Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules

Abstract

Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection.

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

“…We have also shown that IFN‐γ production by NK cells is profoundly decreased after treatment of DENV‐2‐infected Mo‐DCs with apilimod, which selectively and potently inhibits IL‐12 . Consistently, neutralizing IFN‐γ is sufficient to abolish the NK cell response against DENV in an optimized humanized mouse model , the infection of IL‐12p40 −/− and IL‐18 −/− mice by DENV induces a profound decrease of IFN‐γ production; in association with an increase in disease severity displayed by higher viral loads and enhanced lethality . Similar data were reported in patients infected by DENV‐3 , suggesting that the role of IFN‐γ can be extended to different serotypes of DENV.…”

“…Concerning the activating receptors, the ligands for NKp30 and NKp46 were weakly expressed on DENV‐2‐infected cells and thus are not likely to trigger NK cell functional activity. Consistently, Costa et al showed that cell‐to‐cell contacts between Mo‐DCs and autologous NK cells are important for NK‐cell activation and IFN‐γ production while blocking ligands for natural cytotoxicity receptors; NKp30, NKp44, and NKp46 had a minimal impact in humanized mice. The E protein of DENV interacts directly with NKp44 , expressed predominantly on activated NK cells.…”

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…Furthermore, the mice can be infected through mosquito bites, simulating natural transmission . In addition, studies using NSG mice with transient IL‐15 and Flt3 ligand expression via hydrodynamic injection highlight the importance of NK cells during DENV infection and display infected dendritic cells, which bind directly to, and activate NK cells and subsequently prevent DENV infection in monocytes …”

Liver Dysfunctions in Dengue Infection: An Update on its Pathogenesis

“…In this model dengue virus antigen was detected in the hepatocytes and thus is associated with the altered liver functions [27]. It has recently been understood that dengue infected dendritic cells activate other cells via direct contact mediated mechanism as evident that, dendritic cells activate natural killer cells via the mechanism however its mechanism of disease is not yet properly known [28]. Therefore, it is also suggested that it can be an important mechanism of disease via which dendritic cells activate other cells by physical contact or by way of its mediators [28].…”

“…It has recently been understood that dengue infected dendritic cells activate other cells via direct contact mediated mechanism as evident that, dendritic cells activate natural killer cells via the mechanism however its mechanism of disease is not yet properly known [28]. Therefore, it is also suggested that it can be an important mechanism of disease via which dendritic cells activate other cells by physical contact or by way of its mediators [28]. Evidence from an immunocompetent mice model of study has shown that there is a massive liver damage which is responsible for death [29,30].…”