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 recognize an invasion and proliferation of pathogens and promptly activate the protective immunity. Toxoplasma gondii, an intracellular protozoan parasite, establishes chronic infection in the brain, and reactivation of this chronic infection can cause sever encephalitis. For preventing this disease, the immune system needs to rapidly detect proliferation of tachyzoites (the acute stage form) in the brain during the early stage of reactivation of the infection for effectively activating the protective immunity. Thus, the defense system that recognizes the PAMPs-recognizing molecules expressed in the brain should play crucial roles in readily detecting tachyzoite growth and activating the protective immunity during the early stage of reactivation of the infection. We previously identified that IFN-g is required for the protective immunity to prevent reactivation of cerebral T. gondii infection. Our studies also identified that microglia, tissue-resident macrophages in the brain, produce IFN-g in response to cerebral tachyzoite growth, and that production of IFN-g by brain-resident cells is critical for promptly activating cerebral innate immunity and facilitating migration to T cells into the brain to prevent reactivation of the 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 detecting 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 express CD180, and they also play important roles in preventing cerebral tachyzoite growth. CD180 has also been shown to upregulate TNF-a expression in macrophages in a bacterial infection. TNF-a, in addition to IFN-g plays important roles in inhibiting cerebral tachyzoite growth. Thus, it is possible that CD180 activates IFN-g and TNF-a production by microglia and macrophages against tachyzoite growth and promptly activate both innate and T cell-mediated protective immunity to prevent reactivation of T. gondii infection. NOD1 recognizes peptidoglycan moieties from Gram-negative bacteria and single stranded RNA from various viruses. A recent study identified that NOD1 is required for restricting replication of Trypanosoma cruzi, an intracellular parasite, in IFN-g-activated macrophages. In addition, mice deficient in both NOD1 and NOD2 have decreased IFN-g levels in their plasma during cerebral malaria. NOD1 also enhances cerebral TNF-a production in intracerebral haemorrhage. Thus, the proposed studies focus to determine whether CD180 (Aim 1) and NOD1 (Aim 2) expressed in microglia and macrophages play important roles in activating their production of IFN-g and TNFa and promptly activating both innate and T cell-mediated protective immunity to prevent reactivation of T. gondii infection. Project Number: 1R21AI187757-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: YASUHIRO SUZUKI | Institution: UNIVERSITY OF KENTUCKY, LEXINGTON, KY | Award Amount: $423,500 | Activity Code: R21 | Study Section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18775701A1