Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Abstract

24Toxoplasmic encephalitis is an AIDS-defining condition in HIV + individuals. The decline of 25 IFN-γ-producing CD4 + T cells in AIDS is a major contributing factor in reactivation of 26 quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important 27 to identify CD4-independent mechanisms to control acute T. gondii infection. Here we have 28 investigated the targeted expansion and regulation of IFN-γ production by CD8 + T cells, DN T 29 cells and NK cells in response to T. gondii infection using IL-2 complex (IL2C) pre-treatment 30 in an acute in vivo mouse model. Our results show that expansion of CD8 + T cells, DN T cells 31 and NK cell by S4B6 IL2C treatment increases survival rates of mice infected with T. gondii 32 and this increased survival is dependent on both IL-12-and IL-18-driven IFN-γ production. 33 Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of 34 active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic 35 cell types but independent from T. gondii-derived dense granule (GRA) proteins. Our results 36 provide evidence for a protective role of IL2C-mediated expansion of CD8 + T cells, DN T cells 37 and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute 38 toxoplasmosis. 39 40 41 3 Author Summary 42A third of the world's population is chronically infected with the parasite Toxoplasma gondii. 43 In most cases the infection is asymptomatic, but in individuals suffering from AIDS, 44 reactivation of brain and muscle cysts containing T. gondii is a significant cause of death. The 45 gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing 46 factor in reactivation of T. gondii infection and the development of acute disease. In this study, 47 we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease 48 and premature death via increased availability of interferon gamma-producing immune cells. 49 We also demonstrate that the upstream signaling molecule interleukin-18 is required for the 50 protective immune response by non-CD4 cells and show that the sensing of active parasite 51 invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell 52 expansion may be a promising therapy in toxoplasmosis and suggests that the development of 53 novel intervention strategies targeting danger recognition pathways may be useful against 54 toxoplasmosis, particularly in the context of AIDS. 55 57 [1]. It is estimated that one-third of the world's population is infected with T. gondii. In most 58 individuals, infection is asymptomatic and leads to chronic, life-long persistence of T. gondii-59 containing cysts, primarily in brain and muscle tissue [2]. Active disease, also known as 60 toxoplasmosis, usually occurs after reactivation of encysted parasites, and is often associated 61 with immunosuppression. If untreated, toxoplasmosis may be fatal. Addi...