Development Of Dengue Hemorrhagic Fever Research Articles

Facing the escalating burden of dengue: Challenges and perspectives.

Dengue is the most rapidly emerging mosquito-borne infection and, due to climate change and unplanned urbanization, it is predicted that the global burden of dengue will rise further as the infection spreads to new geographical locations. Dengue-endemic countries are often unable to cope with such increases, with health care facilities becoming overwhelmed during each dengue season. Furthermore, although dengue has been predominantly a childhood illness in the past, it currently mostly affects adults in many countries, with higher incidence of severe disease and mortality rates in pregnant women and in those with comorbidities. As there is currently no specific treatment for dengue and no early biomarker to identify those who will progress to develop vascular leakage, all individuals with dengue are closely monitored in case they need fluid management. Furthermore, diagnosing patients with acute dengue is challenging due to the similarity of clinical symptoms during early illness and poor sensitivity and specificity of point-of-care diagnostic tests. Novel vector control methods, such as the release of Wolbachia-infected mosquitoes, have shown promising results by reducing vector density and dengue incidence in clinical trial settings. A new dengue vaccine, TAK-003, had an efficacy of 61.2% against virologically confirmed dengue, 84.1% efficacy against hospitalizations and a 70% efficacy against development of dengue haemorrhagic fever (DHF) at 54 months. While vaccines and mosquito control methods are welcome, they alone are unlikely to fully reduce the burden of dengue, and a treatment for dengue is therefore essential. Several novel antiviral drugs are currently being evaluated along with drugs that inhibit host mediators, such as mast cell products. Although viral proteins such as NS1 contribute to the vascular leak observed in severe dengue, the host immune response to the viral infection also plays a significant role in progression to severe disease. There is an urgent need to discover safe and effective treatments for dengue to prevent disease progression.

Shapley-Additive-Explanations-Based Factor Analysis for Dengue Severity Prediction using Machine Learning.

Dengue is a viral disease that primarily affects tropical and subtropical regions and is especially prevalent in South-East Asia. This mosquito-borne disease sometimes triggers nationwide epidemics, which results in a large number of fatalities. The development of Dengue Haemorrhagic Fever (DHF) is where most cases occur, and a large portion of them are detected among children under the age of ten, with severe conditions often progressing to a critical state known as Dengue Shock Syndrome (DSS). In this study, we analysed two separate datasets from two different countries– Vietnam and Bangladesh, which we referred as VDengu and BDengue, respectively. For the VDengu dataset, as it was structured, supervised learning models were effective for predictive analysis, among which, the decision tree classifier XGBoost in particular produced the best outcome. Furthermore, Shapley Additive Explanation (SHAP) was used over the XGBoost model to assess the significance of individual attributes of the dataset. Among the significant attributes, we applied the SHAP dependence plot to identify the range for each attribute against the number of DHF or DSS cases. In parallel, the dataset from Bangladesh was unstructured; therefore, we applied an unsupervised learning technique, i.e., hierarchical clustering, to find clusters of vital blood components of the patients according to their complete blood count reports. The clusters were further analysed to find the attributes in the dataset that led to DSS or DHF.

Diagnosis and serotyping of dengue using cost-effective high-resolution melting curve based real time PCR

Dengue virus (DENV) is classified into four serotypes: DENV-1, DENV-2, DENV-3, and DENV-4 which are genetically-related but antigenically distinct types. Although primary infection with a serotype of DENV gives lifelong immunity to that serotype, the secondary infection with other serotype leads to the development of dengue hemorrhagic fever and dengue shock syndrome. Serological tests that can detect NS1 antigen on the day one of illness is nonspecific and less sensitive to diagnose dengue in the first week of illness. IgM and IgG antibody detection may not be positive until the later part of first week. Hence it is necessary to develop a nucleic acid-based test kit for detection of DENV in the early phase of the disease such that the complications can be prevented. Simultaneous detection of serotype of DENV helps in understanding the epidemiology of the disease. In the present study, a single primer pair was designed to 3′ untranslated region of DENV genome. After amplification, the melting temperature (Tm) for DENV-1, DENV-2, DENV-3 and DENV-4 was found to be 83.96 ± 0.58 ˚C, 81.99± 0.26 ˚C, 84.54± 0.15 ˚C, and 83.28 ± 0.12 ˚C, respectively. 

