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The infant and child stage is an important stage for the continuation and development of human society. The initial years of life have a lasting impact on a child's future. Children under the age of 5 have an immature immune system, especially infants and young children under 6 months of age. At this stage, the population has a low immunity to pathogen infections, making them vulnerable to bacteria and viruses. Vaccination can enhance the immunity of infants and children to specific diseases, reduce the transmission rate of infectious diseases, and promote the development of global public health. This article summarizes the current application status of Rotavirus (RV) vaccine, Hand-foot -mouth disease (HFMD) vaccine, and Pneumococcal Conjugate Vaccine (PCV) in China, as well as the research progress of clinical trial vaccine, laying a foundation for subsequent vaccine development.
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Hantaan virus (HTNV) is a major public health concern due to its ability to cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Symptoms of HFRS include fever, hemorrhage, immune dysfunction and renal impairment, and severe cases can be fatal. T cell-mediated adaptive immune responses play a pivotal role in countering HTNV infection. However, our understanding of HTNV and T cell interactions in the disease progression is limited. In this study, we found that human CD4+ T cells can be directly infected with HTNV, thereby facilitating viral replication and production. Additionally, T-cell immunoglobulin and mucin 1 (TIM-1) participated in the process of HTNV infection of Jurkat T cells, and further observed that HTNV enters Jurkat T cells via the clathrin-dependent endocytosis pathway. These findings not only affirm the susceptibility of human CD4+ T lymphocytes to HTNV but also shed light on the viral tropism. Our research elucidates a mode of the interaction between the virus infection process and the immune system. Critically, this study provides new insights into the pathogenesis of HTNV and the implications for antiviral research.
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Linfocitos T CD4-Positivos , Virus Hantaan , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Virus Hantaan/inmunología , Virus Hantaan/fisiología , Células Jurkat , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Replicación Viral , Endocitosis , Fiebre Hemorrágica con Síndrome Renal/virología , Fiebre Hemorrágica con Síndrome Renal/inmunología , Interacciones Huésped-Patógeno/inmunología , Tropismo ViralRESUMEN
Angiotensin II (Ang II) is associated with macrophage polarization and apoptosis, but the role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. However, the effect of AT2Rs on alveolar macrophages and mechanical ventilation-induced lung injury has not been determined. Mechanical ventilation-induced lung injury in SpragueâDawley (SD) rats and LPS-stimulated rat alveolar macrophages (NR8383) were used to determine the effects of AT2Rs, selective AT2R agonists and selective AT1Rs or AT2R antagonists. Macrophage polarization, apoptosis, and related signaling pathways were assessed via western blotting, QPCR and flow cytometry. AT2R expression was decreased in LPS-stimulated rat alveolar macrophages (NR8383). Administration of the AT2R agonist CGP-42112 was associated with an increase in AT2R expression and M2 polarization, but no effect was observed upon administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan. In mechanical ventilation-induced lung injury in SpragueâDawley (SD) rats, the administration of the AT2R agonist C21 was associated with attenuation of the pathological damage score, lung wet/dry weight, cell count and protein content in BALF. C21 can significantly reduce proinflammatory factor TNF-α, IL-1ß levels, increase anti-inflammatory factor IL-4, IL-10 levels in BALF, compared with the model group (p < 0.01). Similarly, compared with those at the same time points, the M1/M2 ratios in alveolar macrophages and apoptosis in peritoneal macrophages at 4 h, 6 h and 8 h in the mechanical ventilation models were lower after C21 administration. These findings indicated that the expression of AT2Rs in alveolar macrophages mediates M1 macrophage polarization and apoptosis and that AT2Rs play a protective role in mediating mechanical ventilation-induced lung injury.
