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Dengue is the most common mosquito-borne flaviviral infection in the world today. Several factors contribute and act synergistically to cause severe infection. One of these is dysregulated host immunological mediators that cause transient pathophysiology during infection. These mediators act on the endothelium to increase vascular permeability, whi...
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Citations
... DENV can stimulate the innate immune response, leading to the release of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). These cytokines are crucial in attracting and activating various immune cells involved in inflammatory reactions and initiating adaptive immune responses (Imad et al., 2020). The elevation of these three cytokines has been observed in cases of dengue infection and has been linked to the occurrence of plasma leakage, thrombocytopenia, and tissue damage in dengue infection (Butthep et al., 2012;Masood et al., 2018;Pan et al., 2019;Varghese et al., 2019;). ...
Background
Dengue infection can trigger an immunological response that results in an inflammatory reaction, which acts as a defensive mechanism to protect the host. Dengue infection leads to an elevation in the release of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). These three cytokines have been shown to correlate with the development of thrombocytopenia and plasma leakage, which is related to the severity of the disease.
Aim
This study aims to investigate the effect of faloak (Sterculia quadrifida R. Br) stem bark on TNF-α, IL-1β, and IL-6 levels in Wistar rats infected with dengue, specifically DENV-3.
Methods
A group of 27 male Wistar rats (Rattus norvegicus) aged 2–3 months and weighting 200–300 g were divided into three distinct groups: healthy, dengue, and treatment (dengue infection and extract) groups. The rats in both the dengue and treatment groups were administered an injection of DENV-3 with a titer of 105 pfu at a dosage of 0.8 cc via the intraperitoneal route. The propagation of DENV-3 was initiated using C6/36 cells, and it underwent four passages. The extract was administered orally via a nasogastric tube at a dosage of 1,500 mg/kg body weight once daily for 7 days. The healthy group underwent blood sampling on the first day, whereas the dengue and therapy groups underwent blood sampling on the fifth and eighth, respectively.
Results
Compared with the healthy group, TNF-α levels in the dengue and treatment groups showed significant differences on day 5 post-infection. The post hoc analysis revealed a statistically significant difference between the dengue-treatment and dengue-healthy groups. The IL-1β levels in the dengue and healthy groups significantly differed on days 5 and 8 post-infection compared to the healthy group. The treatment group had less of a decrease in IL-6 levels on days 5 and 8 than the dengue group. However, no statistically significant differences were observed.
Conclusion
The stem bark of S. quadrifida shows potential as an anti-inflammatory agent in dengue infections, particularly in its ability to decrease levels of TNF-α and IL-1β.
... The dengue virus enters the human body via mosquito bites and after replicating in endothelial cells and the mononuclear phagocyte system, it enters the bloodstream, leading to the initial viremia [65]. Common symptoms include persistent fever, headache, muscle and joint pain, and in severe cases, it can be fatal [66]. Hainan Island provides favorable climatic conditions for the breeding of Aedes mosquitoes and the transmission of dengue fever [67]. ...
This review investigates the utilization of the One Health approach to advance sustainable development and enhance health in the Hainan tropical rainforest, which is a unique ecosystem with significant biodiversity and environmental value. The region is confronted with threats arising from human activities and climate change, impacting both the health of the inhabitants and the ecosystem. The Hainan tropical rainforests create an ideal habitat for the transmission of mosquito-borne diseases, such as dengue fever and malaria, between humans and animals. The hot and humid climate creates favorable conditions for mosquito proliferation, while increased human encroachment into forested areas escalates the risk of contact with wildlife reservoirs of these diseases. Proactive surveillance of emerging infectious diseases in the forests and animal populations of Hainan is crucial for early detection and swift response to potential public health hazards. By embracing the interdisciplinary and collaborative principles of the One Health approach, this review aims to safeguard the ecosystem while fostering development. The introduction offers insights into the significance of the One Health concept, its relevance to environmental conservation, human health, and animal health. Subsequently, the paper delves into the practical application of the One Health approach in the Hainan tropical rainforest, using it as a case study. This application entails raising awareness of ecosystem health through educational initiatives and public outreach, implementing effective ecological conservation measures, promoting wildlife conservation efforts, and monitoring and preventing potential disease outbreaks. Furthermore, the paper highlights the importance of the One Health approach in achieving sustainable development in the Hainan tropical rainforest. It also explores potential research directions and associated challenges. By prioritizing the collective well-being of humans, animals, and the environment, the One Health approach offers a means to balance ecosystem conservation and human welfare.
