IL-18: The Forgotten Cytokine in Dengue Immunopathogenesis

Dengue fever is an infection by the dengue virus (DENV) transmitted by vector mosquitoes. It causes many infections in tropical and subtropical countries every year, thus posing a severe disease threat. Cytokine storms, one condition where many proinflammatory cytokines are mass-produced, might lead to cellular dysfunction in tissue/organ failures and often facilitate severe dengue disease in patients. Interleukin- (IL-) 18, similar to IL-1β, is a proinflammatory cytokine produced during inflammation following inflammasome activation. Inflammatory stimuli, including microbial infections, damage signals, and cytokines, all induce the production of IL-18. High serum IL-18 is remarkably correlated with severely ill dengue patients; however, its possible roles have been less explored. Based on the clinical and basic findings, this review discusses the potential immunopathogenic role of IL-18 when it participates in DENV infection and dengue disease progression based on existing findings and related past studies.

Download Full-text

Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II - DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis

Dengue Fever in a One Health Perspective ◽

10.5772/intechopen.93551 ◽

2020 ◽

Author(s):

Henry Puerta-Guardo ◽

Scott B. Biering ◽

Eva Harris ◽

Norma Pavia-Ruz ◽

Gonzalo Vázquez-Prokopec ◽

...

Keyword(s):

Immune Responses ◽

Nonstructural Protein ◽

Severe Disease ◽

Critical Role ◽

Denv Infection ◽

Severe Dengue ◽

Adaptive Immune Responses ◽

Dengue Disease ◽

Adaptive Immune ◽

Monocytes And Macrophages

Severe disease is associated with serial infection with DENV of different serotypes. Thus, primary DENV infections normally cause asymptomatic infections, and secondary heterotypic infections with a new DENV serotype potentially increase the risks of developing severe disease. Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc-γ-receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity. In addition to the adaptive immune responses, a secreted viral factor known as the nonstructural protein 1 (NS1) has been recently proposed as the missing corner piece of the DENV pathogenesis influencing disease. This Part II of the chapter will discuss the interplay between the distinct host adaptive immune responses and viral factors that together contribute to the development of DENV pathogenesis and severe disease.

Download Full-text

Changes in complement alternative pathway components, factor B and factor H during dengue virus infection in the AG129 mouse

Journal of General Virology ◽

10.1099/jgv.0.001547 ◽

2021 ◽

Author(s):

Sheila Cabezas-Falcon ◽

Aidan J. Norbury ◽

Jarrod Hulme-Jones ◽

Sonja Klebe ◽

Penelope Adamson ◽

...

Keyword(s):

Dengue Virus ◽

Alternative Pathway ◽

Severe Disease ◽

Denv Infection ◽

Factor H ◽

Severe Dengue ◽

Complement Alternative Pathway ◽

Factor B ◽

Dengue Disease

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

Download Full-text

Zika virus infection enhances future risk of severe dengue disease

Science ◽

10.1126/science.abb6143 ◽

2020 ◽

Vol 369 (6507) ◽

pp. 1123-1128 ◽

Cited By ~ 15

Author(s):

Leah C. Katzelnick ◽

César Narvaez ◽

Sonia Arguello ◽

Brenda Lopez Mercado ◽

Damaris Collado ◽

...

Keyword(s):

Zika Virus ◽

Severe Disease ◽

Denv Infection ◽

Severe Dengue ◽

Zikv Infection ◽

Dengue Disease ◽

Antibody Titers ◽

Dengue Virus Serotypes ◽

Future Risk ◽

Denv2 Infection

The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.

Download Full-text

Pathogenesis of Dengue: Dawn of a New Era

F1000Research ◽

10.12688/f1000research.7024.1 ◽

2015 ◽

Vol 4 ◽

pp. 1353 ◽

Cited By ~ 35

Author(s):

Scott B. Halstead

Keyword(s):

Severe Disease ◽

Dengue Shock Syndrome ◽

Hemorrhagic Fever ◽

Denv Infection ◽

Severe Dengue ◽

Structural Protein ◽

New Era ◽

Dengue Disease ◽

Toll Receptor

Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings

Download Full-text

Antibody-dependent enhancement of severe dengue disease in humans

Science ◽

10.1126/science.aan6836 ◽

2017 ◽

Vol 358 (6365) ◽

pp. 929-932 ◽

Cited By ~ 359

Author(s):

Leah C. Katzelnick ◽

Lionel Gresh ◽

M. Elizabeth Halloran ◽

Juan Carlos Mercado ◽

Guillermina Kuan ◽

...

Keyword(s):

Vaccine Development ◽

Severe Disease ◽

Severe Dengue ◽

Antibody Dependent Enhancement ◽

Dengue Disease ◽

Symptomatic Disease ◽

Immune Correlates ◽

Antibody Titers ◽

Approaches To Study

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

Download Full-text

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Journal of Virology ◽

10.1128/jvi.02207-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1587-1607 ◽

Cited By ~ 24

Author(s):

Nuntaya Punyadee ◽

Dumrong Mairiang ◽

Somchai Thiemmeca ◽

Chulaluk Komoltri ◽

Wirichada Pan-ngum ◽

...

Keyword(s):

Cell Death ◽

Blood Cell ◽

Dengue Virus ◽

Red Blood Cell ◽

Severe Disease ◽

Denv Infection ◽

Severe Dengue ◽

Bleeding Tendency ◽

Nonstructural Protein 1 ◽

Low Levels

ABSTRACTShedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces.Ex vivoanalysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1–anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP sheddingin vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever.IMPORTANCEDengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care.

