Dengue viruses (DENV) infect up to 390 million individuals each year, of which 500.000 cases require hospitalization (1/S. Bhatt et al., Nature 496, 2013, 2/WHO: Dengue: Guidelines for Diagnosis, treatment, prevention and control, 2009). Since 2012, dengue is the most important vector-borne viral disease of humans and likely more important than malaria globally in terms of morbidity and economic impact (D. J. Gubler, The American journal of tropical medicine and hygiene 86, 2012). The mosquito vectors, Aedes aegypti and Aedes albopictus both thrive well in populated urbanized areas, contributing to the spread of DENV. Costs for dengue treatment are substantially and include both medical care and non-medical costs such as lost working days and preventive measurements and can be estimated to 15-20 USD per person per year. In Cambodia, during the 2006-2008 epidemic, total costs reached between 0.03-0.17 percent of the Gross Domestic Product and was mainly carried by patients themselves (J. Beaute, S. Vong, BMC public health 10, 2010).
DENV is a member of the family Flaviviridae, and consists out of 4 related serotypes (DENV-1 to DENV-4) (L. C. Katzelnick et al., Science 349, 2015). Dengue virus infection results in a range of clinical outcomes, from asymptomatic infection, to classic dengue fever (DF), to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Dengue shock syndrome is characterized by significant loss of intravascular plasma volume leading to hypovolemic shock, and is the most common life-threatening complication of dengue (WHO: Dengue: Guidelines for Diagnosis, treatment, prevention and control, 2009).
Most primary infections are mild and probably provide lifelong protection against the infecting serotype. In contrast, secondary infection with a heterologous DENV serotype can result in more severe dengue, suggesting that primary DENV infection triggers a host memory immune response that can result in either protection or enhancement of subsequent infection (B. R. Murphy, S. S. Whitehead, Annual review of immunology 29, 2011). It remains to be investigated to what extend these mechanisms contribute to human pathogenesis. Due to the incomplete understanding of the relevant adaptive immune responses leading to protection or enhancement of disease in secondary infection and the absence of conclusive biomarkers for protection, vaccine development has been hampered (S. R. Hadinegoro et al., N Engl J Med 373, 2015).
Our research is driven by the hypothesis that proper control of B cell responses such as antigen presentation and regulatory functions are needed for a favorable clinical outcome of secondary flavivirus infection in humans. A deregulated B cell response can lead to exacerbation of disease.