Protective Roles of CD180 and NOD1 in the Protective Immunity Against Cerebral Toxoplasma Infection

The molecules that recognize pathogen-associated molecular patterns (PAMPs) are an important first-line defense system to detect an invasion and proliferation of pathogens and promptly activate the protective immunity to eradicate them. Toxoplasma gondii establishes chronic infection in the brain, and reactivation of this chronic infection can cause potentially sever encephalitis. For preventing this disease, the immune system needs to promptly detect proliferation of tachyzoites (the acute stage form) in the brain during the early stage of reactivation of the infection to efficiently activate the protective immunity. Therefore, the defense system that recognizes the PAMPs-recognizing molecules expressed in the brain should play crucial roles in this first-line defense system for effectively preventing reactivation of this infection. However, the roles of the PAMPs- recognizing molecules in the host defense against reactivation of cerebral T. gondii infection remain unknown. We previously identified that IFN-g is required for the protective immunity to prevent reactivation of the infection. Our studies also identified that microglia, tissue-resident macrophages in the brain parenchyma, produce IFN-g in response to cerebral tachyzoite proliferation, and that production of IFN-g by brain-resident cells, in addition to T cells, is critical for preventing reactivation of T. gondii infection. Notably, our recent study revealed that cerebral mRNA levels for two PAMPs-recognizing molecules, CD180 and nucleotide oligomerization domain 1 (NOD1), markedly increase in association with IFN-g production by brain-resident cells during reactivation of T. gondii infection. CD180 is expressed on microglia and classified as one of sensomes of microglia for sensing endogenous ligands and microbes in both humans and mice. Therefore, it would be possible that CD180 recognizes tachyzoite-derived molecules and activates IFN-g production by microglia. Macrophages also play important roles in preventing cerebral tachyzoite growth, and CD180 is expressed on macrophages. CD180 has also been shown to upregulate TNF-a expression. Since TNF-a plays important roles in inhibiting cerebral tachyzoite proliferation in T. gondii infection, CD180 could also contribute to controlling cerebral tachyzoite growth by increasing TNF-a expression in the brain. NOD1 is known to recognize peptidoglycan moieties from Gram-negative bacteria and single stranded RNA from various viruses. A recent study identified that NOD1 is required for restricting intracellular replication of Trypanosoma cruzi, an intracellular protozoan parasite, in IFN- g-activated macrophages and for preventing mortality in mice following a sub-lethal dose of infection with this parasite. In another model, NOD1 mediates upregulation of cerebral TNF-a production. Thus, the proposed studies focus to determine whether CD180 (Aim 1) and NOD1 (Aim 2) play important roles in the protective immunity to prevent reactivation of T. gondii infection.