An appropriate response by the immune system to viral infection is absolutely critical for survival. A new research study published in the July 2004 issue of Immunity sheds light on the complex and well-orchestrated signals that are mobilized in response to infection with cytomegalovirus.
Cells infected with a virus secrete substances called interferons. Interferon serves to protect other cells from infection by "interfering" with the ability of a virus to make more of itself. Interferon-producing cells (IPCs) are a very small subset of cells in the blood that respond to viral infection by secreting large amounts of interferons and other cytokines, important chemical mediators that stimulate the immune system. It is not clear how IPCs or another interferon-secreting cell type, dendritic cells (DCs), respond to a wide spectrum of viruses. However, a protein called toll-like receptor (TLR) 9 has been implicated.
To better understand how the process is coordinated, Dr. Marco Colonna and colleagues from the Washington University School of Medicine in St. Louis examined immune responses in mice with a systemic murine cytomegalovirus (MCMV) infection. The researchers observed that MCMV causes IPCs and DCs to secrete interferons and other cytokines that activate natural killer (NK) cells that directly attack and kill MCMV-infected cells. IPCs and DCs lacking TLR9 or MyD88, an associated signaling molecule, failed to have this response. Unexpectedly, when IPC cells were experimentally depleted, resulting in a dramatic decrease in interferon levels, other cell types compensated for this deficiency by secreting cytokines that ensured an efficient activation of NK cells and substantial control of MCMV infection.
"In this study, we demonstrate that TLR9 recognizes MCMV in IPC and DC and that TLR9/MyD88 mediates a coordinate cytokine secretion by IPC, DC, and possibly other cell types, which is essential for rapid and efficient activation of antiviral-specific NK cell responses," Colonna explains.
Reference: Krug A, French AR, Barchet W, Fischer JAA, Dzionek A, Pingel JT, Orihuela MM, Akira S, Yokoyama WM, and Colonna M. TLR9-Dependent Recognition of MCMV by IPC and DC Generates Coordinated Cytokine Responses that Activate Antiviral NK Cell Function. Immunity. Vol. 21, No. 1, July 2004, pp. 107-119.