spatial and temporal analyses were conducted to characterize various aspects of the outbreak, including the onset and prevalence of symptoms, demographics, and vaccination status. A visualization tool was also constructed to display the geographical and temporal distribution of the reported measles cases. RESULTS: Approximately 95% of the included participants had not received vaccination within the past decade. Heterogeneity was observed across all facets of the outbreak, including variations in the incubation period and symptom presentation. Age distribution exhibited two peaks, occurring at one year and 18 years of age, and the potential implications of this distribution on predictive analysis were discussed. Additionally, spatial analysis revealed that areas with the highest case densities tended to have the lowest standard of living. CONCLUSION: Understanding the spatial and temporal spread of measles outbreaks provides insights for decision-making regarding measures to mitigate future epidemics.
Assuntos
Sarampo , Humanos , Lactente , Brasil/epidemiologia , Sarampo/epidemiologia , Surtos de Doenças , Vacinação , Análise EspacialRESUMO
BACKGROUD: Diabetic neuropathy (DN) is one of the most common complications of diabetes, affecting about half of individuals with the disease. Among the various symptoms of DN, the development of chronic pain stands out and manifests as exacerbated responses to sensorial stimuli. The conventional clinical treatments used for general neuropathy and associated painful symptoms, still brings uncomplete and unsatisfactory pain relief. Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities which difficult the correct diagnosis of sensory comorbidities and consequently, the appropriate chronic pain management. AIMS: Herein, we aimed to demonstrate the existence of different sensory profiles on diabetic patients by investigating epidemiological and clinical data on the symptomatology of a group of patients with DN. METHODS: This is a longitudinal and observational study, with a sample of 57 volunteers diagnosed with diabetes from outpatient day clinic of Hospital Universitário of the University of São Paulo-Brazil. After being invited and signed the Informed Consent Form (ICF), patients were submitted to clinical evaluation and filled out pain and quality of life questionnaires. They also performed quantitative sensory test (QST) and underwent skin biopsy for correlation with cutaneous neuropathology. RESULTS: Data demonstrate that 70% of the studied sample presented some type of pain, manifesting in a neuropathic or nociceptive way, what has a negative impact on the life of patients with DM. We also demonstrated a positive association between pain and anxiety and depression, in addition to pain catastrophic thoughts. Three distinct profiles were identified in the sample, separated according to the symptoms of pain: (i) subjects without pain; (ii) with mild or moderate pain; (iii) subjects with severe pain. We also identified through skin biopsy that diabetic patients presented advanced sensory impairment, as a consequence of the degeneration of the myelinated and unmyelinated peripheral fibers. This study characterized the painful symptoms and exteroceptive sensation profile in these diabetic patients, associated to a considerable level of sensory degeneration, indicating, and reinforcing the importance of the long-term clinical monitoring of individuals diagnosed with DM, regarding their symptom profiles and exteroceptive sensitivity.
Assuntos
Neuropatias Diabéticas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/diagnóstico , Estudos Longitudinais , Idoso , Medição da Dor/métodos , Adulto , Qualidade de Vida , Fenótipo , Neuralgia/fisiopatologia , Neuralgia/diagnóstico , Neuralgia/etiologiaRESUMO
ABSTRACT Objective: This study aimed to present a temporal and spatial analysis of the 2018 measles outbreak in Brazil, particularly in the metropolitan city of Manaus in the Amazon region, and further introduce a new tool for spatial analysis. Methods: We analyzed the geographical data of the residences of over 7,000 individuals with measles in Manaus during 2018 and 2019. Spatial and temporal analyses were conducted to characterize various aspects of the outbreak, including the onset and prevalence of symptoms, demographics, and vaccination status. A visualization tool was also constructed to display the geographical and temporal distribution of the reported measles cases. Results: Approximately 95% of the included participants had not received vaccination within the past decade. Heterogeneity was observed across all facets of the outbreak, including variations in the incubation period and symptom presentation. Age distribution exhibited two peaks, occurring at one year and 18 years of age, and the potential implications of this distribution on predictive analysis were discussed. Additionally, spatial analysis revealed that areas with the highest case densities tended to have the lowest standard of living. Conclusion: Understanding the spatial and temporal spread of measles outbreaks provides insights for decision-making regarding measures to mitigate future epidemics.
RESUMO
Despite the considerable advances in the last years, the health information systems for health surveillance still need to overcome some critical issues so that epidemic detection can be performed in real time. For instance, despite the efforts of the Brazilian Ministry of Health (MoH) to make COVID-19 data available during the pandemic, delays due to data entry and data availability posed an additional threat to disease monitoring. Here, we propose a complementary approach by using electronic medical records (EMRs) data collected in real time to generate a system to enable insights from the local health surveillance system personnel. As a proof of concept, we assessed data from São Caetano do Sul City (SCS), São Paulo, Brazil. We used the "fever" term as a sentinel event. Regular expression techniques were applied to detect febrile diseases. Other specific terms such as "malaria," "dengue," "Zika," or any infectious disease were included in the dictionary and mapped to "fever." Additionally, after "tokenizing," we assessed the frequencies of most mentioned terms when fever was also mentioned in the patient complaint. The findings allowed us to detect the overlapping outbreaks of both COVID-19 Omicron BA.1 subvariant and Influenza A virus, which were confirmed by our team by analyzing data from private laboratories and another COVID-19 public monitoring system. Timely information generated from EMRs will be a very important tool to the decision-making process as well as research in epidemiology. Quality and security on the data produced is of paramount importance to allow the use by health surveillance systems.
RESUMO
Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.
RESUMO
CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.