Maternal Immunity and Vaccination Influence Disease Severity in Progeny in a Novel Mast Cell-Deficient Mouse Model of Severe Dengue.

Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to a deficiency in Type-I and II IFN receptors for studying dengue virus (DENV) infection. We used this model to understand the influence of MCs in a maternal antibody-dependent model of severe dengue, where offspring born to DENV-immune mothers are challenged with a heterologous DENV serotype. Mice lacking both MCs and IFN receptors were found susceptible to primary DENV infection and showed morbidity and mortality. When these mice were immunized, pups born to DENV-immune mothers were found to be protected for a longer duration from a heterologous DENV challenge. In the absence of MCs and type-I interferon signaling, IFN-γ was found to protect pups born to naïve mothers but had the opposite effect on pups born to DENV-immune mothers. Our results highlight the complex interactions between MCs and IFN-signaling in influencing the role of maternal antibodies in DENV-induced disease severity.

Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control.

Dengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control. According to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers. DHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations. This study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.

Development of Dengue Hemorrhagic Fever in a Patient within 2 Weeks of Contemporaneous Infection of Typhoid Fever and Primary Dengue Fever

Dengue virus is the most important mosquito-borne viral disease in the world. Co-circulation of the four types of dengue viruses and expansion of dengue epidemic give rise to infection enhancement and a big expansion of clinical aspects of the disease. Besides dengue, typhoid fever is an ancient disease, have emerged as major public health problem in developing countries including Bangladesh. Here we report a case of 4 years old boy, who have developed Dengue Hemorrhagic Fever within 2 weeks of contemporaneous infection of Typhoid fever and Primary dengue fever.
 Anwer Khan Modern Medical College Journal Vol. 11, No. 1: Jan 2020, P 78-81

A clinical and epidemiological survey of the largest dengue outbreak in Southern Taiwan in 2015

ObjectivesThis study examined the epidemiological, clinical, and immunological characteristics of the 2015 dengue outbreak in Taiwan. MethodsClinical data were collected from dengue fever (DF) and dengue hemorrhagic fever (DHF) patients. A phylogenetic tree was used to analyze the source of the outbreak strain. Paired plasma samples from DF/DHF patients were used for antibody-dependent enhancement (ADE) assay and cytokine multiplex biometric immunoassay to validate the immunological mechanism. ResultsThis outbreak mainly occurred in two of the southern cities of Taiwan: Tainan (n=22 777; 52%) and Kaohsiung (n=19 784; 45%). A high DHF death rate was noted (34.6%). The case (DHF) and control (DF) study indicated that older age (>60 years), type II diabetes, and hypertension were risk factors correlated with the development of DHF (p< 0.0001). The phylogenetic tree results suggested that the outbreak-associated strain was dengue virus serotype 2 and cosmopolitan genotype, forming a stable cluster with the isolates from Thailand and Indonesia (bootstrap value of 99%). Cytokine analyses demonstrated that levels of interleukin (IL)-6, IL-4, IL-13, IL-1β, interferon gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly higher in DHF patients compared to DF patients (p< 0.001). The ADE assay showed that diluted plasma containing preexisting dengue antibodies from DHF patients significantly enhanced dengue infection (p< 0.05). ConclusionThe results suggest that older age, type II diabetes, hypertension, immunological cytokine dysregulation, and preexisting dengue antibodies inducing ADE infection are correlated with dengue severity. This study also indicates that the largest dengue outbreak in Taiwan might have been a result of imported DF from dengue epidemic regions.

Protein Disulfide Isomerase Inhibitor Suppresses Viral Replication and Production during Antibody-Dependent Enhancement of Dengue Virus Infection in Human Monocytic Cells.

