Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

Pan, Pan; Zhang, Qi; Liu, Weiyong; Wang, Wenbiao; Yu, Zhenyang; Lao, Zizhao; Zhang, Wei; Shen, Miaomiao; Wan, Pin; Xiao, Feng; Shereen, Muhammad Adnan; Zhang, Wen; Tan, Qiuping; Liu, Yuntao; Liu, Xiaohong; Wu, Kailang; Liu, Yingle; Li, Geng; Wu, Jianguo

doi:10.3389/fmicb.2019.02637

Cited by 37 publications

(44 citation statements)

References 50 publications

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“…This study has shown that TNF-a, IL-1b, and IL-12 levels are significantly elevated in dengue patients compared with HCs and that these proinflammatory cytokine levels are associated with dengue severity in Vietnamese patients with dengue infection. These findings are consistent with previous studies indicating a crucial role of TNF-a, IL-1b, and IL-12 in dengue (6,16,19,20). Elevated cytokine levels may contribute to the increase of vascular permeability, initiation of coagulation, AST, aspartate aminotransferase; ALT, alanine aminotransferase; DENV, dengue virus; DWS-, dengue without warning signs; DWS+, dengue patients with warning signs; HC, healthy controls; HCT, hematocrits; IgG, Immunoglobulin G; IU, international unit; NA, not applicable; NS, not significant; NS1, nonstructural antigen 1; PLT, platelet; RBC, red blood cells; SD, severe dengue; WBC, white blood cells.…”

Section: Discussionsupporting

confidence: 93%

Proinflammatory Cytokines Are Modulated in Vietnamese Patients with Dengue Fever

et al. 2020

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The clinical outcome of dengue is due to a complex interplay between dengue virus (DENV) and host immune factors, including complement and cytokine systems. Proinflammatory cytokines are mainly produced by monocytes in response to infectious pathogens. This study investigated the levels of proinflammatory cytokines, including tumor necrosis factor-a (TNF-a), interleukin-1 beta (IL-1b), and IL-12 in Vietnamese patients with dengue, and their correlations with the clinical outcome of dengue infection in 156 patients clinically classified as dengue without warning signs (DWS-, n = 87), dengue with warning signs (DWS+, n = 62), and severe dengue (SD, n = 7) patients as well as in 60 healthy controls (HCs). Serum TNF-a, IL-1b, and IL-12 levels were quantified by enzyme-linked immunosorbent assay (ELISA). The results showed that TNF-a, IL-1b, and IL-12 levels were significantly increased in dengue patients compared with HCs (p < 0.0001). TNF-a levels were significantly correlated with white blood cells and platelet counts (r s = 0.52, 0.2; p < 0.0001, p = 0.018, respectively). IL-1b levels were correlated with red blood cells counts and the levels of aspartate aminotransferase and alanine aminotransferase (r s = 0.23, 0.21, 0.23; p = 0.004, 0.012, 0.005, respectively). The results suggest that these three proinflammatory cytokines are associated with the clinical outcome of dengue and could play roles in the pathogenesis of the disease.

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Section: Discussionsupporting

confidence: 93%

Proinflammatory Cytokines Are Modulated in Vietnamese Patients with Dengue Fever

et al. 2020

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“…IL-1β is a homolog of IL-1α and uses the same receptor as IL-1α. Pan et al reported that DENV infection induces IL-1β secretion from macrophages in patients and mice, and IL-1β induces vascular leakage in both in vitro vascular endothelial monolayers and in mice, while IL-1Ra alleviates these IL-1β-mediated effects ( 29 ). In agreement with the above studies, the results of our work suggest that IL-1α is a crucial mediator that promotes the incidence of JE by disrupting BBB integrity at a very early stage of infection.…”

Section: Discussionmentioning

confidence: 99%

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Wang

Zhen

Fan

et al. 2020

J Virol

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Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis. Despite vaccination, thousands of deaths attributed to JE are reported annually. In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection. The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1α (IL-1α) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h post infection. Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1α levels. Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting PI3K-Akt signaling. Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1α rather than IL-1β. Finally, we assessed the effect of an IL-1α antagonist and demonstrated that it effectively prevented the incidence of JE. Our results indicate that Axl plays a protective role in JEV infection, identify IL-1α released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1α antagonist may be a candidate for JE therapy. IMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide. The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae. Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections. Currently, the involvement of Axl in JEV infection remains enigmatic. In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion. Furthermore, serum IL-1α is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1α antagonist can effectively reduce the incidence of severe JE. Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of IL-1α antagonist may be a promising tactic to prevent severe JE.

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“…DENV infection mediated IL-1β activation are found in infected patient blood samples, human peripheral blood mononuclear cells (PBMCs) and monocyte-differentiated macrophages (THP-1) as well in C57BL/6 mice and mouse bone marrow derived macrophages (BMDMs). Evidence demonstrates that IL-1β augments tissue injury and leakage in IFNAR-/- C57BL/6 mice, although IL-1 receptor antagonist (IL-1RA) protects from this injury (Pan et al, 2019b ). Together, the collected results reveal the mechanism of DENV pathogenesis and establish the contribution of IL-1β in DENV-associated pathology and recommend the consideration of IL-1RA for effective therapeutics in DENV patients' treatment.…”

Section: Response Of Host Inflammasome To Denv Infectionmentioning

confidence: 99%

Inflammasome Fuels Dengue Severity

Shrivastava

Valenzuela-León

Calvo

2020

Front. Cell. Infect. Microbiol.

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Dengue is an acute febrile disease triggered by dengue virus. Dengue is the widespread and rapidly transmitted mosquito-borne viral disease of humans. Diverse symptoms and diseases due to Dengue virus (DENV) infection ranges from dengue fever, dengue hemorrhagic fever (life-threatening) and dengue shock syndrome characterized by shock, endothelial dysfunction and vascular leakage. Several studies have linked the severity of dengue with the induction of inflammasome. DENV activates the NLRP3-specific inflammasome in DENV infected human patients, mice; specifically, mouse bone marrow derived macrophages (BMDMs), dendritic cells, endothelial cells, human peripheral blood mononuclear cells (PBMCs), keratinocytes, monocyte-differentiated macrophages (THP-1), and platelets. Dengue virus mediated inflammasome initiates the maturation of IL-1β and IL-18, which are critical for dengue pathology and inflammatory response. Several studies have reported the molecular mechanism through which (host and viral factors) dengue induces inflammasome, unravels the possible mechanisms of DENV pathogenesis and sets up the stage for the advancement of DENV therapeutics. In this perspective article, we discuss the potential implications and our understanding of inflammasome mechanisms of dengue virus and highlight research areas that have potential to inhibit the pathogenesis of viral diseases, specifically for dengue.

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Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

Cited by 37 publications

References 50 publications

Proinflammatory Cytokines Are Modulated in Vietnamese Patients with Dengue Fever

Proinflammatory Cytokines Are Modulated in Vietnamese Patients with Dengue Fever

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Inflammasome Fuels Dengue Severity

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