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Hantaan virus (HTNV) is prevalent in Eurasia. It causes hemorrhagic fever with renal syndrome (HFRS). Long noncoding RNAs (lncRNAs) play key roles in regulating innate immunity. Among these, lncRNA negative regulator of interferon response (NRIR) was reported as an inhibitor of several interferon (IFN)-stimulated genes. Our results showed that: NRIR expression was upregulated by HTNV infection in a type I IFN-dependent manner. The expression of NRIR in CD14+ monocytes from HFRS patients in acute phase was significantly higher than that in convalescent phase and healthy controls. HTNV infection in some HTNV-compatible cells was promoted by NRIR. NRIR negatively regulated innate immunity, especially IFITM3 expression. Localized in the nucleus, NRIR bound with HNRNPC, and knockdown of HNRNPC significantly weakened the effect of NRIR in promoting HTNV infection and restored IFITM3 expression. These results indicated that NRIR regulates the innate immune response against HTNV infection possibly through its interaction with HNRNPC and its influence on IFITM3.
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Virus Hantaan , Fiebre Hemorrágica con Síndrome Renal , Interferón Tipo I , ARN Largo no Codificante , Humanos , Virus Hantaan/genética , ARN Largo no Codificante/genética , Inmunidad Innata , Proteínas de la Membrana , Proteínas de Unión al ARN/genéticaRESUMEN
Imbalanced data is a problem in that the number of samples in different categories or target value ranges varies greatly. Data imbalance imposes excellent challenges to machine learning and pattern recognition. The performance of machine learning models leans to be partially towards the majority of samples in the imbalanced dataset, which will further affect the effect of the model. The imbalanced data problem includes an imbalanced categorical problem and an imbalanced regression problem. Many studies have been developed to address the issue of imbalanced classification data. Nevertheless, the imbalanced regression problem has not been well-researched. In order to solve the problem of unbalanced regression data, we define an RNGRU model that can simultaneously learn the regression characteristics and neighbor characteristics of regression samples. To obtain the most comprehensive sample information of regression samples, the model uses the idea of confrontation to determine the proportion between the regression characteristics and neighbor characteristics of the original samples. According to the regression characteristics of the regression samples, an index ccr (correlation change rate) is proposed to evaluate the similarity between the generated samples and the original samples. And on this basis, an RNGAN model is proposed to reduce the similarity between the generated samples and the original samples by using the idea of confrontation.
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OBJECTIVES: To develop and validate a simple and effective death risk stratification scale for hemorrhagic fever with renal syndrome (HFRS). METHODS: In this ambispective cohort study, we investigated the epidemiological and clinical data of 2245 patients with HFRS (1873 enrolled retrospectively and constituting the training cohort, 372 prospectively recruited as the validation cohort) from September 2008 to December 2021, and identified independent risk factors for 30-day death of HFRS. Using logistic regression analysis, a nomogram prediction model was established and was further simplified into a novel scoring scale. Calibration plot, receiver operating characteristic curve, net reclassification index, integrated discrimination index, and decision curve analysis were used to assess the calibration, discrimination, precision, and clinical utility in both training and validation cohorts. RESULTS: Of 2245 patients with HFRS, 132 (5.9%) died during hospitalization. The nomogram prediction model and scoring scale were developed using six predictors: comorbid hypertension, hypotensive shock, hypoxemia, neutrophils, aspartate aminotransferase, and activated partial thromboplastin time. Both the scale and nomogram were well calibrated (near-diagonal calibration curves) and demonstrated significant predictive values (areas under receiver operating characteristic curves >0.9, sensitivity and specificity >90% in the training cohort and >84% in the validation cohort). The simplified scoring scale demonstrated equivalent discriminative ability to the nomogram, with net reclassification index and integrated discrimination index of 0.022 and 0.007 in the training cohort, 0.126 and 0.022 in the validation cohort. Decision curve analysis graphically represented significant clinical utility and comparable net benefits of the nomogram and scoring scale across a range of threshold probabilities. DISCUSSION: This evidence-based, factor-weighted, accurate score could help clinicians swiftly stratify HFRS mortality risk and facilitate the implementation of patient triage and tiered medical services during epidemic peaks.
