Abstract
Dengue is a vector-borne viral disease of humans that endemically circulates in many tropical and subtropical regions worldwide. Infection with dengue can result in a range of disease outcomes. A considerable amount of research has sought to improve our understanding of this variation in disease outcomes and to identify predictors of severe disease. Contributing to this research, patterns of viral load in dengue infected patients have been quantified, with analyses indicating that peak viral load levels, rates of viral load decline, and time to peak viremia are useful predictors of severe disease. Here, we take a complementary approach to understanding patterns of clinical manifestation and inter-individual variation in viral load dynamics. Specifically, we statistically fit mathematical within-host models of dengue to individual-level viral load data to test virological and immunological hypotheses explaining inter-individual variation in dengue viral load. We choose between alternative models using model selection criteria to determine which hypotheses are best supported by the data. We first show that the cellular immune response plays an important role in regulating viral load in secondary dengue infections. We then provide statistical support for the process of antibody-dependent enhancement (but not original antigenic sin) in the development of severe disease in secondary dengue infections. Finally, we show statistical support for serotype-specific differences in viral infectivity rates, with infectivity rates of dengue serotypes 2 and 3 exceeding those of serotype 1. These results contribute to our understanding of dengue viral load patterns and their relationship to the development of severe dengue disease. They further have implications for understanding how dengue transmissibility may depend on the immune status of infected individuals and the identity of the infecting serotype.
Highlights
Dengue is an important arthropod-borne virus whose incidence and spatial extent have increased dramatically in recent years [1]
Infection by any one of the four serotypes can result in a range of severity from asymptomatic infection to symptomatic dengue fever (DF) to potentially fatal dengue hemorrhagic fever (DHF)
Our results first indicate that much of the inter-individual variability in dengue viral load dynamics can be explained by differences in the length of individuals’ incubation periods (IP)
Summary
Dengue is an important arthropod-borne virus whose incidence and spatial extent have increased dramatically in recent years [1]. Current understanding of why some dengue-infected individuals develop severe disease while others do not manifest the infection clinically is still limited This is due to the complex relationship between the dengue virus and the immune response [3, 4], the presence of antigenic cross-reactivity between serotypes [3, 5], phenotypic variation between dengue genotypes [6, 7], and the lack of a suitable animal model [8, 9]. Despite limitations in our current understanding of dengue pathogenesis, key risk factors for the development of severe dengue disease have been identified in longitudinal epidemiological studies [10,11,12,13] These studies have shown that the most important risk factor for severe disease manifestation is a secondary heterologous dengue infection [10]. Clinical and experimental studies have indicated that increased disease severity during secondary infection may be explained by poorly-neutralizing antibody responses and suboptimal cross-reactive T-cell responses against the infecting serotype [3, 14,15,16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
