RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

Toxoplasmosis is a healthcare problem in pregnant women and immunocompromised patients. Like humans, rats usually develop a subclinical chronic infection. LEW rats exhibit total resistance to Toxoplasma gondii infection, which is expressed in a dominant mode. A genome-wide search carried out in a cohort of F 2 progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 a major locus of control, which we called Toxo1. Using reciprocal BN and LEW lines congenic for chromosome 10 genomic regions from the other strain, Toxo1 was found to govern the issue of T. gondii infection whatever the remaining genome. Analyzes of rats characterized by genomic recombination within Toxo1, reduced the interval down to a 1.7-cM region syntenic to human 17p13. In vitro studies showed that the Toxo1-mediated refractoriness to T. gondii infection is associated with the ability of the macrophage to impede the proliferation of the parasite within the parasitophorous vacuole. In contrast, proliferation was observed in fibroblasts whatever the genomic origin of Toxo1. Furthermore, ex vivo studies indicate that macrophage controls parasitic infection spreading by a Toxo1-mediated mechanism. This forward genetics approach should ultimately unravel a major pathway of innate resistance to toxoplasmosis and possibly to other apicomplexan parasitic diseases.T he protozoan Toxoplasma gondii is an obligate intracellular parasite that infects humans and a broad spectrum of vertebrate hosts. It is found worldwide, and the infection is common as indicated by a high prevalence of specific Ab among almost all human populations. T. gondii infection occurs by oral ingestion of either cysts from infected animal tissues, or oocysts excreted by cats. In healthy individuals, T. gondii establishes a chronic asymptomatic infection characterized by a specific immune response and the encystment of dormant bradyzoites into host tissues. A serious threat to human health can occur under congenital infection or reactivation of a latent infection in immunodeficient patients (1).Epidemiological studies have indicated that the genetic make-up of the host and of the parasite are involved in the phenotypic expression of toxoplasmosis (2-4). Genetic studies in humans are hampered by both population heterogeneity and environment variability. In experimental conditions, genetic and environmental factors are under control. Results from genetic studies in animal models can be applied to human pathology through comparative genomics (5, 6). Rats, like humans, usually develop subclinical toxoplasmosis (7); this contrasts with the severity of the disease developed in most strains of mice. Surprisingly, the LEW rat strain exhibits a complete resistance to Toxoplasma infection (8). Indeed, unlike susceptible BN and F344 rats, LEW rats do not show trace of parasitic infection as shown by negative serology and lack of brain cysts. F 1 hybrid (LEW ϫ BN) and (LEW ϫ F344) rats are resistant to T. gondii, indicating a dominant effect of the involved gene(s) (9). W...