One of several mechanisms that leads to the development of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) is called antibody-dependent enhancement (ADE). Monocytes can be infected by the ADE phenomenon, which occurs in dengue secondary infection. This study aimed to investigate the proteins involved in ADE of DENV infection in the human monocytic cell line U937. The phosphoproteins were used to perform and analyze for protein expression using mass spectrometry (GeLC-MS/MS). The differential phosphoproteins revealed 1131 altered proteins compared between isotype- and DENV-specific antibody-treated monocytes. The altered proteins revealed 558 upregulated proteins and 573 downregulated proteins. Protein disulfide isomerase (PDI), which is an enzyme that had a high-ranking fold change and that catalyzes the formation, breakage, and rearrangement of disulfide bonds within a protein molecule, was selected for further study. PDI was found to be important for dengue virus infectivity during the ADE model. The effect of PDI inhibition was also shown to be involved in the early stage of life cycle by time-of-drug-addition assay. These results suggest that PDI is important for protein translation and virion assembly of dengue virus during infection in human monocytes, and it may play a significant role as a chaperone to stabilize dengue protein synthesis.

Genome-Wide Analysis to Identify HLA Factors Potentially Associated With Severe Dengue.

The pathogenesis of dengue hemorrhagic fever (DHF), following dengue virus (DENV) infection, is a complex and poorly understood phenomenon. In view of the clinical need of identifying patients with higher likelihood of developing this severe outcome, we undertook a comparative genome-wide association analysis of epitope variants from sequences available in the ViPR database that have been reported to be differentially related to dengue fever and DHF. Having enumerated the incriminated epitope variants, we determined the corresponding HLA alleles in the context of which DENV infection could potentially precipitate DHF. Our analysis considered the development of DHF in three different perspectives: (a) as a consequence of primary DENV infection, (b) following secondary DENV infection with a heterologous serotype, (c) as a result of DENV infection following infection with related flaviviruses like Zika virus, Japanese Encephalitis virus, West Nile virus, etc. Subject to experimental validation, these viral and host markers would be valuable in triaging DENV-infected patients for closer supervision owing to the relatively higher risk of poor prognostic outcome and also for the judicious allocation of scarce institutional resources during large outbreaks.

Association of Single-Nucleotide Polymorphisms in Immune-Related Genes with Development of Dengue Hemorrhagic Fever in a Mexican Population.

Single-nucleotide polymorphisms (SNPs) occurring in immune-related genes have been associated with risk or protection for development of dengue, depending on ethnicity. Here, we genotyped seven SNPs located in immune response-related genes to identify their association with severe forms of dengue in patients from an endemic region in Mexico. One hundred and thirty-eight patients with dengue fever (DF), thirty-one dengue hemorrhagic fever (DHF) patients, as well as 304 healthy donors were genotyped by using a TaqMan-based approach. SNP analysis, including rs1800629 (TNF), rs4804803 (CD209), rs2780831 (JAK1), rs1801274 (FCGR2A), rs231775 (CTLA4), rs12979860, and rs8099917 (IFNL3), was performed. The rs1800629 A-allele in the TNF gene was associated with an increased risk of DHF (OR = 3.4, CI = 1.235-9.284 p = 0.0212) whereas SNPs rs4804803, rs2780831, rs1801274, rs231775, rs12979860, and rs8099917 showed no association in this cohort. These results show that allelic variations in TNF can play an important role in the development of DHF. However, the lack of association between all remaining SNPs and DHF suggests that the genetic background might directly modify the role of these immune-related molecules, leading to the milder illness often observed in a Mexican population.

The Pattern of Adipose Tissue Accumulation during Early Infancy Provides an Environment for the Development of Dengue Hemorrhagic Fever.

BackgroundDengue is the most prevalent arthropod-borne viral illness in humans with half of the world’s population at risk. During early infancy, severe dengue can develop after a primary dengue virus infection. There has been a clinical observation that severe dengue during the first year of life is seen only in chubby infants.Methodology/Principal FindingsWe examined the associations between the development of severe dengue and adipose tissue accumulation patterns during the first year of life in a prospective observational clinical study of infants and dengue virus infections. We found that adipose tissue contains two potential targets for dengue virus infection and production- adipocytes and adipose tissue macrophages. During the first year of life, total body adiposity and visceral adipose tissue stores were at their highest levels in early infancy. Early infancy was also characterized by a relative decrease in alternatively activated (anti-inflammatory) macrophages, and a relative increase in circulating pro-inflammatory cytokines.Conclusions/SignificanceThe data has been used to propose a model where the adipose tissue accumulation pattern and pro-inflammatory environment during early infancy provide the conditions for the potential development of severe dengue in immune-susceptible infants.

