Abstract
BackgroundLactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies.Principal FindingsA known inducer of early lymphocyte activation is IFNα, a cytokine strongly induced by LDV infection. Neutralization of IFNα in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFNα in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFNα response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFNα response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFNα response.ConclusionResults indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by TLR7 pattern recognition receptors in pDC's that respond with a lymphocyte-inducing IFNα response.
Highlights
Lactate dehydrogenase-elevating virus (LDV) is a small, positive sense, single stranded RNA virus of the Arteriviridae family, related to coronaviruses such as the severe acute respiratory syndrome (SARS) virus [1,2,3,4]
Results indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by toll-like receptor 7 (TLR7) pattern recognition receptors in plasmacytoid dendritic cells (pDC’s) that respond with a lymphocyte-inducing IFNa response
No clinical signs are typically associated with LDV infections, co-infection with retroviruses can lead to CNS disease under certain circumstances [11,12], and mice infected with LDV have suppressed immune responses [13,14,15,16]
Summary
Lactate dehydrogenase-elevating virus (LDV) is a small, positive sense, single stranded RNA virus of the Arteriviridae family, related to coronaviruses such as the severe acute respiratory syndrome (SARS) virus [1,2,3,4]. We recently found that acute infection with LDV induced a state of partial and transient activation in the vast majority of splenic lymphocytes. CD69 expression is upregulated by T cell receptor (TCR) ligation [18] but is not dependent upon it and can be induced by inflammatory cytokines such as IFNa [19,20].
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