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Epidemias , Fiebre Hemorrágica con Síndrome Renal , Humanos , Estudios de Cohortes , Fiebre Hemorrágica con Síndrome Renal/diagnóstico , Fiebre Hemorrágica con Síndrome Renal/epidemiología , Estudios Retrospectivos , Medición de RiesgoRESUMEN
Small ubiquitin-like modifier mediated modification (SUMOylation) is a critical post-translational modification that has a broad spectrum of biological functions, including genome replication and repair, transcriptional regulation, protein stability, and cell cycle progression. Perturbation or deregulation of a SUMOylation and deSUMOylation status has emerged as a new pathophysiological feature of lung diseases. In this review, we highlighted the link between SUMO pathway and lung diseases, especially the sumoylated substrate such as C/EBPα in bronchopulmonary dysplasia (BDP), PPARγ in pneumonia, TFII-I in asthma, HDAC2 in chronic obstructive pulmonary disease (COPD), KLF15 in hypoxic pulmonary hypertension (HPH), SMAD3 in idiopathic pulmonary fibrosis (IPF), and YTHDF2 in cancer. By exploring the impact of SUMOylation in pulmonary diseases, we intend to shed light on its potential to inspire the development of innovative diagnostic and therapeutic strategies, holding promise for improving patient outcomes and overall respiratory health.
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Asma , Displasia Broncopulmonar , Enfermedad Pulmonar Obstructiva Crónica , Recién Nacido , Humanos , Sumoilación , HipoxiaRESUMEN
This study aimed to predict the transmission trajectory of the 2019 Corona Virus Disease (COVID-19) and analyze the impact of preventive measures on the spread of the epidemic. Considering that tracking a long-term epidemic trajectory requires explanatory modeling with more complexities than short-term predictions, an improved Susceptible-Exposed-Infected-Removed (SEIR) transmission dynamic model is established. The model depends on defining various parameters that describe both the virus and the population under study. However, it is likely that several of these parameters will exhibit significant variations among different states. Therefore, regression algorithms and heuristic algorithms were developed to effectively adapt the population-dependent parameters and ensure accurate fitting of the SEIR model to data for any specific state. In this study, we consider the second outbreak of COVID-19 in Italy as a case study, which occurred in August 2020. We divide the epidemic data from February to September of the same year into two distinct stages for analysis. The numerical results demonstrate that the improved SEIR model effectively simulates and predicts the transmission trajectories of the Italian epidemic during both periods before and after the second outbreak. By analyzing the impact of anti-epidemic measures on the spread of the disease, our findings emphasize the significance of implementing anti-epidemic preventive measures in COVID-19 modeling.
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COVID-19 , Epidemias , Virosis , Humanos , COVID-19/epidemiología , Brotes de Enfermedades , Italia/epidemiologíaRESUMEN
BACKGROUND: Hantaan virus (HTNV) infection can cause severe hemorrhagic fever with renal syndrome (HFRS). Inflammatory monocytes (iMOs) are involved in early antiviral responses. Previous studies have found that blood iMOs numbers increase in the acute phase of HFRS. Here, we further identified the phenotypic characteristics of iMOs in HFRS and explored whether phenotypic changes in iMOs were associated with HFRS severity. MATERIALS AND METHODS: Blood samples from 85 HFRS patients were used for phenotypic analysis of iMOs by flow cytometry. Plasma HTNV load was determined using RT-PCR. THP-1 cells overexpressing CD226 were used to investigate the effects of CD226 on HLA-DR/DP/DQ and CD80 expression. A mouse model was used to test macrophage phenotype following HTNV infection. RESULTS: The proportion of CD226- iMOs in the acute phase of HFRS was 66.83 (35.05-81.72) %, which was significantly higher than that in the convalescent phase (5.32 (1.36-13.52) %) and normal controls (7.39 (1.15-18.11) %) (p < 0.0001). In the acute phase, the proportion of CD226- iMOs increased more in patients with more severe HFRS and correlated positively with HTNV load and negatively with platelet count. Notably, CD226- iMOs expressed lower levels of HLA-DR/DP/DQ and CD80 than CD226+ iMOs, and overexpression CD226 could enhance the expression of HLA-DR/DP/DQ and CD80. In a mouse model, HTNV also induced the expansion of CD226- macrophages, with decreased expression of I-A/I-E and CD80. CONCLUSIONS: CD226- iMOs increased during HTNV infection and the decrease in CD226 hampered the expression of HLA-DR/DP/DQ and CD80, which may promote the immune escape of HTNV and exacerbate clinical symptoms.
