scholarly journals Addition of Partial Envelope Domain II into Envelope Domain III of Dengue Virus Antigen Potentiates the Induction of Virus-Neutralizing Antibodies and Induces Protective Immunity

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 88 ◽  
Author(s):  
Jisang Park ◽  
Hyun-Young Lee ◽  
Ly Tuan Khai ◽  
Nguyen Thi Thu Thuy ◽  
Le Quynh Mai ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Fever ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Secondary Infection ◽  
Febrile Illness ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Domain Iii

Dengue virus (DENV) comprises four serotypes in the family Flaviviridae and is a causative agent of dengue-related diseases, including dengue fever. Dengue fever is generally a self-limited febrile illness. However, secondary infection of patients with a suboptimal antibody (Ab) response provokes life-threatening severe dengue hemorrhagic fever or dengue shock syndrome. To develop a potent candidate subunit vaccine against DENV infection, we developed the EDII-cEDIII antigen, which contains partial envelope domain II (EDII) including the fusion loop and BC loop epitopes together with consensus envelope domain III (cEDIII) of all four serotypes of DENV. We purified Ab from mice after immunization with EDII-cEDIII or cEDIII and compared their virus neutralization and Ab-dependent enhancement of DENV infection. Anti-EDII-cEDIII Ab showed stronger neutralizing activity and lower Ab-dependent peak enhancement of DENV infection compared with anti-cEDIII Ab. Following injection of Ab-treated DENV into AG129 mice, anti-EDII-cEDIII Ab ameliorated DENV infection in tissues with primary and secondary infection more effectively than anti-cEDIII Ab. In addition, anti-EDII-cEDIII Ab protected against DENV1, 2, and 4 challenge. We conclude that EDII-cEDIII induces neutralizing and protective Abs, and thus, shows promise as a candidate subunit vaccine for DENV infection.

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

2016 ◽  
Vol 113 (3) ◽  
pp. 728-733 ◽  
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.

scholarly journals Engineered Dengue Virus Domain III Proteins Elicit Cross-Neutralizing Antibody Responses in Mice

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Julia C. Frei ◽  
Ariel S. Wirchnianski ◽  
Jennifer Govero ◽  
Olivia Vergnolle ◽  
Kimberly A. Dowd ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Primary Infection ◽  
Vaccine Development ◽  
Secondary Infection ◽  
Severe Disease ◽  
Febrile Illness ◽  
Neutralizing Antibody ◽  
Immunogen Design ◽  
Domain Iii

ABSTRACTDengue virus is the most globally prevalent mosquito-transmitted virus. Primary infection with one of four cocirculating serotypes (DENV-1 to -4) causes a febrile illness, but secondary infection with a heterologous serotype can result in severe disease, due in part to antibody-dependent enhancement of infection (ADE). In ADE, cross-reactive but nonneutralizing antibodies, or subprotective levels of neutralizing antibodies, promote uptake of antibody-opsonized virus in Fc-γ receptor-positive cells. Thus, elicitation of broadly neutralizing antibodies (bNAbs), but not nonneutralizing antibodies, is desirable for dengue vaccine development. Domain III of the envelope glycoprotein (EDIII) is targeted by bNAbs and thus is an attractive immunogen. However, immunization with EDIII results in sera with limited neutralization breadth. We developed “resurfaced” EDIII immunogens (rsDIIIs) in which the A/G strand epitope that is targeted by bNAb 4E11 is maintained but less desirable epitopes are masked. RsDIIIs bound 4E11, but not serotype-specific or nonneutralizing antibodies. One rsDIII and, unexpectedly, wild-type (WT) DENV-2 EDIII elicited cross-neutralizing antibody responses against DENV-1 to -3 in mice. While these sera were cross-neutralizing, they were not sufficiently potent to protect AG129 immunocompromised mice at a dose of 200 μl (50% focus reduction neutralization titer [FRNT50], ∼1:60 to 1:130) against mouse-adapted DENV-2. Our results provide insight into immunogen design strategies based on EDIII.IMPORTANCEDengue virus causes approximately 390 million infections per year. Primary infection by one serotype causes a self-limiting febrile illness, but secondary infection by a heterologous serotype can result in severe dengue syndrome, which is characterized by hemorrhagic fever and shock syndrome. This severe disease is thought to arise because of cross-reactive, non- or poorly neutralizing antibodies from the primary infection that are present in serum at the time of secondary infection. These cross-reactive antibodies enhance the infection rather than controlling it. Therefore, induction of a broadly and potently neutralizing antibody response is desirable for dengue vaccine development. Here, we explore a novel strategy for developing immunogens based on domain III of the E glycoprotein, where undesirable epitopes (nonneutralizing or nonconserved) are masked by mutation. This work provides fundamental insight into the immune response to domain III that can be leveraged for future immunogen design.

