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

Philippe Gros,Irena Radovanovic,Wendy Elizabeth Harrison,Ruben Ramirez-Aquino,Gladis Fragoso-González,Anny Fortin,Irma Aguilar-Delfin,Edda Sciutto-Conde

doi:10.1371/journal.pntd.0001435

Philippe Gros, Irena Radovanovic + Show 6 more

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https://doi.org/10.1371/journal.pntd.0001435

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Abstract

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.

Highlights

Taenia solium seriously affects human health in many countries of Latin America, Asia and Africa [1]
Neurocysticercosis is a severe manifestation of T. solium infection that constitutes an important health concern in developing countries
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

Summary

Introduction

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. 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]. A three to five fold difference in parasite load was detected in a genetically heterogeneous pig cohort experimentally challenged with T. solium eggs [5]

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