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Virus Hantaan , Fiebre Hemorrágica con Síndrome Renal , Animales , Ratones , Humanos , Monocitos/metabolismo , Recuento de Plaquetas , Antígenos HLA-DRRESUMEN
Monocytes are important target cells of various hemorrhagic fever viruses. In viral hemorrhagic fevers (VHFs), monocytes can be infected by viruses and produce different kinds of cytokines, which contribute to the antiviral immune response and participation in the immunopathogenesis of VHFs. During the pathogenesis of various VHFs (early stage), monocytes change in cell counting, subpopulation distribution and expression of surface molecules with an activated phenotype. Several hemorrhagic fever viruses can infect monocytes and induce immune response, which may play an important role in immunopathological injury. Monocytes and the cytokines they produce may interact with platelets and vascular endothelial cells, contributing to disease progression.
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Fiebres Hemorrágicas Virales , Monocitos , Humanos , Células Endoteliales , Fiebres Hemorrágicas Virales/patología , Inmunidad , CitocinasRESUMEN
The fruit peel color is an important factor that affects its quality. However, genes involved in regulating pericarp color in bottle gourd (Lagenaria siceraria) have not been explored to date. Genetic analysis of color traits in bottle gourd peel through a genetic population of six generations demonstrated that the green color of peels is inherited as a single gene dominant trait. Combined phenotype-genotype analysis of recombinant plants using BSA-seq mapped the candidate gene to a 22.645 Kb interval at the head end of chromosome 1. We observed that the final interval contained only one gene, LsAPRR2 (HG_GLEAN_10010973). Sequence and spatiotemporal expression analyses of LsAPRR2 unraveled two nonsynonymous mutations (AâG) and (GâC) in the parental CDS sequences. Further, LsAPRR2 expression was higher in all green-skinned bottle gourds (H16) at various stages of fruit development than in white-skinned bottle gourds (H06). Cloning and sequence comparison of the two parental LsAPRR2 promoter regions indicated 11 bases insertion and 8 SNPs mutations in the region -991~-1033, upstream of the start codon in white bottle gourd. Proof of GUS reporting system, Genetic variation in this fragment significantly reduced the expression of LsAPRR2 in the pericarp of white bottle gourd. In addition, we developed a tightly linked (accuracy 93.88%) InDel marker for the promoter variant segment. Overall, the current study provides a theoretical basis for comprehensive elucidation of the regulatory mechanisms underlying the determination of bottle gourd pericarp color. This would further help in the directed molecular design breeding of bottle gourd pericarp.
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Background: Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2, is a rare but serious complication of SARS-CoV-2 infection in children that typically occurs 2-6 weeks after SARS-CoV-2 infection. The pathophysiology of MIS-C is unknown. MIS-C, first recognized in April 2020, is characterized by fever, systemic inflammation, and multi-system organ involvement. Post-vaccination adverse effects have increased with COVID-19 vaccinations, and MIS linked to immunization with COVID-19 vaccines has also been observed. Case Report: An 11-year-old Chinese girl presented with a high-grade fever, rash, and dry cough for 2 days. She had her 2nd SARS-CoV-2 inactivated vaccination dose five days before hospital admission. On day 3 & 4, she experienced bilateral conjunctivitis, hypotension (66/47â mmHg), and a high CRP level. She was diagnosed with MIS-C. The patient's condition deteriorated rapidly, necessitating intensive care unit admission. The patient's symptoms improved after intravenous immunoglobulin, methylprednisolone, and oral aspirin therapy. She was discharged from the hospital after 16 days as her general condition, and laboratory biomarkers returned to normal. Conclusion: Inactivated Covid-19 vaccination might trigger MIS-C. Further research is needed to evaluate whether a correlation exists between COVID-19 vaccination and MIS-C development.
