The NS4A Proteins from 4 Dengue Serotypes, Substantially Different in Sequence, Function Similarly to Induce Autophagy and Protect Mammalian Cells using ATM Pathways

There are five serotypes of dengue, a lethal arbovirus that can potentially infect half of humanity. Infection by more than one serotype can produce Antibody Dependent Enhancement (ADE) with devastating consequences. We previously showed that the ability of dengue 2 to induce autophagy is important to the survival of the infected cell and persistence of the virus in the host. Here we evaluate the homology of all 4 dengue serotypes known to infect humans and find that they can trigger autophagy in canine kidney (MDCK) cells and protect infected cells from toxic insults such as Camptothecin (CPT). Thus even though they differ in amino acid sequences they are functionally the same. As is true for the whole virus, NS4A from DEN2 induces autophagy and protects cells by activating ATM. This may be a means by which dengue persists in patients after the acute infection has subsided. All serotypes appear to use the same mechanism.