scholarly journals Dengue Virus Targets Nrf2 for NS2B3-Mediated Degradation Leading to Enhanced Oxidative Stress and Viral Replication

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Matteo Ferrari ◽  
Alessandra Zevini ◽  
Enrico Palermo ◽  
Michela Muscolini ◽  
Magdalini Alexandridi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dengue Virus ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Progressive Increase ◽  
Severe Dengue ◽  
Oxygen Species

ABSTRACT Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.

scholarly journals Complexity of Neutralizing Antibodies against Multiple Dengue Virus Serotypes after Heterotypic Immunization and Secondary Infection Revealed by In-Depth Analysis of Cross-Reactive Antibodies

2015 ◽  
Vol 89 (14) ◽  
pp. 7348-7362 ◽  
Author(s):  
Wen-Yang Tsai ◽  
Anna Durbin ◽  
Jih-Jin Tsai ◽  
Szu-Chia Hsieh ◽  
Stephen Whitehead ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Secondary Infection ◽  
Denv Infection ◽  
Primary Immunization ◽  
Dengue Vaccine ◽  
Alternative Strategies ◽  
Live Attenuated Vaccines ◽  
Human Sera ◽  
Arboviral Diseases

ABSTRACTThe four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted of GR and CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.IMPORTANCEThe four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Despite the presence of neutralizing antibodies, a moderate efficacy was recently reported in phase 2b and 3 trials of a dengue vaccine; a better understanding of neutralizing antibodies in polyclonal human sera is urgently needed. We studied vaccinees who received heterotypic immunization of live-attenuated vaccines, as they were known to have received the first and second DENV serotype exposures. We found anti-envelope antibodies consist of group-reactive (GR), complex-reactive (CR), and type-specific (TS) antibodies, and that both GR and CR antibodies contribute significantly to multitypic neutralizing activities after secondary DENV immunization. These findings have implications for alternative strategies for DENV vaccination. Certain TS antibodies were recently discovered to contribute to the monotypic neutralizing activity and protection after primary DENV infection; our findings of the complexity of neutralizing activities after secondary immunization/infection provide new insights for neutralizing antibodies as surrogates of protection.

scholarly journals FEVER AS INDICATOR TO SECONDARY INFECTION IN DENGUE VIRAL INFECTION

2018 ◽  
Vol 7 (1) ◽  
pp. 21
Author(s):  
Soegeng Soegijanto ◽  
Sufiandika Nuryandari ◽  
Siti Churrotin ◽  
Teguh Hari Sucipto
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Viral Infection ◽  
Dengue Fever ◽  
Clinical Manifestation ◽  
Secondary Infection ◽  
Salmonella Typhi ◽  
Severe Dengue ◽  
Concurrent Infection ◽  
Dengue Virus Infection

Dengue Virus Infections are distributed in tropical and sub-tropical regions and transmitted by the mosquitoes such as Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome or dengue and severe dengue classified by World Health Organization. Beside it concurrent infection virus salmonella had been found some cases who showed fever more than 7 days. Concurrent infection with two agents can result in an illness having overlapping symptoms creating a diagnostic dilemma for treating physician, such as dengue fever with typhoid fever. The aim of this research is detection of dengue virus and secondary infection with Salmonella typhi in patients suspected dengue virus infection. Detection of dengue virus and Salmonella typhi using immunochromatography test such as NS1, IgG/IgM for dengue virus infection, and IgM/IgG Salmonella and blood culture. The fifty children with dengue virus infection came to Soerya hospital and 17 cases suspected dengue virus infection, five cases showed a positive NS1 on the second day of fever and one case concurrent with clinical manifestation of convulsi on the third days of fever there were five cases only showed positive. It was showed in this study that on the fourth to six day of fever in dengue virus infection accompanied by antibody IgM & IgG dengue. There were 12 cases showed the clinical manifestation of concurrent dengue viral infection and Salmonella, all of them showed a mild clinical manifestation and did not show plasma leakage and shock. In this study we found the length of stay of concurrent Dengue Virus Infection and Salmonella infection is more than 10 days. These patients were also more likely to have co-existing haemodynamic disturbances and bacterial septicaemia which would have required treatment with inotropes and antibiotics. This idea is very important to make update dengue viral management to decrease mortality in outbreak try to gain new prevention method before the occurrence of outbreak.