... Higher levels of TNF-α, IL-6, and IL-17, yet lower of IL-10 levels, were significantly correlated with symptoms such as nausea, vomiting, and bleeding, with varying strengths of correlation coefficients; yet, a notable finding in the present study was a strong correlation between IL-17 and bleeding in DF patients. IL-17 acts as a protective mediator in barrier immunity, supporting epithelial integrity by modulating tight junction proteins, subsequently linking and stabilizing epithelial cell connections to maintain barrier and exclude gut luminal contents and commensal microbes [21]. However, the present study introduced a new finding alongside common ones, as IL-8 levels were significantly higher in bleeding DF compared to nonbleeding DF, contributing to thrombocytopenia and increased bleeding [22]. ...
Recent studies have demonstrated that cytokine dysregulation has a critical role in the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The aim of this study was to investigate the association between tumor necrosis factor (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 17 (IL-17) with infection status, and severity of dengue. A prospective cross-sectional study was conducted at three hospitals in Gianyar regency and Denpasar municipality, Bali, Indonesia, from June to December 2022. Sixty-four dengue infected patients were involved. Patients’ serum was tested for dengue infection using NS1 antigen rapid test, dengue virus immunoglobulin M (IgM) and immunoglobulin G (IgG) test, and reverse transcription polymerase chain reaction (RT-PCR). Cytokine levels (TNF-α, IL-6, IL-10, and IL-17) were measured using enzyme-linked immunosorbent assay (ELISA). Infection status was determined by combining serological and RT-PCR results, categorizing patients into primary and secondary infections. The present study found that DF patients had lower TNF-α, IL-6, and IL-17 but higher IL-10 levels compared to DHF patients (p<0.001). Elevated TNF-α, IL-6, and IL-17 levels were higher in secondary infection, while IL-10 level was higher in primary infection (p<0.001). In conclusion, cytokines play a crucial role in the interplay between cytokine dysregulation and dengue infection dynamics.
... A common consequence in such cases is viral interference. During viral interference, one virus competes with the other, interfering with the replication mechanism [52]. ...
Rhinovirus causes respiratory tract infections in children and is found in co-infections. The objective of this research was to study the clinical profile of rhinovirus infection and co-infection in children with severe acute respiratory infection (SARI) during the COVID-19 pandemic period. We included 606 children ranging in age from 0.1 to 144 months of age from March 2020 to December 2021, hospitalized in the Pediatric Intensive Care Unit (PICU). The samples were collected by secretion from the nasopharynx region. A total of 259 children were tested positive for viral infection, 153 (59.07%) of them had a single rhinovirus infection and, 56 (36.6%) were aged between 60.1 and 144 months. Nine types of co-infections were identified and were found coinfection with three or more viruses (22/104, 21.15%). Observing the seasonality, the number of cases was similar between 2020 (49.53%) and 2021 (51.47%). Patients with a single infection (86.88%) and coinfection (67.30%) were more likely to have coughed. Patients with co-infection required the use of O2 for longer than those with a single rhinovirus infection. Hemogram results obtained from individuals with a single infection had higher levels of urea when compared to patients with co-infection with and other respiratory viruses. Multiple correspondence analyses indicated different clinical symptoms and comorbidities in patients with co-infection compared to those with single infection. The results found that the rhinovirus was much prevalent virus during the pandemic period and was found in co-infection with other virus types, what is important to diagnostic for the correct treatment of patients.
