Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity

The complex interactions between serotype-specific immunity and viral genetics drive dengue disease outcomes in endemic populations. Dissecting Dengue Dynamics In some parts of the world, mosquito bites cause more than a maddening itch. These tiny insect vessels can host dengue viruses (DENVs), which the mosquitoes transmit to human beings. DENVs cause disease states that range in severity from asymptomatic infection to the potentially fatal dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Infection with one DENV serotype offers a person lifelong protection against that serotype and temporary immune protection from severe dengue disease caused by a different DENV serotype. But once this immune-protected period passes, the individual becomes at increased risk for more severe disease. “What line separates the rumble of the wheels from the howl of the wolves? ”1 Now, OhAinle et al. dissect the complex interactions between DENV immunity and viral genetics that drive dengue disease outcomes in endemic Nicaraguan populations. To address this worldwide public health problem, the authors carried out two independent clinical studies of dengue epidemics in Managua, Nicaragua, from 2004/5 to 2008/9. In these populations, patients displayed a striking increase in severe dengue disease outcomes caused by DENV-2 infection across several epidemic seasons. The increase in severe cases in later seasons could be attributed, in part, to waning DENV-1 immunity. However, OhAinle et al. also determined that the increased risk of severe DENV-2–related disease correlated with substitution, in patients, of the Asian/American DENV-2 NI-1 clade with a new virus clade, NI-2B. The authors then molecularly characterized the various viral genomes, assessed the viruses’ fitness levels in vitro, and measured the extent of viremia in patient blood samples; experimental results supported the emergence of a fitter virus in later epidemic seasons. OhAinle et al. also found that the NI-1 clade displayed enhanced virulence specifically in children who had been immune to DENV-1; in contrast, DENV-3 immunity correlated with more severe disease resulting from NI-2B infections. These data highlight the complex interplay between viral genetics and population dynamics that increase the risk of severe dengue disease. This study offers insights into viral evolution and the effects of a patient’s immunological background on viral fitness and virulence. A detailed understanding of DENV epidemiology and pathogenesis should aid in the design of a much-needed dengue vaccine. 1From Invisible Cities by Italo Calvino The rapid spread of dengue is a worldwide public health problem. In two clinical studies of dengue in Managua, Nicaragua, we observed an abrupt increase in disease severity across several epidemic seasons of dengue virus serotype 2 (DENV-2) transmission. Waning DENV-1 immunity appeared to increase the risk of severe disease in subsequent DENV-2 infections after a period of cross-protection. The increase in severity coincided with replacement of the Asian/American DENV-2 NI-1 clade with a new virus clade, NI-2B. In vitro analyses of viral isolates from the two clades and analysis of viremia in patient blood samples support the emergence of a fitter virus in later, relative to earlier, epidemic seasons. In addition, the NI-1 clade of viruses was more virulent specifically in children who were immune to DENV-1, whereas DENV-3 immunity was associated with more severe disease among NI-2B infections. Our data demonstrate that the complex interaction between viral genetics and population dynamics of serotype-specific immunity contributes to the risk of severe dengue disease. Furthermore, this work provides insights into viral evolution and the interaction between viral and immunological determinants of viral fitness and virulence.