NK Cells Activated through Antibody-Dependent Cell Cytotoxicity and Armed with Degranulation/IFN-γ Production Suppress Antibody-dependent Enhancement of Dengue Viral Infection

Abstract

Antibody (Ab)-dependent enhancement (ADE) is a hypothesized mechanism of increased disease severity during secondary dengue virus (DENV) infection. This study investigates Ab-dependent cell cytotoxicity (ADCC) in counteracting ADE. In our system, DENV and DENV-immune sera were added to peripheral blood mononuclear cells (PBMCs), and ADE and NK cell activation were simultaneously monitored. ADE was detected in monocytes and a concurrent activation of NK cells was observed. Activated NK cells expressed IFN-γ and CD107a. IFN-γ was detected at 24 hours (24 h) followed by a rapid decline; CD107a expression peaked at 48 h and persisted for >7 days. Optimal activation of NK cells required the presence of enhancement serum together with ADE-affected monocytes and soluble factors, suggesting the coexistence of the counteractive ADCC Abs, in the same ADE-serum, capable of strongly promoting NK cell activation. The function of NK cells against ADE was demonstrated using a depletion assay. NK cell-depleted PBMCs had increased ADE as compared to whole PBMCs. Conversely, adding activated NK cells back into the NK-depleted-PBMCs or to purified monocytes decreased ADE. Blocking IFN-γ expression also increased ADE. The study suggests that under ADE conditions, NK cells can be activated by ADCC Abs and can control the magnitude of ADE.

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

“…These data suggest that MIC-A/B ligands are central in the cross-talk between NK cells and Mo-DCs in response to DENV infection, and allows to hypothesize that DCs and NK cells coordinate their response through direct contacts to create a positive feedback loop for DCs-derived IL-12 and NK-derived IFN-γ which drives T cell-mediated immunity in response to DENV-2 infection, as also seen after an influenza infection [40]. In a context of ADE/ADCC, monocytes infected by DENV can produce type I IFN (IFN-α), TNF-α, and IL-10, but not IL-12 [41]. It is likely that the ligation of FcR during ADE, in addition to IFN-α and IL-10 cytokines detected in ADE-affected monocytes, suppressed IL-12 production and could explain the short-lived IFN-γ production, detectable at 24 h but not at 48 h post-infection in ADE condition [41].…”

“…In a context of ADE/ADCC, monocytes infected by DENV can produce type I IFN (IFN-α), TNF-α, and IL-10, but not IL-12 [41]. It is likely that the ligation of FcR during ADE, in addition to IFN-α and IL-10 cytokines detected in ADE-affected monocytes, suppressed IL-12 production and could explain the short-lived IFN-γ production, detectable at 24 h but not at 48 h post-infection in ADE condition [41]. These data contrast with our and other data observed in the absence of FcR ligation, in which a high level of IFN-γ production was detected whatever the time post-infection and associated with the production of IL-12 by infected Mo-DCs [42].…”

Aspirin Decreases Hepatocellular Carcinoma Risk in Hepatitis C Virus Carriers: A Nationwide Cohort Study

“…Our hypothesis is that aspirin could relieve chronic inflammation because of inhibition of cyclooxygenase enzyme so lower HCC occurrence at first [24] [25]. However, inhibition of cyclooxygenase enzyme also restrains the immune system, making HCV out of control [26] [27]. Due to accumulation of liver cell damage and duplication of HCV, the HCC incidence rate gradually became higher.…”

Aspirin decreases hepatocellular carcinoma risk in hepatitis C virus carriers: a nationwide cohort study

“…Our hypothesis is that aspirin could relieve chronic inflammation via the inhibition of the cyclooxygenase enzyme, thus lowering the occurrence of HCC at first [31,32]. However, the inhibition of the cyclooxygenase enzyme also restrains the immune system, such that an HCV infection may become uncontrolled [33,34]. Due to the resulting accumulation of liver cell damage and the duplication of HCV, the HCC incidence rate then gradually becomes higher.…”