... Several previous studies have investigated the cytokine response in Dengue patients. However, most studies involve stratification of the patients according to the Dengue severity and then measuring the cytokine levels crossectional (Imad et al., 2020). The only longitudinal cytokine profiles during febrile, defervescence, and convalescent stages grouped the patients into dengue fever (DF) and dengue hemorrhagic fever (DHF) (Kumar et al., 2012). ...
The immunopathogenesis of dengue severity is convoluted. The primary objective of the research was to examine the dynamics of cytokine storm and its correlation with disease development in individuals affected by DENV infection. Additionally, the study aimed to discover potential biomarkers that could indicate severe dengue infection and determine the most suitable timeframe for predicting the severity of these biomarkers during the acute stage of dengue infections. We conducted a temporal analysis of the daily viral load and cytokine levels in 60 hospitalized dengue patients until discharge. Our findings reveal a distinct cytokine profile (elevated IL-8, IL-10, IL-6, GM-CSF, MCP-1, IL-13, and IL-4 and decreased IL-12, MIP-1β) on the third day after symptom onset is predictive of severe dengue in secondary dengue infection. The imbalanced cytokine signature may inform clinical decision-making in treating severe dengue infections.
... We evaluated some of the proinflammatory (IFNγ, IL-6, TNF-α, IL-17a, and IL-2) and antiinflammatory (IL-13, IL-5, IL-4, IL-10, and IL-22) cytokines in the patient's plasma as well as in EVs derived from them. These cytokines are also reported in dengue viral infection and inflammation (23,24). Analysis of individual cytokines in EVs revealed that eight cytokines, IFNγ, TNF-α, IL-2, IL-6, IL-17a, IL-13, IL-5, and IL-4, were found in greater levels in SDV-EVs and their corresponding plasma than in OFI-EVs and MDV-EVs ( Fig. 3A and B). ...
Extracellular vesicles (EVs) are small membrane vesicles secreted into biological fluids, which play crucial roles in influencing the cellular function in different pathological processes. However, there is less clarity on how plasma EVs influence proliferation activation and functions of immune cells during dengue virus (DV) infection. In this study, we aimed to characterize circulating EVs from different categories of dengue patients and examined the consequence of naïve CD4+ T cells to EVs isolated from the plasma of mild or severe dengue patients. We observed that severe dengue infection was associated with an increased release of CD41a+ platelet extracellular vesicles compared with that from patients with mild disease or healthy donors. These EVs carried an increased level of pro- and anti-inflammatory cytokines along with immunoregulatory proteins on the surface that caused CD4+ T cell suppression. Treatment of purified naïve CD4+ T cells with EVs derived from severe dengue plasma drove CD4+ proliferation toward specific subtypes and modulated surface receptor CXCR3 and CCR6 expression. Subsequent studies indicated a notable rise in programmed cell death ligand 1 (PD-L1) expression within CD41a+ severe DV (SDV) EVs. Additionally, CD4+ T cells showed an elevated increase in programmed cell death 1 (PD-1) after incubating with SDV-EVs. We also demonstrated that blocking PD-L1 on SDV-EVs or PD-1 on late-activating CD4⁺ T cells partially reversed the SDV-EV-induced suppression of CD4+ T cell proliferation. Overall, our study highlights the immunosuppressive property of EVs derived from plasma of severe dengue patients, which might contribute to immune pathogenesis by shaping the immune response.
IMPORTANCE
Severe dengue manifestations caused by the dengue virus are a global health problem. Studies suggest that severe dengue disease depends on uncontrolled immune cell activation, and excessive inflammation adds to the pathogenesis of severe dengue disease. Therefore, it is important to understand the process that triggers the uncontrolled activation of the immune cells. The change in immune response in mild to severe dengue may be due to direct virus-to-cell interaction or it could be a contact-independent process through the extracellular vesicles (EVs) released from infected cells. The importance of circulating EVs in the context of dengue virus infection and pathogenesis remains unexplored. Therefore, understanding the possible biological function of circulating EVs may help to delineate the role of EVs in the progression of disease. Our present study highlights that EVs from plasma of severe dengue patients can have immunosuppressive properties on CD4+ T cells which may contribute to T cell suppression and may contribute to dengue disease progression.