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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe clinical conditions with a high mortality rate. Nucleotidebinding oligomerization domain (NOD)like receptor containing pyrin domain 3 (NLRP3) and nuclear factor E2related factor 2 (Nrf2) have been reported to be associated with ALI. However, the dynamic changes in the levels of these factors in lipopolysaccharide (LPS)induced lung injury remain unclear. Thus, the present study aimed to determine the LPSinduced activation of immunological cascades, as well as the NLRP3/Nrf2 signaling pathway at different stages of lung injury. For this purpose, mice were divided into six groups as follows: The control, LPS4 h, LPS24 h, LPS48 h, LPS96 h and LPS144 h groups. LPS (4 mg/kg) was administered intratracheally to induce lung injury. Flow cytometry was used to determine the changes in macrophages, neutrophils and Tcell subsets in lung tissue, hematoxylin and eosin staining were used to measure the histopathological changes in lung tissues, ELISA was performed to evaluate the levels of cytokines, western blot analysis was used to measure the levels of inflammatory proteins, and reverse transcriptionquantitative PCR used to determine the mRNA level of a target gene. Following LPS administration, evident histopathological damage with neutrophil infiltration was observed which peaked at 48 h. The levels of interleukin1ß, keratinocytederived chemokine, macrophage inflammatory protein 2 and tumor necrosis factor a were markedly increased in bronchoalveolar lavage fluid and serum from the mice, and these levels peaked at 4 h. Moreover, LPS promoted Toll like receptor4 expression and reactive oxygen species production, thus activating NLRP3/Nrf2 signaling and pyroptosis. Collectively, the present study demonstrates that LPS triggers multiple inflammatory molecules and immune cells during ALI, which may be closely involved in the irregular redox status, NLRP3/Nrf2 pathway and pyroptosis.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Ratones , Animales , Lipopolisacáridos/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Inflamasomas/metabolismo , Ratones Endogámicos C57BL , Lesión Pulmonar Aguda/patología , Pulmón/patologíaRESUMEN
As the global prototypical zoonotic hantavirus, Hantaan virus (HTNV) is prevalent in Asia and is the leading causative agent of severe hemorrhagic fever with renal syndrome (HFRS), which has profound morbidity and mortality. Macrophages are crucial components of the host innate immune system and serve as the first line of defense against HTNV infection. Previous studies indicated that the viral replication efficiency in macrophages determines hantavirus pathogenicity, but it remains unknown which factor manipulates the macrophage activation pattern and the virus-host interaction process. Here, we performed the transcriptomic analysis of HTNV-infected mouse bone marrow-derived macrophages and identified the long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1), especially the isoform NEAT1-2, as one of the lncRNAs that is differentially expressed at the early phase. Based on coculture experiments, we revealed that silencing NEAT1-2 hinders inflammatory macrophage activation and facilitates HTNV propagation, while enhancing NEAT1-2 transcription effectively restrains viral replication. Furthermore, sterol response element binding factor-2 (SREBP2), which controls the cholesterol metabolism process, was found to stimulate macrophages by promoting the production of multiple inflammatory cytokines upon HTNV infection. NEAT1-2 could potentiate SREBP2 activity by upregulating Srebf1 expression and interacting with SREBP2, thus stimulating inflammatory macrophages and limiting HTNV propagation. More importantly, we demonstrated that the NEAT1-2 expression level in patient monocytes was negatively correlated with viral load and HFRS disease progression. Our results identified a function and mechanism of action for the lncRNA NEAT1 in heightening SREBP2-mediated macrophage activation to restrain hantaviral propagation and revealed the association of NEAT1 with HFRS severity.