Augmented miR-150 expression associated with depressed SOCS1 expression involved in dengue haemorrhagic fever

Suppressors of cytokine signalling (SOCS) proteins regulate cytokine responses and control immune balance. The objective of our study was to determine whether the expression of SOCS1 and its potential regulatory microRNAs (miRNAs) in leukocytes is correlated to the development of dengue haemorrhagic fever (DHF). We performed a case-control study to investigate the SOCS1 and miRNA expression in leukocytes for patients with DF and DHF in a DENV-2 outbreak that occurred in Taiwan between 2002 and 2003. We performed reverse transcription polymerase chain reaction to evaluate the expression of SOCS1 and its regulatory miRNAs in mononuclear leukocytes obtained from patients with or without DHF. The reciprocal relationship between SOCS1 and miR-150 expression was validated in DENV-2-infected peripheral mononuclear cells (PBMCs). SOCS1 expression and lower IFN-γ level were significantly reduced in DHF patients, but not in patients with DF. Elevated SOCS1 and reduced miR-150 levels were detected 24h after DENV-2 infection in PBMCs. Transfection of a miR-150 mimic into CD14(+) cells infected with DENV-2 suppressed the induction of SOCS1 expression in a dose-dependent manner. We demonstrate for the first time that augmented miR-150 expression with depressed SOCS1 expression in CD14(+) cells are associated with the pathogenesis of DHF.

Predictive Value of Proteinuria in Adult Dengue Severity

BackgroundDengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool.Methodology and principal findingsAdult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF.ConclusionsProteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.

Does Comorbidity Increase the Risk of Dengue Hemorrhagic Fever and Dengue Shock Syndrome?

Background. Dengue fever is an emerging public health problem in Pakistan. The aim of this study was to determine the relationship between comorbid conditions in individuals suffering from dengue fever and the development of dengue hemorrhagic fever or dengue shock syndrome. Methods. In this age- and sex-matched case control study, total of 132 cases of dengue hemorrhagic fever/dengue shock syndrome and 249 randomly selected controls were recruited from two major teaching hospitals of Lahore, Pakistan. A semistructured questionnaire was used to collect data through interview and by reviewing clinical records. SPSS version 18 was utilized for statistical analysis including conditional logistic regression. Results. Odds of developing dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) among diabetics are higher than in controls, but this association was not found statistically significant (OR. 1.26; 95% CI. 0.78–2.03; P=0.34). Similarly, no association was observed in individuals suffering from hypertension (OR. 0.93; 95% CI. 0.57–1.49; P=0.76). Odds of developing DHF and DSS were higher for bronchial asthma (adjusted OR. 1.34) and pulmonary tuberculosis (adjusted OR. 1.41); however P values were insignificant. Conclusion. Presence of diabetes mellitus, hypertension, ischemic heart disease and bronchial asthma among patients contracted dengue fever will not increase the risk of dengue hemorrhagic fever and dengue shock syndrome.

The 2011 dengue haemorrhagic fever outbreak in Lahore - an account of clinical parameters and pattern of haemorrhagic complications.