... Some authors have indicated that a Th1 CD4 + profile is protective against dengue, while a shift to Th2 is involved in disease severity [41][42][43]. A Th2 cytokine profile was observed in Thailand DENV patients presenting high viremia and plasma leakage, which was associated with higher levels of IL-6 and IL-8 at the early phase of disease [73]. ...
The pathogenesis of Dengue virus (DENV) infection is complex and involves viral replication that may trigger an inflammatory response leading to severe disease. Here, we investigated the correlation between viremia and cytokine levels in the serum of DENV-infected patients. Between 2013 and 2014, 138 patients with a diagnosis of acute-phase DENV infection and 22 patients with a non-dengue acute febrile illness (AFI) were enrolled. Through a focus-forming assay (FFU), we determined the viremia levels in DENV-infected patients and observed a peak in the first two days after the onset of symptoms. A higher level of viremia was observed in primary versus secondary DENV-infected patients. Furthermore, no correlation was observed between viremia and inflammatory cytokine levels in DENV-infected patients. Receiver operating characteristic (ROC) curve analysis revealed that IL-2 has the potential to act as a marker to distinguish dengue from other febrile illnesses and is positively correlated with Th1 cytokines. IFN-α and IFN-γ appear to be potential markers of primary versus secondary infection in DENV-infected patients, respectively. The results also indicate that viremia levels are not the main driving force behind inflammation in dengue and that cytokines could be used as infection biomarkers and for differentiation between primary versus secondary infection.
... TNFα, IL6 and IL8 are known to alter the vascular permeability of capillaries, triggering cases of vascular leakage in dengue. (63) The reduced blood flow to the kidney likely leads to an ischemic process, and is the reason for the necrosis of tubular cells. (6) The presence of blood in later portions of the nephron suggests alterations in the kidney filtering capabilities. ...
Background:
Dengue is a disease caused by dengue virus (DENV-1 through -4). Among the four serotypes, DENV-4 remains the least studied. Acute kidney injury is a potential complication of dengue generally associated with severe dengue infection.
Objectives:
The goal of this study was to investigate the alterations caused by experimental dengue infection in the kidney of adult BALB/c mice.
Methods:
In this study, BALB/c mice were infected through the intravenous route with a DENV-4 strain, isolated from a human patient. The kidneys of the mice were procured and subject to histopathological and ultrastructural analysis.
Findings:
The presence of the viral antigen was confirmed through immunohistochemistry. Analysis of tissue sections revealed the presence of inflammatory cell infiltrate throughout the parenchyma. Glomerular enlargement was a common find. Necrosis of tubular cells and haemorrhage were also observed. Analysis of the kidney on a transmission electron microscope allowed a closer look into the necrotic tubular cells, which presented nuclei with condensed chromatin, and loss of cytoplasm.
Main conclusions:
Even though the kidney is probably not a primary target of dengue infection in mice, the inoculation of the virus in the blood appears to damage the renal tissue through local inflammation.
... 27 Among them, there are cells involved in inflammation that are known to play a pivotal role in enhancing the innate immune response and the induction of the adaptive immunity. 46 To compare the cyto-and chemokine profile of DENV vaccine strains, we utilized Multiplex ELISAs analyzed a panel of cyto-and chemokines (IFNα2, IL-10, IL-1β, Il-6, IL-8, IP-10, MCP-1, MIP-1β, RANTES, TNFα) that have been characterized to play an important role in DENV infection. [47][48][49][50][51] We did not observe differences in the secretion between the vaccine viruses for IL-8, MIP-1β, TNFα, and RANTES (Supplementary Figure 1, A-E). ...
