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RNA Sensors Enable Human Mast Cell Anti-Viral Chemokine Production and IFN-Mediated Protection in Response to Antibody-Enhanced Dengue Virus Infection  [PDF]
Michael G. Brown, Sarah M. McAlpine, Yan Y. Huang, Ian D. Haidl, Ayham Al-Afif, Jean S. Marshall, Robert Anderson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034055
Abstract: Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cells are tissue-resident innate immune cells that play a sentinel cell role in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recruitment and normal vascular homeostasis. Most importantly, mast cells are susceptible to antibody-enhanced dengue virus infection and respond with selective cytokine and chemokine responses. In order to obtain a global view of dengue virus-induced gene regulation in mast cells, primary human cord blood-derived mast cells (CBMCs) and the KU812 and HMC-1 mast cell lines were infected with dengue virus in the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cells responded to antibody-enhanced dengue virus infection or polyinosini?polycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokines including CCL4, CCL5 and CXCL10. Multiple interferon-stimulated genes were also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-I and MDA5. Dengue virus-induced chemokine production by KU812 cells was significantly modulated by siRNA knockdown of RIG-I and PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cells provided protection from subsequent infection with dengue virus in a type I interferon-dependent manner. These findings support a role for tissue-resident mast cells in the early detection of antibody-enhanced dengue virus infection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of leukocytes via chemokine production.
The Diagnostic Sensitivity of Dengue Rapid Test Assays Is Significantly Enhanced by Using a Combined Antigen and Antibody Testing Approach  [PDF]
Scott R. Fry,Michelle Meyer,Matthew G. Semple,Cameron P. Simmons,Shamala Devi Sekaran,Johnny X. Huang,Catriona McElnea,Chang-Yi Huang,Andrea Valks,Paul R. Young,Matthew A. Cooper
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001199
Abstract: Background Serological tests for IgM and IgG are routinely used in clinical laboratories for the rapid diagnosis of dengue and can differentiate between primary and secondary infections. Dengue virus non-structural protein 1 (NS1) has been identified as an early marker for acute dengue, and is typically present between days 1–9 post-onset of illness but following seroconversion it can be difficult to detect in serum. Aims To evaluate the performance of a newly developed Panbio? Dengue Early Rapid test for NS1 and determine if it can improve diagnostic sensitivity when used in combination with a commercial IgM/IgG rapid test. Methodology The clinical performance of the Dengue Early Rapid was evaluated in a retrospective study in Vietnam with 198 acute laboratory-confirmed positive and 100 negative samples. The performance of the Dengue Early Rapid in combination with the IgM/IgG Rapid test was also evaluated in Malaysia with 263 laboratory-confirmed positive and 30 negative samples. Key Results In Vietnam the sensitivity and specificity of the test was 69.2% (95% CI: 62.8% to 75.6%) and 96% (95% CI: 92.2% to 99.8) respectively. In Malaysia the performance was similar with 68.9% sensitivity (95% CI: 61.8% to 76.1%) and 96.7% specificity (95% CI: 82.8% to 99.9%) compared to RT-PCR. Importantly, when the Dengue Early Rapid test was used in combination with the IgM/IgG test the sensitivity increased to 93.0%. When the two tests were compared at each day post-onset of illness there was clear differentiation between the antigen and antibody markers. Conclusions This study highlights that using dengue NS1 antigen detection in combination with anti-glycoprotein E IgM and IgG serology can significantly increase the sensitivity of acute dengue diagnosis and extends the possible window of detection to include very early acute samples and enhances the clinical utility of rapid immunochromatographic testing for dengue.
The NS1 Glycoprotein Can Generate Dramatic Antibody-Enhanced Dengue Viral Replication in Normal Out-Bred Mice Resulting in Lethal Multi-Organ Disease  [PDF]
Andrew K. I. Falconar, Fernando Martinez
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021024
Abstract: Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD50) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human “severe dengue” cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice.
