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Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization.

ABSTRACT: Dengue virus (DENV) infection manifests as a febrile illness with three distinct phases: early acute, late acute, and convalescent. Dengue can result in clinical manifestations with different degrees of severity, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Interferons (IFNs) are antiviral cytokines central to the anti-DENV immune response. Notably, the distinct global signature of type I, II, and III interferon-regulated genes (the interferome) remains uncharacterized in dengue patients to date. Therefore, we performed an in-depth cross-study for the integrative analysis of transcriptome data related to DENV infection. Our systems biology analysis shows that the anti-dengue immune response is characterized by the modulation of numerous interferon-regulated genes (IRGs) enriching, for instance, cytokine-mediated signaling (e.g., type I and II IFNs) and chemotaxis, which is then followed by a transcriptional wave of genes associated with cell cycle, also regulated by the IFN cascade. The adjunct analysis of disease stratification potential, followed by a transcriptional meta-analysis of the interferome, indicated genes such as IFI27, ISG15, and CYBRD1 as potential suitable biomarkers of disease severity. Thus, this study characterizes the landscape of the interferome signature in DENV infection, indicating that interferome dynamics are a crucial and central part of the anti-dengue immune response.

SUBMITTER: Usuda JN

PROVIDER: S-EPMC10449254 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization.

Usuda Júlia Nakanishi JN Plaça Desirée Rodrigues DR Fonseca Dennyson Leandro M DLM Marques Alexandre H C AHC Filgueiras Igor Salerno IS Chaves Victor Gabriel Bastos VGB Adri Anny Silva AS Torrentes-Carvalho Amanda A Hirata Mario Hiroyuki MH Freire Paula Paccielli PP Catar Rusan R Cabral-Miranda Gustavo G Schimke Lena F LF Moll Guido G Cabral-Marques Otavio O

Frontiers in immunology 20230810

Dengue virus (DENV) infection manifests as a febrile illness with three distinct phases: early acute, late acute, and convalescent. Dengue can result in clinical manifestations with different degrees of severity, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Interferons (IFNs) are antiviral cytokines central to the anti-DENV immune response. Notably, the distinct global signature of type I, II, and III interferon-regulated genes (the interferome) remains uncharacterized in d ...[more]

PMID: 37638052

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Project description:BackgroundDermacentor reticulatus (Fabricius, 1794) is distributed in Europe and Asia where it infests and transmits disease-causing pathogens to humans, pets and other domestic and wild animals. However, despite its role as a vector of emerging or re-emerging diseases, very little information is available on the genome, transcriptome and proteome of D. reticulatus. Tick larvae are the first developmental stage to infest hosts, acquire infection and transmit pathogens that are transovarially transmitted and are exposed to extremely stressing conditions. In this study, we used a systems biology approach to get an insight into the mechanisms active in D. reticulatus unfed larvae, with special emphasis on stress response.Principal findingsThe results support the use of paired end RNA sequencing and proteomics informed by transcriptomics (PIT) for the analysis of transcriptomics and proteomics data, particularly for organisms such as D. reticulatus with little sequence information available. The results showed that metabolic and cellular processes involved in protein synthesis were the most active in D. reticulatus unfed larvae, suggesting that ticks are very active during this life stage. The stress response was activated in D. reticulatus unfed larvae and a Rickettsia sp. similar to R. raoultii was identified in these ticks.SignificanceThe activation of stress responses in D. reticulatus unfed larvae likely counteracts the negative effect of temperature and other stress conditions such as Rickettsia infection and favors tick adaptation to environmental conditions to increase tick survival. These results show mechanisms that have evolved in D. reticulatus ticks to survive under stress conditions and suggest that these mechanisms are conserved across hard tick species. Targeting some of these proteins by vaccination may increase tick susceptibility to natural stress conditions, which in turn reduce tick survival and reproduction, thus reducing tick populations and vector capacity for tick-borne pathogens.

Project description:In tropical and subtropical regions, dengue fever is a common febrile illness that is mostly spread by Aedes mosquitoes. Urban population migration, inadequate water storage facilities, and high mosquito density are features associated with this disease. The severity of the illness ranges from mild to deadly dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), often with severe cases causing profound shock from extensive plasma leakage, and may result in demise. The symptoms of the illness include headache, myalgia, retro-orbital pain, and hemorrhagic signs. There may also be an intermittent shift in blood vessel integrity and coagulation, but recovery is typically complete and rapid. In this review, we emphasize the immunological aspects of this illness. The intricate interactions among the virus, host genes, and host immune systems impact the pathophysiology of dengue. Postinfection antibody-dependent enhancement is prominent, which significantly influences the etiology and virulence of the disease. Whereas the severe form only manifests when the host immune system is actively working to eradicate the infection by secreting several inflammatory cytokines, chemokines, and lipid mediators, for example, early dengue virus infection (DVI) resulted in the production of Interleukin 2 (IL-2), IL-6, and later infection, IL-4, IL-5, and IL-10. Higher concentrations of interferons gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor (MIF), IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-13 were found in DHF patients. These are significantly more prevalent in severe infections than in mild ones. Numerous immunopathogenic processes involving both virus and host variables influence the severity of dengue. There is growing evidence that a compromised immune system limits viral clearance and causes severe inflammation, which in turn causes dengue hemorrhagic fever and dengue shock syndrome. Furthermore, the capacity of DENV to infect a broad range of immune cells, such as macrophages, dendritic cells, mast cells, T and B cells, and monocytes, further dysregulates these cells' antiviral activities, leading to the spread of the virus. Even though a number of risk factors linked to the advancement of the disease have been suggested, further research and evaluation of novel technologies are necessary to understand the complicated etiology and develop reliable and effective vaccines to fight against this febrile illness.

Project description:Background: Increasing evidence illustrated that m6A regulator-mediated modification plays a crucial role in regulating tumor immune and angiogenesis microenvironment. And the combination of immune checkpoint inhibitor and anti-angiogenic therapy has been approved as new first-line therapy for advanced HCC. This study constructed a novel prognosis signature base on m6A-mediated modification and explored the related mechanism in predicting immune and anti-angiogenic responses. Methods: Gene expression profiles and clinical information were collected from TCGA and GEO. The ssGSEA, MCPCOUNT, and TIMER 2.0 algorithm was used to Estimation of immune cell infiltration. The IC50 of anti-angiogenic drugs in GDSC was calculated by the "pRRophetic" package. IMvigor210 cohort and Liu et al. cohort were used to validate the capability of immunotherapy response. Hepatocellular carcinoma single immune cells sequencing datasets GSE140228 were collected to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients. Results: Three m6A clusters with distinct immune and angiogenesis microenvironments were identified by consistent cluster analysis based on the expression of m6A regulators. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drug response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response, and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Conclusion: We constructed a novel prognosis signature and identified B2M and SMOX for predicting immune and anti-angiogenic efficacy in HCC, which may guide the combined treatment strategies of immunotherapy and anti-angiogenic therapy in HCC.

Dataset Information

Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization.

Publications

Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization.

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