Annually, roughly 2.5 billion people are at risk for dengue virus (DENV) infection, and the incidence of infection has increased 30-fold since its discovery in the 1900s. At present, there are no globally licensed antiviral treatments or vaccines that protect against all four of the DENV serotypes. The NIAID Live Attenuated Tetravalent Vaccine (LATV) dengue vaccine candidate is composed of variants of three DENV serotypes attenuated by a 30 nucleotide (Δ30) deletion in the 3' untranslated region and a fourth component that is a chimeric virus in which the prM and E genes of DENV-2 replace those of DENV-4 on the rDEN4Δ30 backbone. The vaccine candidate encodes the non-structural proteins of DENV-1, DENV-3, and DENV-4, which could be of critical importance in the presentation of DENV-specific epitopes in a manner that facilitates antigen presentation and confers higher protection. Our findings demonstrate that the attenuation mechanism (Δ30) resulted in decreased viral infectivity and replication for each vaccine virus in monocyte-derived dendritic cells but were able to generate a robust innate immune response. When tested as monovalent viruses, DEN-4Δ30 displayed the most immunogenic profile. In addition, we found that the tetravalent DENV formulation induced a significantly greater innate immune response than the trivalent formulation. We demonstrate that the presence of two components with a DENV-4Δ30 backbone is necessary for the induction of RANTES, CD40, IP-10, and Type I IFN by the tetravalent formulation. Finally, we found that the DEN-4Δ30 backbone in the DENV-2 component of the vaccine enhanced its antigenic properties, as evidenced by enhanced ability to induce IP-10 and IFNα2 in monocyte-derived dendritic cells. In sum, our study shows that the Δ30 and Δ30/Δ31 mutations attenuate the DENV vaccine strains in terms of replication and infectivity while still allowing the induction of a robust innate immune response.
... Studies have examined cytokine expression in dengue fever and attempted to link this to organ specific complications. Expression of tumor necrosis factor alpha (TNF-α) and interleukin 8 (IL-8), among others, correlate with disease severity of dengue [53][54][55], and severe disease is associated with an excessive and long-lasting inflammatory response with inadequate response to anti-inflammatory cytokines [55]. Increased expression of TNF-α has been associated with decreased myocardial contractile function and worse outcome in heart failure participants PLOS ONE [56], whereas higher levels of IL-8 are associated lower risk of myocardial ischemia [57]. ...
Background
Dengue virus can affect the cardiovascular system and men may be at higher risk of severe complications than women. We hypothesized that clinical dengue virus (DENV) infection could induce myocardial alterations of the left ventricle (LV) and that these changes could be detected by transthoracic echocardiography.
Methodology/Principal findings
We examined individuals from Acre in the Amazon Basin of Brazil in 2020 as part of the Malaria Heart Study. By questionnaires we collected information on self-reported prior dengue infection. All individuals underwent transthoracic echocardiography, analysis of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). We included 521 persons (mean age 40±15 years, 39% men, 50% urban areas) of which 253 (49%) had a history of dengue infection. In multivariable models adjusted for clinical and sociodemographic data, a history of self-reported dengue was significantly associated with lower LVEF (β = -2.37, P < 0.01) and lower GLS (β = 1.08, P < 0.01) in men, whereas no significant associations were found in women (P > 0.05). In line with these findings, men with a history of dengue had higher rates of LV systolic dysfunction (LVEF < 50% = 20%; GLS < 16% = 17%) than those without a history of dengue (LVEF < 50% = 7%; GLS < 16% = 8%; P < 0.01 and 0.06, respectively).
Conclusions/Significance
The findings of this study suggest that a clinical infection by dengue virus could induce myocardial alterations, mainly in men and in the LV, which could be detected by conventional transthoracic echocardiography. Hence, these results highlight a potential role of echocardiography for screening LV dysfunction in participants with a history of dengue infection. Further larger studies are warranted to validate the findings of this study.