scholarly journals Frequency and Clinical Manifestations of Dengue in Urban Medellin, Colombia

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Berta Nelly Restrepo ◽  
Mark E. Beatty ◽  
Yenny Goez ◽  
Ruth E. Ramirez ◽  
G. William Letson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Fever ◽  
Low Income ◽  
Dengue Infection ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Febrile Illness ◽  
Hemorrhagic Fever ◽  
Dengue Virus Infection ◽  
Medical Facilities

A dengue fever surveillance study was conducted at three medical facilities located in the low-income district of San Javier in Medellin, Colombia. During March 2008 to 2009, 781 patients with fever regardless of chief complaint were recruited for acute dengue virus infection testing. Of the 781 tested, 73 (9.3%) were positive for dengue infection. Serotypes DENV-2 (77%) and -3 (23%) were detected by PCR. One patient met the diagnostic criteria for dengue hemorrhagic fever. Only 3 out of 73 (4.1%) febrile subjects testing positive for dengue infection were diagnosed with dengue fever by the treating physician. This study confirms dengue virus as an important cause of acute febrile illness in Medellin, Colombia, but it is difficult to diagnose without dengue diagnostic testing.

scholarly journals High-Avidity and Potently Neutralizing Cross-Reactive Human Monoclonal Antibodies Derived from Secondary Dengue Virus Infection

2013 ◽  
Vol 87 (23) ◽  
pp. 12562-12575 ◽  
Author(s):  
Wen-Yang Tsai ◽  
Chih-Yun Lai ◽  
Yi-Chieh Wu ◽  
Hong-En Lin ◽  
Carolyn Edwards ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Secondary Infection ◽  
Significant Proportion ◽  
Denv Infection ◽  
Protein Domain ◽  
High Avidity ◽  
E Protein

The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies (Abs) and vaccine development. Previous studies of human dengue-immune sera reported that a significant proportion of anti-E Abs, known as group-reactive (GR) Abs, were cross-reactive to all four DENV serotypes and to one or more other flaviviruses. Based on studies of mouse anti-E monoclonal antibodies (MAbs), GR MAbs were nonneutralizing or weakly neutralizing compared with type-specific MAbs; a GR response was thus not regarded as important for vaccine strategy. We investigated the epitopes, binding avidities, and neutralization potencies of 32 human GR anti-E MAbs. In addition to fusion loop (FL) residues in E protein domain II, human GR MAbs recognized an epitope involving both FL and bc loop residues in domain II. The neutralization potencies and binding avidities of GR MAbs derived from secondary DENV infection were stronger than those derived from primary infection. GR MAbs derived from primary DENV infection primarily blocked attachment, whereas those derived from secondary infection blocked DENV postattachment. Analysis of the repertoire of anti-E MAbs derived from patients with primary DENV infection revealed that the majority were GR, low-avidity, and weakly neutralizing MAbs, whereas those from secondary infection were primarily GR, high-avidity, and potently neutralizing MAbs. Our findings suggest that the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potently neutralizing MAbs against the four serotypes after secondary infection. The observation that the dengue immune status of the host affects the quality of the cross-reactive Abs generated has implications for new strategies for DENV vaccination.

scholarly journals Karakteristik Klinis dan Virologis Penderita Demam Berdarah Dengue di Kota Bandar Lampung

2020 ◽  
Vol 12 (2) ◽  
pp. 85-92
Author(s):  
Nurminha Nurminha ◽  
Tori Rihiantoro ◽  
Mara Ipa
Keyword(s):  
Dengue Virus ◽  
Clinical Symptoms ◽  
Serological Test ◽  
Secondary Infection ◽  
Dengue Infection ◽  
Clinical Manifestations ◽  
Denv Infection ◽  
Severe Dengue ◽  
Virus Serotype ◽  
Degree Of Severity

