Abstract
Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS). Whether M2-2 regulates the innate immunity in human dendritic cells (DC), an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2) produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT), suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88), an essential adaptor for Toll-like receptors (TLRs), plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.
Highlights
Human metapneumovirus is a recently identified human pathogen belonging to the genus Metapneumovirus in the Pneumovirinae subfamily of the Paramyxoviridae family [1]
We have recently shown that TLR4 is essential in regulating hMPVinduced cellular signaling in human monocytes-derived DC (moDC), while TLR2 and 3 are not important [21]
Human moDC represent an appropriate model for lung Myeloid DC (mDC) because monocytes give rise to mDC in the resting lung [36] and mucosa [37], and are phenotypically similar to dendritic cells (DC) located at the sites of inflammation in vivo [38]
Summary
Human metapneumovirus (hMPV) is a recently identified human pathogen belonging to the genus Metapneumovirus in the Pneumovirinae subfamily of the Paramyxoviridae family [1]. It is a leading cause of lower respiratory tract disease in children, the elderly and immunocompromised patients worldwide [2,3,4,5]. Phosphoprotein P, glycoprotein G, and small hydrophobic SH proteins have been shown to modulate hMPV-induced innate immune response, the first line of host defense against invading pathogens [6,7,8,9]. Whether M2-2 regulates host immunity in other cell types, including human dendritic cells (DC), a family of potent antigen presenting cells (APC), is not currently known
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