Question

1. The primary host cell targets of Dengue Virus (DENV) are macrophages and dendritic cells. Discuss how Fc? receptors may contribute to the proliferation of infection in host cells, and state what type of hypersensitivity reaction this would represent.

Answer 1

Dendritic cells (DCs) are immune cells that migrate and reside in barrier tissues such as skin and mucosal epithelium during infection. When one dengue virus subtype infects a host, antibodies are generated to the viral surface antigens. In a second infection with another subtype of the virus, the antibodies are generated to the surface antigens, which are similar for the four subtypes. As these antibodies are non-specific, they cannot neutralize the infection. However, they can trigger antibody dependent enhancement (ADE). In ADE, sub-neutralizing concentrations of cross reactive anti-DENV antibodies allow entry of the dengue virus into host cells that have Fcgamma receptors. Thus, the virus can multiply within these cells and increase the viral load, leading to more severe infection.

Dengue virus shows enhance infection of macrophages and dendritic cells when there are anti-DENV antibodies. Most myeloid cells express Fcgamma receptors, which can bind to Fc portion on the antibodies. Binding of Fc to the receptors leads to transmission of activating or inhibitory signals to the cells. Only Fc?RI and Fc?RIIA mediate enhanced DENV infection in the host cells.

The viruses enter cells via receptor-mediated endocytosis. Replication is initiated in the cytoplasm. The viruses partially inhibit protein and RNA synthesis of host cells.

Two types of suppression pathways are activated. These include the deoxyadenosine kinase (DAK), NF-?B activator pathway along with IL-10 pathway. These pathways downregulate antiviral responses in target cells. There is reduced synthesis of inflammatory cytokines by the host cell. Nitric oxide pathway is also inhibited. As a result, the virus proliferates in these host cells.

This is type III hypersensitivity response wherein there is formation of immune complexes. It leads to Dengue haemorrhagic fever and shock syndrome.