Abstract. Clinical symptoms of dengue virus (DENV) infection range from asymptomatic mild dengue fever(DF), more severe dengue hemorrhagic fever (DHF) up to dengue shock syndrome. One of the determinantsof dengue infection severity was virus virulence. This study aimed to determine the clinical and virologicalcharacteristics of dengue virus infection patients based on the severity degree. A cross-sectional study wasconducted in RSUD Dr. H. Abdul Moeloek, Lampung Province between July-November 2016 with 56 denguepatients as samples selected using purposive sampling. The serological test was done using a rapiddiagnostic test. Blood samples for DENV serotype identification were examined using reverse-transcriptionpolymerase chain reaction. Classification of DENV infection severity was obtained from the patient’s medicalrecord. The results showed that the most common clinical manifestations were fever, headache, and retroorbitalpain, appearing in all patients from every degree of severity. There were Grade I DHF patients whoexperienced Myalgia (15.6%) and petechiae (22.2%). Laboratory results showed that thrombocytopeniaappeared in every grade, even though 13.3% of grade I patients did not experience it. Secondary infectionwas found in 92.9% of samples, and all DENV serotype can be detected in 39.2%samples: DENV-1 (46.7%),DENV-2 (6.7%), DENV-3 (26.7%), and DENV-4 (20%). This study concluded that the majority of clinicalcharacteristics in DHF patients are in line with the degree of severity, with the bleeding as the dominantmanifestation in patients with grade II-IV. Virological characteristics of DENV-1 are dominant in all patientswith DHF grade I-IV.Keywords: dengue virus, serotype, severity, secondary infection, Bandar Lampung

scholarly journals Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Usha K. Nivarthi ◽  
Nurgun Kose ◽  
Gopal Sapparapu ◽  
Douglas Widman ◽  
Emily Gallichotte ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Fever ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Antibody Responses ◽  
Human Antibodies ◽  
E Protein ◽  
Virus Serotype

ABSTRACT The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination. IMPORTANCE The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long-term neutralizing antibody responses, but these principally recognize only the infecting serotype. An effective vaccine against dengue should elicit long-lasting protective antibody responses to all four serotypes simultaneously. We and others have defined antigenic sites on the envelope (E) protein of viruses of dengue virus serotypes 1, 2, and 3 targeted by human neutralizing antibodies. The epitopes on DENV4 E protein targeted by the human neutralizing antibodies and the mechanisms of serotype 4 neutralization are poorly understood. Here, we report the properties of human antibodies that neutralize dengue virus serotype 4. People exposed to serotype 4 infections or a live attenuated serotype 4 vaccine developed neutralizing antibodies that bound to similar sites on the viral E protein. These studies have provided a foundation for developing and evaluating DENV4 vaccines.

scholarly journals Pathogenesis of Dengue virus in Host immune system and its genomic variation

2021 ◽  
Vol 6 (1) ◽  
pp. 16-30
Author(s):  
Sohail Sohail ◽  
Mukarram Farooq ◽  
Fareeha Sohail ◽  
Hamza Rana ◽  
Husnain Karim ◽  
...  
Keyword(s):  
T Cells ◽  
Dengue Virus ◽  
Febrile Illness ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Genomic Variation ◽  
Severe Dengue ◽  
Host Immune System ◽  
Ns1 Protein ◽  
Protein Cleavage

Dengue viruses are the most prevalent arthropod-borne viral diseases in humans, infecting 50-100 million people each year. Its serotypes are the most common causes of arboviral illness, putting half of the world's population at risk of infection. Because there is no vaccine or antiviral medicines, the only way to manage the disease is to reduce the Aedes mosquito vectors. DENV infection can be asymptomatic or cause a self-limiting, acute febrile illness with varying degrees of severity. High fever, headache, stomach discomfort, rash, myalgia, and arthralgia are the typical symptoms of dengue fever (DF). Thrombocytopenia, vascular leakage, and hypotension are symptoms of severe dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Systemic shock characterizes DSS, which can be deadly. Dengue virus infection pathogenesis is linked to a complex interaction between virus, host genes, and host immune response. Major drivers of disease vulnerability include host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity, and genetic variables. The NS1 protein and anti-DENV NS1 antibodies were thought to be involved in the development of severe dengue. The progressive infection may change the cytokine response of cross reactive CD4+ T cells. The need for dengue vaccines that can generate strong protective immunity against all four serotypes is required. To create such vaccines, a thorough understanding of DENV adaptive immunity is required. Structural and functional research have shown that the degree of prM protein cleavage as well as the ensemble of conformational states sampled by virions influence DENV sensitivity to antibody-mediated neutralization, which has crucial implications for vaccine formulation.

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