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This study introduces the nanobromhexine lipid particle (NBL) platform designed for effective pulmonary drug delivery. Inspired by respiratory virus transport mechanisms, NBL address challenges associated with mucus permeation and inflammation in pulmonary diseases. Composed of low molecular weight polyethylene glycol-coated lipid nanoparticles with bromhexine hydrochloride, NBL exhibit a size of 118 ± 24 nm, a neutral zeta potential, osmolarity of 358 ± 28 mOsmol/kg, and a pH of 6.5. Nebulizing without leakage and showing no toxicity to epithelial cells, NBL display mucoadhesive properties with a 60% mucin-binding efficiency. They effectively traverse the dense mucus layer of Calu-3 cultures in an air-liquid interface, as supported by a 55% decrease in MUC5AC density and a 29% increase in nanoparticles internalization compared to non-exposed cells. In assessing immunomodulatory effects, NBL treatment in SARS-CoV-2-infected lung cells leads to a 40-fold increase in anti-inflammatory MUC1 gene expression, a proportional reduction in pro-inflammatory IL-6 expression, and elevated anti-inflammatory IL-10 expression. These findings suggest a potential mechanism to regulate the excessive IL-6 expression triggered by virus infection. Therefore, the NBL platform demonstrates promising potential for efficient pulmonary drug delivery and immunomodulation, offering a novel approach to addressing mucus permeation and inflammation in pulmonary diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Chikungunya virus (CHIKV) infection generates strong immune responses that are associated with the disease pathophysiology. Regulatory T cells (Treg-cluster of differentiation (CD)-4 + CD25 high forkhead box P3 (FOXP3 + )) are essential for the induction and maintenance of peripheral tolerance. Thus, they play key roles in determining the patient prognosis by preventing excessive immune responses via different suppression immune mechanisms. However, the regulatory mechanisms involved in human CHIKV infection are still poorly understood. Here, we characterize for the first time the Treg cell molecule-associated-mechanism during acute and chronic human Chikungunya disease. Here, we assessed the Treg cell population and molecule-associated mechanism in the peripheral blood samples of acute and chronic patients with Chikungunya. Our results indicate that CHIKV infection is associated with reduced frequency of Tregs, along with the impaired expression and production of Treg functional markers, including CD39, CD73, perforin, granzyme, programmed death 1 (PD-1), cytotoxic T lymphocyte antigen (CTLA)-4, and transforming growth factor (TGF)-β. This observation suggests that Treg cells possess the poor regulatory capacity in both acute and chronic phases of the disease. Taken together, these data provide significant evidence that the imbalanced response of Treg cells plays an essential role in establishing the pathogenesis of Chikungunya., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2021 Institut Pasteur. All rights reserved.)

Chikungunya is an important mosquito-borne disease caused by the arthritogenic chikungunya virus, characterized by sporadic outbreaks all around the world. Although CD4+ T cells seem to have an important role in the pathogenesis of chikungunya, the mechanisms involved in this process are not yet fully elucidated. The ectoenzymes CD39 and CD73, also expressed by CD4 T lymphocytes, are involved in the hydrolysis of pro-inflammatory extracellular ATP and generation of immunosuppressive adenosine and seem to be modulated in some arthritogenic pathologies. However, their involvement in Chikungunya disease is unclear. Thus, using flow cytometry, we investigated peripheral CD4+ T cells from patients with acute and chronic chikungunya to assess the expression of ectonucleotidases CD39 and CD73 and coinhibitory receptors and production of cytokine and cytolytic granules. Patients in the acute phase displayed increased levels of PD-1, CTLA-4, IL-10, and IFN-γ compared to healthy individuals and patients in the chronic phase. Moreover, during chronic Chikungunya, analyses of Mean Fluorescent Intensity (MFI) demonstrated a reduced density of LAP, Perforin and Granzyme B compared to the healthy control. Finally, reduced levels of the ectoenzymes CD39 and CD73 expression was found during the chronic phase suggesting a possible modulation of extracellular ATP and adenosine by CD4+ T cells that may be involved in the persistence of arthritogenic symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Zika virus (ZIKV), alongside Dengue virus (DENV), Chikungunya virus (CHIKV), and Yellow Fever Virus (YFV) are prevalent arboviruses in the Americas. Each of these infections is associated with the development of associated disease immunopathology. Immunopathological processes are an outcome of counter-balancing impacts between effector and regulatory immune mechanisms. In this context, regulatory T cells (Tregs) are key in modulating the immune response and, therefore, in tissue damage control. However, to date, Treg phenotypes and mechanisms during acute infection of the ZIKV in humans have not been fully investigated. The main aim of this work was to characterize Tregs and their immunological profile related to cytokine production and molecules that are capable of controlling the exacerbated inflammatory profile in acute Zika infected patients. Using whole blood analyses of infected patients, an ex vivo phenotypical characterization of Tregs, circulating during acute Zika virus infection, was conducted by flow cytometry. We found that though there are no differences in absolute Treg frequency between infected and healthy control groups. However, pro-inflammatory cytokine up-regulation such as IFN-γ and LAP was observed in the acute disease. Furthermore, acute ZIKV patients expressed increased levels of CD39/CD73, perforin/granzyme B, PD-1, and CTLA-4, all markers involved in mechanisms used by Tregs to attempt to control strong inflammatory responses. Thus, the data indicates a potential contribution of Tregs during the inflammatory ZIKV infection response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2 -/- ) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2 -/- mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2 -/- mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