Virus Antibody Dynamics in Primary and Secondary Dengue Infections  [PDF]
Tanvi P. Gujarati,G. Ambika
Physics , 2012,
Abstract: Dengue viral infections show unique infection patterns arising from its four serot- ypes, (DENV-1,2,3,4). Its effects range from simple fever in primary infections to potentially fatal secondary infections. We analytically and numerically analyse virus dynamics and humoral response in a host during primary and secondary dengue infection for long periods using micro-epidemic models. The models presented here incorporate time delays, antibody dependent enhancement (ADE), a dynamic switch and a correlation factor between different DENV serotypes. We find that the viral load goes down to undetectable levels within 7-14 days as is observed for dengue infection, in both cases. For primary infection, the stability analysis of steady states shows interesting dependence on the time delay involved in the production of antibodies from plasma cells. We demonstrate the existence of a critical value for the immune response parameter, beyond which the infection gets completely cured. For secondary infections with a different serotype, the homologous antibody production is enhanced due to the influence of heterologous antibodies. The antibody production is also controlled by the correlation factor, which is a measure of similarities between the different DENV serotypes involved. Our results agree with clinically observed humoral responses for primary and secondary infections.
Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification  [PDF]
Scott J. Balsitis equal contributor,Katherine L. Williams equal contributor,Ruben Lachica,Diana Flores,Jennifer L. Kyle,Erin Mehlhop,Syd Johnson,Michael S. Diamond,P. Robert Beatty,Eva Harris
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000790
Abstract: Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.
The Human Antibody Response to Dengue Virus Infection  [PDF]
Wahala M. P. B. Wahala,Aravinda M. de Silva
Viruses , 2011, DOI: 10.3390/v3122374
Abstract: Dengue viruses (DENV) are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). Here we review the current state of knowledge about the human antibody response to dengue and identify important knowledge gaps. A large body of work has demonstrated that antibodies can neutralize or enhance DENV infection. Investigators have mainly used mouse monoclonal antibodies (MAbs) to study interactions between DENV and antibodies. These studies indicate that antibody neutralization of DENVs is a “multi-hit” phenomenon that requires the binding of multiple antibodies to neutralize a virion. The most potently neutralizing mouse MAbs bind to surface exposed epitopes on domain III of the dengue envelope (E) protein. One challenge facing the dengue field now is to extend these studies with mouse MAbs to better understand the human antibody response. The human antibody response is complex as it involves a polyclonal response to primary and secondary infections with 4 different DENV serotypes. Here we review studies conducted with immune sera and MAbs isolated from people exposed to dengue infections. Most dengue-specific antibodies in human immune sera are weakly neutralizing and bind to multiple DENV serotypes. The human antibodies that potently and type specifically neutralize DENV represent a small fraction of the total DENV-specific antibody response. Moreover, these neutralizing antibodies appear to bind to novel epitopes including complex, quaternary epitopes that are only preserved on the intact virion. These studies establish that human and mouse antibodies recognize distinct epitopes on the dengue virion. The leading theory proposed to explain the increased risk of severe disease in secondary cases is antibody dependent enhancement (ADE), which postulates that weakly neutralizing antibodies from the first infection bind to the second serotype and enhance infection of FcγR bearing myeloid cells such as monocytes and macrophages. Here we review results from human, animal and cell culture studies relevant to the ADE hypothesis. By understanding how human antibodies neutralize or enhance DENV, it will be possible to better evaluate existing vaccines and develop the next generation of novel vaccines.
Interaction of Mean Temperature and Daily Fluctuation Influences Dengue Incidence in Dhaka, Bangladesh  [PDF]
Sifat Sharmin?,Kathryn Glass?,Elvina Viennet?,David Harley
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0003901
Abstract: Local weather influences the transmission of the dengue virus. Most studies analyzing the relationship between dengue and climate are based on relatively coarse aggregate measures such as mean temperature. Here, we include both mean temperature and daily fluctuations in temperature in modelling dengue transmission in Dhaka, the capital of Bangladesh. We used a negative binomial generalized linear model, adjusted for rainfall, anomalies in sea surface temperature (an index for El Ni?o-Southern Oscillation), population density, the number of dengue cases in the previous month, and the long term temporal trend in dengue incidence. In addition to the significant associations of mean temperature and temperature fluctuation with dengue incidence, we found interaction of mean and temperature fluctuation significantly influences disease transmission at a lag of one month. High mean temperature with low fluctuation increases dengue incidence one month later. Besides temperature, dengue incidence was also influenced by sea surface temperature anomalies in the current and previous month, presumably as a consequence of concomitant anomalies in the annual rainfall cycle. Population density exerted a significant positive influence on dengue incidence indicating increasing risk of dengue in over-populated Dhaka. Understanding these complex relationships between climate, population, and dengue incidence will help inform outbreak prediction and control.
