Identification of Loci Controlling Restriction of Parasite Growth in Experimental Taenia crassiceps Cysticercosis

et al. (2011) Identification of Loci Controlling Restriction of Parasite Growth in Experimental Taenia crassiceps Cysticercosis. PLoS Negl Trop Dis 5(12): e1435. doi:10.1371/journal.pntd.0001435 Identification of Loci Controlling Restriction of Parasite Growth in Experimental Taenia crassiceps Cysticercosis Ruben Ramirez-Aquino 0 Irena Radovanovic 0 Anny Fortin 0 Edda Sciutto-Conde 0 Gladis Fragoso- 0 Gonza lez 0 Philippe Gros 0 Irma Aguilar-Delfin 0 Wendy Elizabeth Harrison, Imperial College, United Kingdom 0 1 Departament of Immunology, Instituto de Investigaciones Biome dicas, Universidad Nacional Auto noma de Me xico, Ciudad de Me xico, Me xico, 2 Department of Biochemistry, McGill University , Montreal , Canada , 3 Laboratory of Immunogenomics and Metabolic Diseases, Instituto Nacional de Medicina Geno mica (INMEGEN) , Ciudad de Me xico, Me xico Human neurocysticercosis (NC) caused by Taenia solium is a parasitic disease of the central nervous system that is endemic in many developing countries. In this study, a genetic approach using the murine intraperitoneal cysticercosis caused by the related cestode Taenia crassiceps was employed to identify host factors that regulate the establishment and proliferation of the parasite. A/J mice are permissive to T. crassiceps infection while C57BL/6J mice (B6) are comparatively restrictive, with a 10-fold difference in numbers of peritoneal cysticerci recovered 30 days after infection. The genetic basis of this inter-strain difference was explored using 34 AcB/BcA recombinant congenic strains derived from A/J and B6 progenitors, that were phenotyped for T. crassiceps replication. In agreement with their genetic background, most AcB strains (A/J-derived) were found to be permissive to infection while most BcA strains (B6-derived) were restrictive with the exception of a few discordant strains, together suggesting a possible simple genetic control. Initial haplotype association mapping using .1200 informative SNPs pointed to linkages on chromosomes 2 (proximal) and 6 as controlling parasite replication in the AcB/BcA panel. Additional linkage analysis by genome scan in informative [AcB55xDBA/2]F1 and F2 mice (derived from the discordant AcB55 strain), confirmed the effect of chromosome 2 on parasite replication, and further delineated a major locus (LOD = 4.76, p,0.01; peak marker D2Mit295, 29.7 Mb) that we designate Tccr1 (T. crassiceps cysticercosis restrictive locus 1). Resistance alleles at Tccr1 are derived from AcB55 and are inherited in a dominant fashion. Scrutiny of the minimal genetic interval reveals overlap of Tccr1 with other host resistance loci mapped to this region, most notably the defective Hc/C5 allele which segregates both in the AcB/BcA set and in the AcB55xDBA/2 cross. These results strongly suggest that the complement component 5 (C5) plays a critical role in early protective inflammatory response to infection with T. crassiceps. - Funding: This work was supported by a research grant from the Quebec-Mexico joint working group program of the Quebec Ministry of International Relations to P. Gros and G. Fragoso-Gonzalez. P. Gros is supported by a James McGill Professorship at McGill University. R. Ramirez-Aquino was supported by a fellowship from CONACyT, Mexico. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. " These authors also contributed equally to this work. Taenia solium seriously affects human health in many countries of Latin America, Asia and Africa [1]. The life cycle of T. solium includes a larval phase (cysticercus), which develops in both pigs and humans from ingested eggs contaminating the environment. When humans ingest improperly cooked pork meat infected with live cysticerci, the cysticerci develop to the stage of an adult intestinal tapeworm, which produces millions of eggs that are then shed to the environment in human faeces [2]. In rural communities where the disease is endemic, unsanitary conditions and presence of free-roaming pigs result in up to 9% of the human open population of these areas to be infected. Despite this high infection rate, only a small fraction of carriers become symptomatic and develop NC, suggesting intrinsic differences in host susceptibility to infection and pathogenesis of the disease [3]. Indeed, several reports have pointed at possible genetic effects in response to cysticercosis in human and pigs. In humans, multicase families were identified in areas of highly endemic disease, favoring the idea of the participation of multiple genes in NC causality [3]. In a case-control study, resistance to NC was found associated to HLA [4]. Also, a three to five fold difference in parasite load was detected in a genetically heterogeneous pig cohort experimentally challenged with T. solium eggs [5]. Taenia crassiceps is a tapeworm of wild and domestic animals, which does not cause clinical disease in non-immunocompromised humans [6]. T. crassiceps has been used as an experimental model for cysticercosis due to its ability to proliferate by budding [7] and colonize the peritoneal cavity of the murine host [7], where its replication can be measured over time by enumeration of recovered metacestodes. Although the T. crassiceps ORF strain is unable to develop into adult tapeworms [8], its property to rapidly Infection with the cestode Taenia solium causes cysticercosis in humans and pigs. Neurocysticercosis is a severe manifestation of T. solium infection that constitutes an important health concern in developing countries. Studies in humans living in areas of endemic disease and in pigs experimentally infected have suggested a large spectrum of permissiveness to T. solium multiplication, with the possible contribution of genetic factors. In the present report, we have used an experimental mouse model of intraperitoneal infection with Taenia crassiceps to study the potential role of genetic factors in regulating replication of this parasite. Our study focused on two inbred mouse strains A/J and C57BL/6J that are respectively permissive and non-permissive to intraperitoneal multiplication of T. crassiceps. We have used a set of AcB/ BcA recombinant congenic strains of mice along with standard F2 crosses to decipher the complexity and nature of the genetic component of the A/J vs. C57BL/6J interstrain difference in permissiveness. Our results point to a major role of the complement component 5 (C5) in early response and protection against T. crassiceps infection. multiply in the peritoneal cavity of infected mice has been extensively used to explore the relevance of biological factors in host-parasite interactions [9], and to identify protective antigens of interest for vaccine development [9,10]. The mechanisms involved in the protective immunity against T (...truncated)