Dengue virus infection: current concepts in immune mechanisms and lessons from murine models

Abstract

Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1-4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection.

Figure 1

Schematics showing the intricate role of chemokines, cytokines and inflammatory leucocytes in the pathogenesis of dengue virus (DENV) infection. After mosquito bite and infection of host skin and bystander immune cells, certain organs such as liver and spleen will become important sites of viral replication and inflammation. The disseminated inflammatory response observed in dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS) will allow a great production of CC chemokines in blood, liver and spleen. This elevated production of chemokines will contribute to local tissue damage and to the recruitment of different leucocyte populations from the capillary veins into the target organs through the activation of chemokine receptors. The spleen and blood appear to be primary and privileged sites of leucocyte activation, especially for T helper type 17 (Th17)/Th22 lymphocytes and thrombocytes, which can express the CCR4 receptor and produce interleukin-22 (IL-22), or produce IL-1β and microparticles, respectively. Once leucocytes are activated they come into contact with CC chemokines (b) and are recruited into the liver. (a) Invariant natural killer T (iNKT) cells can be recruited trough the CCR2 and CCR4 receptors and play a deleterious role in the liver, greatly contributing to tissue injury. Natural killer (NK) cells are the main sources of IL-22 in the hepatic parenchyma, and appear to play a pro-homeostatic role during DENV infection. γδ T cells are major sources of IL-17 in the liver, that together with CC chemokines contribute to the massive inflammatory response observed during DHF/DSS. Targeting the CC chemokines, IL-17A and IL-1 family of cytokines may represent an effective adjunct therapy to attenuate the severity of disease manifestations observed in DHF/DSS.