Regulation of innate immune responses in macrophages differentiated in the presence of vitamin D and infected with dengue virus 2

Jorge Andrés Castillo, Diana M. Giraldo, Juan C. Hernandez, Jolanda M. Smit, Izabela A. Rodenhuis-Zybert, Silvio Urcuqui-Inchima*

*Corresponding author for this work

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A dysregulated or exacerbated inflammatory response is thought to be the key driver of the pathogenesis of severe disease caused by the mosquito-borne dengue virus (DENV). Compounds that restrict virus replication and modulate the inflammatory response could thus serve as promising therapeutics mitigating the disease pathogenesis. We and others have previously shown that macrophages, which are important cellular targets for DENV replication, differentiated in the presence of bioactive vitamin D (VitD3) are less permissive to viral replication, and produce lower levels of pro-inflammatory cytokines. Therefore, we here evaluated the extent and kinetics of innate immune responses of DENV-2 infected monocytes differentiated into macrophages in the presence (D-3-MDMs) or absence of VitD3 (MDMs). We found that D-3-MDMs expressed lower levels of RIG I, Toll-like receptor (TLR)3, and TLR7, as well as higher levels of SOCS-1 in response to DENV-2 infection. D-3-MDMs produced lower levels of reactive oxygen species, related to a lower expression of TLR9. Moreover, although VitD3 treatment did not modulate either the expression of IFN-alpha or IFN-beta, higher expression of protein kinase R (PKR) and 2 '-5 '-oligoadenylate synthetase 1 (OAS1) mRNA were found in D-3-MDMs. Importantly, the observed effects were independent of reduced infection, highlighting the intrinsic differences between D-3-MDMs and MDMs. Taken together, our results suggest that differentiation of MDMs in the presence of VitD3 modulates innate immunity in responses to DENV-2 infection.

Author summary

Dengue virus (DENV) accounts for one of the most transmitted mosquito-borne infectious diseases worldwide. While an estimated 390 million infections occur per year, no specific antiviral compounds are available yet. Further, Denvaxia approved vaccine is not fully protective. Research of new therapies that could control infection caused by DENV is thus important to the field. Also, therapies that can modulate the inflammatory immune response, critical for severe progression in DENV-infected patients, may represent good candidates for fighting DENV infections. Here, we continued the research that we have been doing the last years, regarding the antiviral and immunomodulatory properties of Vitamin D (VitD3) against DENV infection in human macrophages, which represent a natural target for DENV replication. We show that VitD3 modulates innate immune responses of macrophages in response to DENV 2 infection, through i) downregulation of TLRs ii) decrease in ROS production, and iii) upregulation of SOCS 1 and IFN-stimulated genes such as PKR and OAS. Our study increases our insights into the mechanisms underlying the antiviral and anti-inflammatory effects of VitD3 in DENV-2 infected macrophages, which ultimately would contribute to the progress of VitD3 as a candidate for anti-DENV therapy.

Original languageEnglish
Article number0009873
Number of pages21
JournalPLoS Neglected Tropical Diseases
Issue number10
Publication statusPublished - Oct-2021



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