An early activated CD38highCD209highCD36low monocyte phenotype is associated with progression to severe dengue

Background: Although monocytes are among the principal target cells of dengue virus (DENV) infection we sought to investigate monocyte phenotypic markers associated with disease severity and evaluate their potential as prognostic biomarkers and therapeutic targets. Methods: Differences in monocyte subpopulations and phenotypic markers were assessed by flow cytometry in patients with dengue fever (DF=33) and dengue haemorrhagic fever (DHF=21) and compared to health controls (HCs=20). Further in vitro experiments were done by co-culturing peripheral blood mononucleocytes (PBMCs) of healthy individuals (n=8) with DENV2, DENV3, NS1 antigen of both serotypes and LPS. The changes in expression of CD36 and CD38 in vitro in monocytes were assessed. Results: A significant expansion of intermediate monocytes and a contraction of the classical monocytes was seen in patients with DHF compared to DF and HCs, with no significant differences within the non-classical monocytes. Patients who progressed to develop DHF, exhibited an activated monocyte phenotype characterized by, expansion of CD38high, CD209high, CD86high, HLA-DRhigh, CD36low, intermediate monocyte subset. The highest expression of CD38 and CD86 was seen in non-classical monocytes, and CD209 and HLA-DR in intermediate monocytes. Most significant downregulation of CD36 was observed in non-classical monocytes. CD38 expression on monocytes (especially classical monocytes) positively and significantly correlated with liver transaminases and serum ferritin levels. Co-culture of PBMCs with DENV3 led to significant downregulation of CD36 (p=0.023). Conclusions: These results suggest that early alterations in monocyte activation, antigen presentation, viral entry, and lipid sensing pathways contribute to dengue immunopathogenesis.