To describe the frequency and outcome of dengue haemorrhagic fever (DHF) cases and determine the association of clinical and laboratory parameters with haemorrhagic complications. A descriptive study. Combined Military Hospital, Lahore, from August to November 2011. Clinical profile and outcome of 640 adult patients hospitalized with a strong clinical suspicion of dengue fever (DF) was evaluated. Based on serological confirmation, these patients were divided into confirmed DF and probable DF cases. They were also categorized according to severity into dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) cases according to WHO guidelines. After detailed clinical evaluation, blood samples were taken for a complete blood count, urea, creatinine, sodium, potassium, bilirubin, alanine aminotransferase (ALT), prothrombin time (PT) and activated partial thromboplastin time (APTT). Patients were managed according to standard protocols with intravenous fluids and symptomatic treatment. SPSS 18 was used for statistical analysis of clinical data. Comparison of features among the groups was made using chi-square or t-test with significance at p < 0.05. There was 359 probable DF and 281 confirmed DF cases. The development of DHF, neurological manifestations and overall mortality was more frequent in confirmed DF group. Comparison between DHF/DSS and DF cases revealed a significant difference in vomiting (p = 0.04), purpuric rash (p < 0.001), systolic blood pressure (p = 0.002), serum ALT (p < 0.001), hospital stay (p < 0.001), neurological involvement (p < 0.001) and coagulopathy (p < 0.001) between the two groups. Among 159 DHF patients, 108 (67.9%) had bleeding from gums and oral cavity, 73 (45.9%) had haemetemesis and 82 (51.5%) malaena, 41 (25.8%) had epistaxis, 12 (7.5%) developed intracranial bleeding, 18 (11%) had hematuria, 12 (7.5%) had fresh bleeding per rectum and 37 (23%) developed haemoptysis. Overall mortality was 3%, but mortality in DHF/DSS cases was 6% and 41.6% for DSS cases. Logistic regression analysis showed that abdominal pain, purpuric rash, ascites, thrombocytopenia, coagulopathy and raised ALT had a statistically significant predictability for developing DHF. A variety of manifestations including that abdominal pain, purpuric rash, ascites, thrombocytopenia, coagulopathy and raised ALT had a statistically significant predictability for developing DHF. A knowledge and understanging of these complictions would be useful for the management of patients if such outbreaks of DHF are encountered again.

Increased Production of Interleukin-4, Interleukin-10, and Granulocyte-Macrophage Colony-Stimulating Factor by Type 2 Diabetes’ Mononuclear Cells Infected with Dengue Virus, but Not Increased Intracellular Viral Multiplication

It has been reported that diabetes mellitus (DM) was an epidemiologically identified risk factor for development of dengue hemorrhagic fever (DHF)/severe dengue in dengue virus (DENV) affected patients, and T helper 2 (Th2) cytokines such as interleukin-4 (IL-4) and IL-10 each plays an important role in the immunopathogenesis of DHF in studies involving general population. To better understand the relationship between these epidemiological and immunological findings, we performed an in vitro study evaluating the sequential immunological reactions and viral load in the DENV infected mononuclear cells of adults with type 2 DM (T2DM group, n = 33) and normal adults (control group, n = 29). We found in the T2DM group significantly higher IL-4 level on the first (P = 0.049) and the third (P = 0.022) postinfection days, while higher IL-10 (P = 0.042) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P = 0.009) were detected on the third postinfection day. No significant difference in DENV viral load between the cultured mononuclear cells from both groups was found on the first and third post-infection days. These data immunologically suggest that patients with T2DM are at higher risk for development of DHF/severe dengue and strengthen the previously epidemiologically identified role of DM being a predictive risk factor for progressing into DHF/severe dengue in DENV-affected patients.

Influence of Human Leukocyte Antigens on Altered Immunopathology of Dendue Virus

Dengue fever has become one of the most important human viral diseases transmitted by arthropod vector in tropical and subtropical countries of the world. As many as 100 million people are infected yearly resulting in estimated 21,000 deaths. DENV has four antigenically related but genetically distinct serotypes (DENV 1-4). Infection with any of the four serotypes may present as asymptomatic or self limiting mild febrile illness known as dengue fever (DF). However , in some dengue-infected individual, the disease progresses to its severe, life-threatening form, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) which may prove fatal without proper early intervention. The pathogenesis of DHF/DSS, however, is not yet completely understood. There are several possible reasons why the primary mild disease progresses to severe form of hemorrhagic manifestations in some individuals. The immune response, Antibody dependent enhancement, virus virulence, and host genetic background are considered risk factors contributing to disease severity . Genetic polymorphisms concerning human leukocyte antigens (HLA) with immunomodulatory effect in dengue infection have been determined in various studies. Human leukocyte antigens (HLA) are highly polymorphic group of genes located on chromosome 6 of human major histocompatibility complex (MHC). HLAs expressed on the cell surface function as antigen presenting molecules and that polymorphism can change individual's immune response. The development of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) has been associated with HLA alleles. Several studies demonstrate the association of various identified versions (alleles) of HLA class I and class II with conferring susceptibility or protection to DHF/DSS. This review discusses recently identified associations of various HLA class I and class II alleles on enhanced or diminished immune response in the course of dengue viral infection, in ethnically and geographically distinct populations.

