5 Monivong Boulevard, P.O Box. 983, Phnom Penh, Cambodia [email protected]

Dengue is caused by dengue virus (DENV), a virus which can be transmitted by Aedes mosquitos. Currently, half of the world population live in areas at risk of DENV transmission and infection. Vaccine development for the prevention of dengue infection is challenging because there are 4 different serotypes of dengue and an individual can be infected consecutively with different serotypes. Infection by one serotype make the individual more susceptible to severe disease due to a mismatch between the immune response and the infecting virus. This leads to an abnormal and exacerbated immune answer which in the end results in clinical symptoms of ranging severity. The mechanistic understanding of this phenomenon and insight on how to avoid it and re-direct the immune response is essential for the development of effective vaccines.

Our flavivirus research focuses on following aims:

  1. Mechanisms of protection in asymptomatic acute infected individuals

Most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses associated with virus elimination without development of immune-mediated pathology. We investigated the immune responses in Cambodian children without disease compared to hospitalized children after DENV infection. Here, we found important differences in the adaptive immune response associated to outcome of infection

Hence, we aim to understand in detail the mechanisms of generation and protective function of the adaptive immune response in these individuals. We are performing cutting edge high throughput single cell methodologies to deconvolute the immune response on a single cell level in collaborations with our collegues from IP Paris.
Next to neutralization, the humoral immune response provides protection trough Fc-mediated effector functions. Using in vitro cell-based assays our laboratory is deciphering the functional role of DENV-specific IgG in protection or enhancement of infection and disease.

Antibody-effector functions important during DENV infection

  1. biomarkers discovery during flavivirus infection

Dengue virus infection results in a range of clinical outcomes, going from classic dengue fever (DF), to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Dengue shock syndrome is the most common life-threatening complication of dengue. Even though there is no specific treatment for dengue, early identification of severe disease is the most important factor determining patient survival. Therefore we aim to identify novel biomarkers predictive for the development of severe dengue within 96 hours after onset of symptoms in a hospital cohort. Early detection of severe cases will help to identify patients that would benefit from intensive therapy and will help tremendously in patient triage.

  1. Determination of antibody-independent B cell functions during acute DENV infection

Antibodies are produced by terminally differentiated B cells, plasmablasts and plasma cells. However, besides antibody production, B cells have diverse functions and play an important role in antigen presentation, inflammation and cytokine production. In this project, we are investigating the function of B cells during acute DENV infection in protection or enhancement of disease.

  1. Novel vaccine development for DENV prevention

As part of an international consortium we are currently evalualting a new T-cell based vaccine in different animal models of DENV infection. We have shown that a novel polypeptide containing non-structural proteins can activate CD8 T cells in mouse models of infection, and that vaccination with this polypeptide can lower viremia after experimental infection in mice models.

  1. Immune responses to Aedes Mosquito Saliva

DENV is transmitted by mosquitos. During a blood meal, the mosquito ejects a mix of salivary proteins in the epidermis and dermis of the human host. However, little is known about the skin immunity to mosquito saliva and the effect on DENV infection and spread.