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Background: Japanese encephalitis virus (JEV) is the main cause of viral encephalitis in Asia. Nowadays, no effective and specific therapy for JE patients is available except supportive treatment. The fatality rate of JE patients is still about 30%, and more than half of survivors suffered from various neuropsychiatric sequelae. Thus, more attention should be paid to JE. Methods: In this study, a retrospective cohort of JE patients was collected and the general features of JE patients admitted into the Department of Infectious Diseases were analyzed. Meanwhile, the dynamic change of plasma cytokines and immune cells in JE patients with divergent prognosis was detected and analyzed. Results: We found a mounted proportion of adult/old patients in JE cases. The level of IL-6 and IL-18 increased in JE patients especially in fatal individuals. There was a continuous decreased percentage of CD4+ T and B cells in severe JE patients with fatal outcome compared with the surviving JE patients. Conclusions: The consistent high level of IL-6 and IL-18 in the plasma and low proportion of CD4+ T and B cells in the PBMCs might be the indicators of poor prognosis.
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Encefalitis Japonesa , Adulto , Citocinas , Humanos , Interleucina-18 , Interleucina-6 , Estudios RetrospectivosRESUMEN
BACKGROUND: Hepatitis C virus (HCV) dysregulates innate and adaptive immune responses while monocytes (M) play a crucial role in linking innate and adaptive immunity to control viral infection. A transcription factor T-bet is upregulated to dampen M functions via the c-Jun N-terminal kinase (JNK) pathway, followed by enhanced Tim-3 expression in chronic HCV infection. However, the molecular mechanisms that control the expression in M are yet unknown. miR-155 has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression, but the influences of miR-155 on these regulators and effectors still need to be studied. METHODS: Forty HCV-infected patients and 40 healthy subjects (HS) were recruited, THP-1 cells (human acute monocyte leukemia cell line) were cultured with HCV-infected Huh 7.5 cells. The expression levels of miR-155 and JNK1/JNK2/JNK3 were measured by real-time RT-PCR. IL-10/IL-12 was detected by flow cytometry. THP-1 cells were transfected with mimics-155 and negative control, SOCS1, p-STAT1, p65, p-smad, p-p38, and p-JNK were measured by Western blot. TNF-α levels were measured by ELISA. Student's t-test was used in statistics. RESULTS: The study showed that miR-155 was upregulated in CD14+ M in HCV-infected patients compared to healthy subjects (P<0.05). Moreover, the upregulation of miR-155 in CD14+ M from HCV-infected patients induced TNF-α production and JNK gene expression, which, in turn, led to T-bet upregulation. Also, miR-155 upregulation in CD14+ M of HCV-infected patients increased the IL-12 and decreased the IL-10 production. CONCLUSIONS: The obtained results indicated that miR-155 upregulation in M during HCV infection enhances the activation of TNF-α and JNK pathways, promotes the expression of transcription factor T-bet, and triggers pro- and anti-inflammatory mediators. Together, these data reveal new information regarding the mechanisms of chronic HCV infection.
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Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, IL-18, and cleaved caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at Ì´ 1532 to Ì´1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2.