HLA Class I and Class II Associations in Dengue Viral Infections in a Sri Lankan Population

BackgroundHLA class I and class II alleles have been shown to be associated with the development of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in different populations. However, the majority of studies have been based on limited numbers of patients. In this study we aimed to investigate the HLA-class I and class II alleles that are positively and negatively associated with the development of DSS in a cohort of patients with DHF and also the alleles associated with development of DHF during primary dengue infections in a Sri Lankan population.Methodology/Principal FindingsThe allele frequencies of HLA class I and class II alleles were compared in 110 patients with DHF and 119 individuals from the population who had never reported a symptomatic dengue infection at the time of recruitment. We found that HLA-A*31 (corrected P = 0.01) and DRB1*08 (corrected P = 0.009) were associated with susceptibility to DSS when infected with the dengue virus, during secondary dengue infection. The frequency of DRB1*08 allele was 28.7 times higher than in the normal population in patients with DSS. HLA-A*31 allele was increased 16.6 fold in DHF who developed shock when compared to those who did not develop shock. A*24 (corrected P = 0.03) and DRB1*12 (corrected P = 0.041) were strongly associated with the development of DHF during primary dengue infection.Conclusions/SignificanceThese data suggest that certain HLA alleles confer susceptibility/protection to severe dengue infections. As T cell epitope recognition depend on the HLA type of an individual, it would be now important to investigate how epitope specific T cells associate with primary and secondary dengue infections and in severe dengue infections.

Complement Protein C1q Reduces the Stoichiometric Threshold for Antibody-Mediated Neutralization of West Nile Virus

Virus neutralization is governed by the number of antibodies that bind a virion during the cellular entry process. Cellular and serum factors that interact with antibodies have the potential to modulate neutralization potency. Although the addition of serum complement can increase the neutralizing activity of antiviral antibodies in vitro, the mechanism and significance of this augmented potency in vivo remain uncertain. Herein, we show that the complement component C1q increases the potency of antibodies against West Nile virus by modulating the stoichiometric requirements for neutralization. The addition of C1q does not result in virolysis but instead reduces the number of antibodies that must bind the virion to neutralize infectivity. For IgG subclasses that bind C1q avidly, this reduced stoichiometric threshold falls below the minimal number of antibodies required for antibody-dependent enhancement (ADE) of infection of cells expressing Fc-gamma receptors (CD32) and explains how C1q restricts the ADE of flavivirus infection.

Polymorphisms of the TAP 1 and 2 Gene May Influence Clinical Outcome of Primary Dengue Viral Infection

Antigen peptides are actively transported across the endoplasmic reticulum by the transporters associated with antigen presentation (TAP). TAP genes polymorphism could influence the selection process that determines which antigen peptides play a role in the pathogenesis of dengue infection. The aim of this study was to investigate the association of TAP genes polymorphism in diverse pathogenesis of dengue infection. This study included 197 dengue-infected patients who were further categorized into 64, 23 and 11 primary dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) cases, respectively and 26, 52, and 21 secondary DF, DHF and DSS cases, respectively as per WHO grading system. TAP1 and 2 gene polymorphisms were performed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Analysis of TAP1 gene polymorphism demonstrated decreased frequency of Ile/Ile genotype at TAP1(333) in primary DHF cases (39.1%) when compared with primary DF (64.1%, P < 0.034, OR = 0.611). The genotype frequency of Val/Val at TAP2(379) locus was significantly decreased among primary DHF (43.5%) in comparison to primary DF (71.9%, P = 0.015, OR = 0.605). Significant low proportion of primary DSS were found to have TAP1(637) Asp/Asp genotypes (54.5%) when compared with primary DF (70.3%, P = 0.043). Asp/Asp genotype at TAP1(637) was found to reduce the risk by 0.643 times for primary DSS. There was no significant difference in the genotypes studied between primary and secondary infection and also within secondary dengue infection in all three clinical groups. This report on TAP gene polymorphisms in dengue suggested that among the primary-infected individuals, homozygous patterns for Ile at TAP1(333) Val at TAP2(379) loci and Asp at TAP1(637) were found to be a protective factor against development of DHF and DSS, respectively.