The role of complement properdin in murine infection with Listeria monocytogenes

Properdin or complement factor P is a conserved serum glycoprotein of the immune defence. It plays a role in strengthening the activation of complement, a system of proteins essential in the first line defence against infection. Properdin is the only positive regulator and plays a major role in regulating the alternative pathway of the complement system, an effector system of the innate immune response, by binding and stabilising two specific converting enzyme complexes, which are normally labile (C3bBb and C3bBbC3b). Mouse models have shown that complement, in particular complement receptor 3 (CR3) and complement 5 (C5), contributes to survival of infection with Listeria monocytogenes. The purpose of the project was to characterise the contribution of properdin in the response to L. monocytogenes (EGD-e), a Gram-positive, intracellular pathogen, which can cause severe infectious disease in human and animals, by using in vitro and in vivo methods. In vitro assays for the first time point to the significant role of properdin in infection with L. monocytogenes: using dendritic cells and macrophages derived from the bone marrows of properdin-deficient (KO) and wild type mice (WT), cells from WT mice showed greater intracellular load of viable L. monocytogenes at an early time point. Cells from KO mice produced less IFN-γ and nitric oxide compared to cells from WT mice and showed less surface expression of CD40. In addition properdin is found to react as a hypoxia sensitive gene; its expression in WT macrophages was also significantly decreased after infection compared to uninfected cells. In vivo experiments demonstrated for the first time that properdin is necessary in the survival of acute murine listeriosis: properdin-deficient mice were more susceptible to intravenous infection with L. monocytogenes compared to wild type mice, and had a greater systemic IFN-gamma and splenic IL-17A response and greater disease severity with impaired M1 type activation. In conclusion, these findings show that properdin is essential in survival of murine listeriosis and in sustaining a cellular response to the intracellular pathogen L. monocytogenes.