Activation of the IDO1-GCN2-ATF4-CHOP Pathway During the Massive Generation of Antibody-Secreting Cells in Dengue...

Dengue, a widespread mosquito-borne disease, annually afflicts millions globally, posing substantial mortality risks. Preceding disease defervescence, a marked and transient surge in antibody-secreting cell (ASC) frequency correlates with disease severity, paralleled by heightened tryptophan degradation. Investigating details of this process through single-cell transcriptomics from public repositories, our data pinpoint CD14+ monocytes as principal IDO1 and IDO2 expressors, implicating them, rather than B cells, in initiating tryptophan metabolism. Interestingly, naive B cells exhibit altered gene expression indicative of early impact by tryptophan deficiency before defervescence with a potential impact on the B cell fate. Dengue-induced ASCs upregulated GCN2, PERK, eIF2a, ATF4 genes as well as BIM and CASP-3. However, the high expression of anti-apoptotic genes (FKBP8 [a CHOP-regulated gene], BCL-XL, BCL-2, MCL-1) allows enhanced ASC survival. Proliferation and differentiation-related genes (eIF4EBP1, RRM2, and HIF1a) were also upregulated in ASCs. These findings untangle how Dengue modulates the host metabolism and B-cell responses, although further research is needed to fully understand their implications on disease progression.