Download Full-text

Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1522136113 ◽

2016 ◽

Vol 113 (3) ◽

pp. 728-733 ◽

Cited By ~ 89

Author(s):

Leah C. Katzelnick ◽

Magelda Montoya ◽

Lionel Gresh ◽

Angel Balmaseda ◽

Eva Harris

Keyword(s):

Dengue Virus ◽

Neutralizing Antibodies ◽

Secondary Infection ◽

Severe Disease ◽

Neutralizing Antibody ◽

Denv Infection ◽

Severe Dengue ◽

Symptomatic Infection ◽

Denv Serotypes ◽

Antibody Titers

The four dengue virus serotypes (DENV1–4) are mosquito-borne flaviviruses that infect ∼390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.

Download Full-text

Comparative analysis reveals no consistent association between the secondary structure of the 3′-untranslated region of dengue viruses and disease syndrome

Journal of General Virology ◽

10.1099/vir.0.81994-0 ◽

2006 ◽

Vol 87 (9) ◽

pp. 2595-2603 ◽

Cited By ~ 13

Author(s):

Yang Zhou ◽

Mammen P. Mammen ◽

Chonticha Klungthong ◽

Piyawan Chinnawirotpisan ◽

David W. Vaughn ◽

...

Keyword(s):

Genetic Variation ◽

Comparative Analysis ◽

Secondary Structure ◽

Untranslated Region ◽

Denv Infection ◽

Viral Fitness ◽

Severe Dengue ◽

Dengue Disease ◽

Structural Interactions ◽

Complex Structural

A comparative analysis was performed of the 3′-untranslated region (UTR) of Dengue virus (DENV) sampled from Bangkok, Thailand, over a 30 year period and representing all four serotypes. Considerable genetic variation was observed both within and among serotypes. Notably, a full-length version of the critical 3′-long stable hairpin structure was absent from some isolates, suggesting the occurrence of complex structural interactions within the 3′-UTR, including the influence of upstream mutations. The Thai sequences were then combined with 61 globally sampled isolates of DENV taken from patients with either dengue fever or severe dengue disease. No consistent association was found between 3′-UTR secondary structure and the clinical outcome of DENV infection, although some evidence for a trend in this direction was observed in DENV-2. It was concluded that the 3′-UTR is not the sole determinant of DENV virulence in nature, although variation in secondary structure may greatly influence viral fitness.

Download Full-text

Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue

Frontiers in Immunology ◽

10.3389/fimmu.2020.605087 ◽

2020 ◽

Vol 11 ◽

Author(s):

Vinit Upasani ◽

Carolina Scagnolari ◽

Federica Frasca ◽

Nikaïa Smith ◽

Vincent Bondet ◽

...

Keyword(s):

Single Molecule ◽

Dengue Shock Syndrome ◽

Hemorrhagic Fever ◽

Denv Infection ◽

Type I Interferons ◽

Severe Dengue ◽

Type I ◽

Type I Ifn ◽

Dengue Disease ◽

Healthy Donors

The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.

Download Full-text

Serum IL-18 Is a Potential Biomarker for Predicting Severe Dengue Disease Progression

Journal of Immunology Research ◽

10.1155/2021/7652569 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Josephine Diony Nanda ◽

Chiau-Jing Jung ◽

Rahmat Dani Satria ◽

Ming-Kai Jhan ◽

Ting-Jing Shen ◽

...

Keyword(s):

Acute Phase ◽

Disease Onset ◽

Dengue Shock Syndrome ◽

Hemorrhagic Fever ◽

Denv Infection ◽

Severe Dengue ◽

Dengue Disease ◽

Potential Biomarker ◽

Tnf Α ◽

Principal Finding

Background. Dengue virus (DENV) infection is the most common arboviral disease that affects tropical and subtropical regions. Based on the clinical hallmarks, the different severities of patients range from mild dengue fever (MDF) to severe dengue diseases (SDDs) and include dengue hemorrhagic fever or dengue shock syndrome. These are commonly associated with cytokine release syndrome (CRS). The types and levels of cytokines/chemokines, which are suppressed or enhanced, are varied, indicating CRS’s pathogenic and host defensive effects. Principal Finding. In this study, we created an integrated and precise multiplex panel of cytokine/chemokine assays based on our literature analysis to monitor dengue CRS. A 24-plex panel of cytokines/chemokines was evaluated to measure the plasma levels of targeting factors in dengue patients with an MDF and SDD diagnosis without or with comorbidities. As identified in sixteen kinds of cytokines/chemokines, ten were significantly ( P < 0.05 ) (10/16) increased, one was significantly ( P < 0.01 ) (1/16) decreased, and five were potentially (5/16) altered in all dengue patients ( n = 30 ) in the acute phase of disease onset. Compared to MDF, the levels of IL-8 (CXCL-8) and IL-18 in SDD were markedly ( P < 0.05 ) increased, accompanied by positively increased IL-6 and TNF-α and decreased IFN-γ and RANTES. With comorbidities, SDD significantly ( P < 0.01 ) portrayed elevated IL-18 accompanied by increased IL-6 and decreased IFN-α2 and IL-12. In addition, decreased platelets were significantly ( P < 0.05 ) associated with increased IL-18. Significance. These results demonstrate an efficient panel of dengue cytokine/chemokine assays used to explore the possible level of CRS during the acute phase of disease onset; also, we are the first to report the increase of IL-18 in severe dengue with comorbidity compared to severe dengue without comorbidity and mild dengue.

Download Full-text