The Complexity of a Dengue Vaccine: A Review of the Human Antibody Response  [PDF]
Jacky Flipse?,Jolanda M. Smit
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0003749
Abstract: Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV vaccine of Sanofi Pasteur. This vaccine has recently cleared Phase III, and efficacy results have been published. Excellent tetravalent seroconversion was seen, yet the protective efficacy against infection was surprisingly low. Here, we will describe the complicating factors involved in the generation of a safe and efficacious dengue vaccine. Furthermore, we will discuss the human antibody responses during infection, including the epitopes targeted in humans. Also, we will discuss the current understanding of the assays used to evaluate antibody response. We hope this review will aid future dengue vaccine development as well as fundamental research related to the phenomenon of antibody-dependent enhancement of dengue virus infection.
Maternal and perinatal outcomes of dengue in PortSudan, Eastern Sudan
Ishag Adam, Ammar M Jumaa, Hagir M Elbashir, Mubarak S Karsany
Virology Journal , 2010, DOI: 10.1186/1743-422x-7-153
Abstract: This was a retrospective Cohort study where medical files of women with dengue were reviewed.There were 10820 deliveries and 78 (0.7%) pregnant women with confirmed dengue IgM serology at the mean (SD) gestational age of 29.4(8.2) weeks. While the majority of these women had dengue fever (46, 58.9%), hemorrhagic fever and dengue shock syndrome were the presentations in 18 (23.0%) and 12, (15.3%) of these women, respectively. There were 17(21.7%) maternal deaths. Fourteen (17.9%) of these 78 women had preterm deliveries and 19 (24.3%) neonates were admitted to neonatal intensive care unit. Nineteen (24.3%) women gave birth to low birth weight babies. There were seven (8.9%) perinatal deaths. Eight (10.2%) patients delivered by caesarean section due to various obstetrical indications.Thus dengue has poor maternal and perinatal outcomes in this setting. Preventive measures against dengue should be employed in the region, and more research on dengue during pregnancy is needed.Dengue is the most common mosquito-borne infection, with an estimated 100 million infections worldwide per year [1-3]. Many factors like urbanization, increased population density, air travel, and limited resources for dengue prevention has led to dengue becoming a major public health problem in the tropics [3]. Of the 100 million annual infections, 250-500 thousand persons manifest severe disease, with the remainder being mild, nonspecific, or even asymptomatic [1-3].Classic dengue fever (DF) is defined by the World Health Organization as an acute febrile illness with two more of the following signs or symptoms: intense headache, retro-orbital pain, myalgia, arthralgia, rash, leucopenia, and a hemorrhagic manifestation [4]. A small proportion of infected persons develop (dengue hemorrhagic fever (DHF), which is characterized by fever, thrombocytopenia, hemorrhagic manifestations, and increased vascular permeability with plasma leakage primarily into the pleural cavity and peritoneum [5]. The main
The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection  [PDF]
Maria G. Guzman,Susana Vazquez
Viruses , 2010, DOI: 10.3390/v2122649
Abstract: Antibody-dependent enhancement (ADE) has been proposed as a mechanism to explain dengue hemorrhagic fever (DHF) in the course of a secondary dengue infection. Very recently, Dejnirattisai et al., 2010 [1], published an important article supporting the involvement of anti-prM antibodies in the ADE phenomenon. The complexity of ADE in the context of a secondary dengue infection is discussed here.
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