Toxoplasmosis is a widespread zoonotic infection caused by the obligate intracellular parasite Toxoplasma gondii (T. gondii) first described in the early 1900s. T. gondii is among the most widely spread parasites, infecting any avian or mammalian cells. Toxoplasmosis has a major medical importance in pregnancy and in immunocompromised patients. The immune response against this parasite starts with its detection by the complement system and the resulting fixation of C3 fragments on its surface.
It has been observed that C5aR1 deficiency leads to an increased parasite load in the brain accompanied by reduction in systemic IL-12 and IFN-ϒ, two major molecules involved in the early immune response to T. gondii, and the subsequent increase in mortality.
NK cells are crucial to IFN-ϒ production during the early stage of T. gondii infection in response to IL-12 from dendritic cells (DCs). It has been found that NK cells do not express C5aR1, instead they express C5aR2. This suggests that C5aR2 plays an important role in IL-12 mediated IFN-ϒ production from NK cells.
To test this, I will be developing new monoclonal antibodies (mAbs) targeting the murine C5aR2 receptor. The mAbs producing clones will be further tested, validated, and commercialized at Hycult Biotech in the Netherlands. Next, the commercialized mAbs will be tested in a 3D cell culture model in Prof. Wilflingseder’s lab at the Medical University of Innsbruck to define the role of C5aR2 on DC, NK cell, and macrophage activation during the early stage of T.gondii infection. Finally, such C5aR2-specific mAbs will be used together with C5aR2 reporter mice to monitor C5aR2 expression in an experimental model of T.gondii infection in mice and to assess the impact of C5aR2 targeting using C5aR2-deficient mice.
