Work

Depletion of myeloid cells in AG129 mice reduces the infection-mediated oxidative stress and restrains dengue virus-induced thymic atrophy

Year: 2025

Type: article

Abstract: Infection-associated thymic atrophy is common and results in T-cell imbalance and immune dysfunction. Severe dengue, caused by infection with the dengue virus (DV), is associated with perturbation of T cell functions. However, it is unclear whether perturbation of T cell functions is linked to changes in thymic function during dengue infection. Herein, we employed a dengue virus serotype 2 (DV-2)-infected mouse model and Neonatal Thymic Organ Culture (NTOC) to study the impact of DV-2 infection on thymic function. Further, the contribution of infiltrating immune cells, especially myeloid cells, and reactive oxygen species (ROS) in the thymus on DV-2-induced thymic atrophy was studied by depleting Gr-1 + myeloid cells and quenching ROS in mice. We have demonstrated that DV-2 infection caused a massive thymic atrophy, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, reduction in naïve T cells in blood and spleen, a significant increase in the infiltration of myeloid cells, and a reactive oxygen species (ROS) burst in the thymus. Using Neonatal Thymic Organ Culture (NTOC), we confirmed that DV-2 infection alone cannot induce thymic atrophy. Further, we documented that depletion of Gr-1 + myeloid cells, or quenching of ROS using N-acetylcysteine (NAC) during DV-2 infection, partially protected thymic architecture. This protection of thymus function is also reflected in the thymic interstitial fluid proteome profile, where myeloid cells depletion or NAC treatment in DV-2-infected mice confirmed the reversal of protein expression associated with oxidative stress and neutrophil degranulation pathways within the thymus. Further, managing oxidative stress also influenced cytokine production by T cells in the spleen of infected mice. Thus, our study confirms that thymic atrophy does not depend on viremia level but on the interaction between immune cells and the virus, highlighting the contribution of infiltrating myeloid cells and, thus, ROS in DV-2-associated thymic atrophy. Dengue virus serotypes 2 & 3 (DV-2, DV-3) infection, but not serotype 1 (DV-1), leads to thymic atrophy in an experimental mouse model. Thymic atrophy depends not on the viremia level but on the specific host-virus interaction. Myeloid cells abundance and ROS level affect thymic output in severe dengue. The thymic interstitial fluid (TIF) protein profile reflects the atrophied. and non-involuted thymus status. Myeloid cells depletion or ROS quenching reverses the thymic atrophy-associated proteins in the TIF. ROS inhibition modulates the cytokine expression profile of T cells in the splenocytes of DV-2-infected mice.

Source: Cell Communication and Signaling

DOI: 10.1186/s12964-025-02572-7