Dr Juthathip Monkgolsapaya

Immunopathogenesis of dengue haemorrhagic fever

Our research has focussed on the immunopathogenesis of dengue haemorrhagic fever. Dengue virus is an arthropod-borne flavivirus, which can be subdivided into 4 major serotypes, Dengue 1-4. Dengue virus infections are now one of the biggest threats to public health in a number of developing countries. The majority of infections is asymptomatic or causes a self-limiting febrile illness known as Dengue fever (DF). The more severe form of Dengue infection, Dengue haemorrhagic fever (DHF) may be life threatening. Today, some 2.5 billion people are at risk of infection and there are estimated to be around 50 million Dengue infections per year.

The pathogenesis of DHF is not fully characterized, but key epidemiological studies indicate that it often, but not always, occurs when a Dengue immune person becomes secondarily infected with a dengue virus of different serotype. And pre-existing dengue-specific immunity, both humoral and cellular systems, is proposed to be a key factor. On a humoral arm, antibody-dependent enhancement has been proposed where by antibodies generated to a previous infection may not be of high enough avidity or titre to neutralise a second serotype, but may instead enhance infection of Fc receptor baring cells driving higher viral loads. On a cellular arm, we have demonstrated that, during the secondary infection, partial cross-reactive memory T cells from the first infection seem to show suboptimal cytotoxicity but high proinflammatory production which may contribute to the severe disease.

Because of the scale of the problem there is an urgent need for a vaccine. Dengue vaccines have been the subject of much research over the last three decades and although there are several promising candidates under evaluation full scale phase 3 trials seem some way off. In close collaboration with Prof. Gavin Screaton at Imperial College and Dr Prida Malasit at Mahidol University Thailand, we have pursued our study on the roles of both arms of immune system. The research would aid in both the design and evaluation of Dengue vaccines.

Publications:

1. Dejnirattisai W, Duangchinda T, Lin CL, Vasanawathana S, Jones M, Jacobs M, Malasit P, Xu XN, Screaton G, Mongkolsapaya J.(2008). A complex interplay among virus, dendritic cells, T cells, and cytokines in dengue virus infections. J Immunol. 181:5865-74.  Publishers weblink

2. Chotiyarnwong P, Stewart-Jones GB, Tarry MJ, Dejnirattisai W, Siebold C, Koch M, Stuart DI, Harlos K, Malasit P, Screaton G, Mongkolsapaya J, Jones EY. (2007). Humidity control as a strategy for lattice optimization applied to crystals of HLA-A*1101 complexed with variant peptides from dengue virus. Acta Crystallogr Sect F Struct Biol Cryst Commun. 63:386-92.  Publishers weblink

3. Mongkolsapaya J, Duangchinda T, Dejnirattisai W, Vasanawathana S, Avirutnan P, Jairungsri A, Khemnu N, Tangthawornchaikul N, Chotiyarnwong P, Sae-Jang K, Koch M, Jones Y, McMichael A, Xu X, Malasit P, Screaton G. (2006). T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal? J Immunol.176:3821-9.  Publishers weblink

4. Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S, Yenchitsomanus PT, McMichael A, Malasit P, Screaton G. (2003). Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 9:921-7. Publishers weblink