Type B coxsackieviruses (CVB) are enteroviruses responsible for a common infectious myocarditis and pancreatitis. DCs and regulatory T cells (Tregs) are key players in controlling virus replication and regulating the immune response and tissue damage, respectively. However, the mechanisms underlying cellular migration to target tissues remain unclear. In the present study, we found that CVB5 infection induced CCL17 production and controlled the migration of CCR4 + DCs and CCR4 + Tregs to the pancreatic lymph nodes (pLN). CVB5 infection of CCR4 -/- mice reduced the migration of the CD8α + DC subset and reduced DC activation and production of IFN-β and IL-12. Consequently, CCR4 -/- mice presented decreased IFN-γ-producing CD4 + and CD8 + T cells, an increased viral load and more severe pancreatitis. In addition, CCR4 -/- mice had impaired Treg accumulation in pLN as well as increased T lymphocyte activation. Adoptive transfer of CCR4 + Tregs but not CCR4 - Tregs was able to regulate T lymphocyte activation upon CVB5 infection. The present data reveal a previously unknown role for CCR4 in coordinating immune cell migration to CVB-infected tissues and in controlling subsequent pancreatitis. These new insights may contribute to the design of future therapies for acute and chronic infection of non-polio enteroviruses.

Dengue, a reemerging disease, is one of the most important viral diseases transmitted by mosquitoes. In this study, 55,680 cases of dengue between 2007 and 2015 were reported in Paraíba State, among which, 30% were reported in João Pessoa city, with peaks in 2015, 2011 and 2013. Weather is considered to be a key factor in the temporal and spatial distribution of vector-transmitted diseases. Thus, the relationship between rainfall occurrence and dengue incidences reported from 2007 to 2015 in João Pessoa city, Paraíba State, Brazil, was analyzed by means of wavelet transform, when a frequency analysis of both rainfall and dengue incidence signals was performed. To determine the relationship between rainfall and the incidence of dengue cases, a sample cross correlation function was performed to identify lags in the rainfall and temperature variables that might be useful predictors of dengue incidence. The total rainfall within 90 days presented the most significant association with the number of dengue cases, whereas temperature was not found to be a useful predictor. The correlation between rainfall and the occurrence of dengue cases showed that the number of cases increased in the first few months after the rainy season. Wavelet analysis showed that in addition to the annual frequency presented in both time series, the dengue time series also presented the 3-year frequency from 2010. Cross wavelet analysis revealed that such an annual frequency of both time series was in phase; however, after 2010, it was also possible to observe 45° up phase arrows, which indicated that rainfall in the present year led to an increased dengue incidence the following year. Thus, this approach to analyze surveillance data might be useful for developing public health policies for dengue prevention and control., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is a need for more detailed elucidation of T-cell immunity in chikungunya infection. CD8 T cells are one of main actors against viruses. Here, we analysed CD8 + T lymphocytes from patients in the acute and chronic phases of chikungunya disease (CHIKD). Our results demonstrate that CD8 + T cells expressed higher ex vivo granzyme B, perforin and CD107A expression in patients in the acute phase of CHIKD compared with healthy individuals and higher ex vivo expression of CD69, interleukin-17A, interleukin-10 and CD95 ligand, and co-expression of CD95/CD95 ligand. These results elucidate the importance of these lymphocytes, demonstrating immune mechanisms mediated in human chikungunya infection., (© 2018 John Wiley & Sons Ltd.)

Introduction:: Despite being the most prevalent arboviral disease worldwide, dengue has been neglected lately. However, recent epidemics of arboviruses such as Zika and chikungunya in locations throughout the world have alerted health authorities to these diseases. This study evaluated the incidence pattern of dengue, its clinical characteristics, and co-circulation of serotypes from 2007 to 2015 in Paraiba State, Northeast Brazil., Methods:: Data on dengue cases from 2007 to 2015 were extracted from clinical reports of the National System for Notifiable Diseases [Sistema Nacional de Agravos de Notificação (SINAN)] of Brazil provided by the Paraiba Health Department. Reverse transcription polymerase chain reaction (RT-PCR) assays for dengue serotypes were carried out on plasma samples obtained from patients with suspected dengue. The data were analysed using descriptive statistics., Results:: According to clinical features, dengue fever [n = 39,083 (70.2%)] and dengue without warning signs [n = 15,365 (27.7%)] were the most common classifications of dengue. On RT-PCR, DENV 1 was the most commonly identified serotype (80.5%) in all years studied. Co-circulation of all four DENV serotypes was observed in 2013 and 2014. Furthermore, we observed an increase in dengue notifications in 2015, possibly due to the rise of Zika and chikungunya., Conclusions:: Our findings support the hypothesis that co-circulation of the four DENV serotypes may be a reason for the increased prevalence of severe forms of dengue in the years studied. This study may contribute to directing research, health policy, and financial resources toward reducing poorly controlled epidemic diseases.