Loss of plasmacytoid dendritic cell function coincides with lymphopenia and viremia during foot-and-mouth disease infection

Authors: NFON, CHARLES - Oak Ridge Institute For Science And Education (ORISE); Toka, Felix; Kenney, Mary; Pacheco Tobin, Juan; Golde, William

Submitted to: Viral Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/9/2009
Publication Date: 1/1/2010
Citation: Nfon, C.K., Toka, F.N., Kenney, M.A., Pacheco Tobin, J., Golde, W.T. 2010. Loss of plasmacytoid dendritic cell function coincides with lymphopenia and viremia during foot-and-mouth disease infection. Viral Immunology. 23(1):29-41.

Interpretive Summary: The pathogenesis of any infection plays a key role in designing the most effective intervention to combat the disease. In the case of foot-and-mouth disease (FMD), the causative virus, FMDV, has evolved to be very contagious and induce a highly acute infection resulting in rapid onset of disease and quick resolution. This new data, and a series of studies we have already published, clearly indicate that the virus induces cellular responses that block cells from producing hormones, called cytokines. An important class of these cytokines are the interferon proteins that are so named because they interfere with viral infections. Interferons are nonspecific, antiviral hormones that induce cellular responses making the cell resistant to infection. These hormones are usually produced early in an infection and have a second role in addition to interfering with viral replication, that of initiating the activation of cells involved in the adaptive immune response. An important blood cell mediating this response, i.e. producing IFN', is the plasmacytoid dendritic cell (pDC). Here we report an analysis of the function of this important population isolated from the blood of animals infected with FMDV. Infection in pigs leads to a block of the pDCs ability to produce interferon alpha. The paper discusses the critical balance between interferon induction blocking virus replication and cellular responses to viral infection that inhibit the animal’s interferon response. The information is useful for further development of effective interventions for FMD.

Technical Abstract: Foot and mouth disease virus (FMDV) causes an acute, highly contagious disease of livestock. Though FMDV is very sensitive to interferon (IFN) alpha, beta, and gamma, the virus has evolved mechanisms to evade such innate responses. For instance, during acute infection, FMDV suppresses IFNa production by skin and myeloid dendritic cells (DCs). We have previously reported that FMDV infection induces a transient lymphopenia and interruption of T lymphocyte responses to mitogenic stimulus. To further understand the immunopathogenesis of FMD, we have now analyzed the serum IFNa response in relation to lymphopenia and the number and function of plasmacytoid DCs (pDCs) following infection of pigs with multiple serotypes of FMDV. Serum IFNa peaked 2-3 days post-infection (PI), irrespective of FMDV serotype. Lymphopenia, coincided with peak viremia and the serum IFNa response. Circulating pDC numbers and in vitro pDC IFNa secretion transiently declined by 48hrs following infection. Infection of lymphocytes or pDCs was never detected regardless of the FMDV serotype inoculated or the age of the animal infected. These data indicate that, like other DC subsets, there is suppression of interferon production by pDCs which abrogates this important innate response. However, rapid induction of serum IFNa, albeit short lived, may contribute to the rapid resolution of FMDV viremia prior induction of specific immunity.