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Thymosin α1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo
Abstract
Reactivation of latent human cytomegalovirus following allogeneic transplantation is a major cause of morbidity and mortality and predisposes to severe complications. Thymosin α1 (Tα1), a naturally occurring thymic peptide, is approved for treatment of some viral infections and as an immune adjuvant. Tα1 successfully primed dendritic cells (DCs) for anti-microbial T helper type 1 resistance through Toll-like receptor (TLR) 9 signaling. We sought to determine here whether Tα1 could play a role in murine cytomegalovirus infection (MCMV). To this purpose, susceptible, resistant and TLR-deficient mice were infected with MCMV, treated with Tα1 and assessed for protection in term of microbiological and immunological parameters. Tα1 protected susceptible and resistant mice from MCMV infection. The anti-viral effect of Tα1 occurred through the activation of plasmacytoid DCs via the TLR9/myeloid differentiation primary response gene 88-dependent viral recognition sensing, leading to the activation of IFN regulatory factor 7 and the promotion of the IFN-α/IFN-γ-dependent effector pathway.
Introduction
Medical advances such as allogeneic transplantation can expose patients to periods of marked immunosuppression, during which human cytomegalovirus (HCMV) reactivation is a major cause of morbidity and mortality (1–3). HCMV, a member of the Herpesviridae family, is a ubiquitous opportunistic pathogen that has intimate lifelong relationship with its human host and establishes latency after clearance of primary infection (4). Reactivation of latent virus following allogeneic transplantation results in progressive tissue damage manifesting as overt HCMV disease that usually presents as pneumonia, colitis or hepatitis or complications of this infection, including acute and chronic graft rejection, graft-versus-host disease and superinfection by other viruses, bacteria and fungi, particularly Aspergillus spp (3). Currently available anti-viral pharmacotherapy is limited by toxicities and lack of efficacy in established HCMV disease. Efforts have therefore focused on the development of adoptive immunotherapeutic strategies to hasten host immune reconstruction (5–7). Control of infection will depend ultimately on the restoration of adequate anti-viral immunity, and cellular immunotherapy is an attractive approach to improving immune protection (6, 7).
The immune control of murine cytomegalovirus (MCMV) infection requires elements from both innate and adaptive immune systems (4, 8–10). Through the participation of member of the Toll-like receptors (TLRs) (11–13) and IFN regulatory factor (IRF) families (14–16), MCMV induces early dendritic cell (DC)-dependent type I IFN and IL-12 responses that are essential for mouse resistance to MCMV (17–21). The TLR9/myeloid differentiation primary response gene 88 (MyD88)-signaling pathway mediates anti-viral cytokine responses by plasmacytoid dendritic cell (pDC) that, through their unique capacity to secrete IFN-α, and to a lesser extent IL-12 and other innate cytokines, is a cornerstone in the initiation of both innate and adaptive immune responses to MCMV. However, conventional CD11b+DCs also produce IFN-α independently of TLR9 and MyD88 (11, 12, 22). In addition to directly interfering with viral replication through ubiquitous cellular mechanisms, IFN-α controls NK cell cytotoxic activity (18) and regulates T cell functions by activating classical DC to more efficiently present antigens (18). IL-12 and IL-18 secretion are instead required to prime a strong NK cell-dependent IFN-γ response (21, 23, 24), a process that is essential to counteract MCMV infection in the liver, in contrast to a perforin-dependent mechanism in the spleen (25).
Thymosin α1 (Tα1), a naturally occurring thymic peptide, is approved in 30 countries as a biological response modifier for treatment of some viral infections, either as monotherapy or in combination with IFN-α, and as an immune adjuvant (26). Additional indications are some immunodeficiencies, malignancies and acquired immune deficiency syndromes. It has recently been shown that Tα1 modulated DC functioning through direct and indirect effects on TLR9 signaling, thus acting as an endogenous regulator of the innate and adaptive immune systems (27). Given the prominent role of TLR9 as a pattern recognition receptor for murine MCMV, we sought to determine whether Tα1 could play a role in MCMV infection. To this purpose, susceptible, resistant and TLR-deficient mice were infected with MCMV, treated with Tα1 and assessed for protection in term of microbiological and immune parameters. Tα1 decreased the viral load in both susceptible and resistant mice. The anti-viral effect of Tα1 occurred through the activation of pDC via the TLR9/MyD88-dependent viral recognition sensing leading to the activation of IRF7 and the promotion of the IFN-α/IFN-γ-dependent effector pathway.
http://intimm.oxfordjournals.org/content/19/11/1261.full |
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楼主: IC
发表于 2010-11-23 03:54