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Lesión Pulmonar Aguda , Inflamasomas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Retroalimentación , Inflamasomas/genética , Interleucina-1beta , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Factor 2 Relacionado con NF-E2/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Phenotypic plasticity is the exhibition of various phenotypic traits produced by a single genotype in response to environmental changes, enabling organisms to adapt to environmental changes by maintaining growth and reproduction. Despite its significance in evolutionary studies, we still know little about the genetic control of phenotypic plasticity. In this study, we designed and conducted a genome-wide association study (GWAS) to reveal genetic architecture of how Staphylococcus aureus strains respond to increasing concentrations of vancomycin (0, 2, 4, and 6 µg/mL) in a time course. We implemented functional mapping, a dynamic model for genetic mapping using longitudinal data, to map specific loci that mediate the growth trajectories of abundance of vancomycin-exposed S. aureus strains. 78 significant single nucleotide polymorphisms were identified following analysis of the whole growth and development process, and seven genes might play a pivotal role in governing phenotypic plasticity to the pressure of vancomycin. These seven genes, SAOUHSC_00020 (walR), SAOUHSC_00176, SAOUHSC_00544 (sdrC), SAOUHSC_02998, SAOUHSC_00025, SAOUHSC_00169, and SAOUHSC_02023, were found to help S. aureus regulate antibiotic pressure. Our dynamic gene mapping technique provides a tool for dissecting the phenotypic plasticity mechanisms of S. aureus under vancomycin pressure, emphasizing the feasibility and potential of functional mapping in the study of bacterial phenotypic plasticity.
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Hantaan virus infection may cause severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. The chemokine fractalkine (CX3CL1) acts as a proinflammatory cytokine, and it is elevated in several infectious diseases. However, little is known about the contributions of CX3CL1 to HFRS pathogenesis. Present study detected plasma CX3CL1 levels and expression of the receptor CX3CR1 in HFRS patients and discussed the possible effects of CX3CL1 on pathogenesis of HFRS. Plasma CX3CL1 in acute phase and Critical/Severe groups of HFRS patients were significantly increased compared to that in normal controls (p < 0.001 and p < 0.01, respectively). High plasma CX3CL1 was negatively correlated with platelet count (r = -0.5844, p < 0.0001) and positively correlated with blood urea nitrogen (r = 0.3668, p = 0.0039), creatinine (r = 0.42, p = 0.0008), and white blood cells (r = 0.2646, p = 0.0411). Expression of CX3CR1 on nonclassical and intermediate monocytes was also increased in the acute phase (p < 0.01 for both the cells) and Critical/Severe groups (p < 0.05 and p < 0.01, respectively) of HFRS patients compared to that in normal controls. Taken together, elevation of plasma CX3CL1 in HFRS patients and expression of CX3CR1 on nonclassical and intermediate monocyte subsets might provide new insights into the potential role of CX3CL1/CX3CR1 in pathogenesis of HFRS.
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Quimiocina CX3CL1 , Fiebre Hemorrágica con Síndrome Renal , Quimiocina CX3CL1/sangre , Quimiocina CX3CL1/metabolismo , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/patología , Humanos , Riñón/patología , Recuento de Leucocitos , Monocitos/metabolismoRESUMEN
Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human coronavirus causing severe disease and mortality. MERS-CoV infection failed to elicit robust IFN response, suggesting that the virus might have evolved strategies to evade host innate immune surveillance. In this study, we identified and characterized type I IFN antagonism of MERS-CoV open reading frame (ORF) 8b accessory protein. ORF8b was abundantly expressed in MERS-CoV-infected Huh-7 cells. When ectopically expressed, ORF8b inhibited IRF3-mediated IFN-ß expression induced by Sendai virus and poly(I:C). ORF8b was found to act at a step upstream of IRF3 to impede the interaction between IRF3 kinase IKKε and chaperone protein HSP70, which is required for the activation of IKKε and IRF3. An infection study using recombinant wild-type and ORF8b-deficient MERS-CoV further confirmed the suppressive role of ORF8b in type I IFN induction and its disruption of the colocalization of HSP70 with IKKε. Ectopic expression of HSP70 relieved suppression of IFN-ß expression by ORF8b in an IKKε-dependent manner. Enhancement of IFN-ß induction in cells infected with ORF8b-deficient virus was erased when HSP70 was depleted. Taken together, HSP70 chaperone is important for IKKε activation, and MERS-CoV ORF8b suppresses type I IFN expression by competing with IKKε for interaction with HSP70.