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Evidence for genes controlling resistance to Heligmosomoides bakeri on mouse chromosome 1

Published online by Cambridge University Press:  07 November 2014

Institute of Integrative Biology, Biosciences Building, University of Liverpool Crown Street, Liverpool L69 7ZB, UK
International Livestock Research Institute (ILRI), P.O. Box 30709, Nairobi, Kenya
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK
International Livestock Research Institute (ILRI), P.O. Box 30709, Nairobi, Kenya
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK
*Corresponding author: School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. E-mail:


Resistance to infections with Heligmosomoides bakeri is associated with a significant quantitative trait locus (QTL–Hbnr1) on mouse chromosome 1 (MMU1). We exploited recombinant mice, with a segment of MMU1 from susceptible C57Bl/10 mice introgressed onto MMU1 in intermediate responder NOD mice (strains 1094 and 6109). BALB/c (intermediate responder) and C57Bl/6 mice (poor responder) were included as control strains and strain 1098 (B10 alleles on MMU3) as NOD controls. BALB/c mice resisted infection rapidly and C57Bl/6 accumulated heavy worm burdens. Fecal egg counts dropped by weeks 10–11 in strain 1098, but strains 1094 and 6109 continued to produce eggs, harbouring more worms when autopsied (day 77). PubMed search identified 3 genes (Ctla4, Cd28, Icos) as associated with ‘Heligmosomoides’ in the B10 insert. Single nucleotide polymorphism (SNP) differences in Ctla4 could be responsible for regulatory changes in gene function, and a SNP within a splice site in Cd28 could have an impact on function, but no polymorphisms with predicted effects on function were found in Icos. Therefore, one or more genes encoded in the B10 insert into NOD mice contribute to the response phenotype, narrowing down the search for genes underlying the H. bakeri resistance QTL, and suggest Cd28 and Ctla4 as candidate genes.

Research Article
Copyright © Cambridge University Press 2014 

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† Current address: Kemet Company, P.O. Box 39099-00623, Nairobi, Kenya.



Abel, L. and Dessein, A. J. (1997). The impact of host genetics on susceptibility to human infectious diseases. Current Opinions in Immunology 9, 509516.Google Scholar
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S. and Sunyaev, S. R. (2010). A method and server for predicting damaging missense mutations. Nature Methods 7, 248249.Google Scholar
Araki, M., Chung, D., Liu, S., Rainbow, D. B., Chamberlain, G., Garner, V., Hunter, K. M., Vijayakrishnan, L., Peterson, L. B., Oukka, M., Sharpe, A. H., Sobel, R., Kuchroo, V. K. and Wicker, L. S. (2009). Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. Journal of Immunology 183, 51465157.CrossRefGoogle ScholarPubMed
Behnke, J. M. and Harris, P. D. (2010). Heligmosomoides bakeri – a new name for an old worm? Trends in Parasitology 26, 524529.Google Scholar
Behnke, J. M. and Parish, H. A. (1979). Nematospiroides dubius: arrested development of larvae in immune mice. Experimental Parasitology 47, 116127.CrossRefGoogle ScholarPubMed
Behnke, J. M. and Wahid, F. N. (1991). Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius): H-2 genes determine worm survival. Parasitology 103, 157164.Google Scholar
Behnke, J. M., Keymer, A. E. and Lewis, J. W. (1991). Heligmosomoides polygyrus or Nematospiroides dubius? Parasitology Today 7, 177179.Google Scholar
Behnke, J. M., Lowe, A., Clifford, S. and Wakelin, D. (2003). Cellular and serological responses in resistant and susceptible mice exposed to repeated infection with Heligmosomoides polygyrus bakeri . Parasite Immunology 25, 333340.CrossRefGoogle ScholarPubMed
Behnke, J. M., Iraqi, F. A., Mugambi, J. M., Clifford, S., Nagda, S., Wakelin, D., Kemp, S. J., Baker, R. L. and Gibson, J. P. (2006 a). High resolution mapping of chromosomal regions controlling resistance to gastro-intestinal nematode infections in an advanced intercross line of mice. Mammalian Genome 17, 584597.Google Scholar
Behnke, J. M., Mugambi, J. M., Clifford, S., Iraqi, F., Baker, R. L., Gibson, J. P. and Wakelin, D. (2006 b). Genetic variation in resistance to repeated infections with Heligmosomoides polygyrus bakeri, in inbred mouse strains selected for the Mouse Genome Project. Parasite Immunology 28, 8594.Google Scholar
Behnke, J. M., Menge, D. M. and Noyes, H. (2009). Heligmosomoides bakeri: a model for exploring the biology and genetics of resistance to chronic gastrointestinal nematode infections. Parasitology 136, 15651580.CrossRefGoogle Scholar
Behnke, J. M., Menge, D. M., Nagda, S., Noyes, H., Iraqi, F. A., Kemp, S. J., Mugambi, R. J. M., Baker, R. L., Wakelin, D. and Gibson, J. P. (2010). Quantitative trait loci for resistance to Heligmosomoides bakeri and associated immunological and pathological traits in mice: comparison of loci on chromosomes 5, 8 and 11 in F2 and F6/7 inter-cross lines of mice. Parasitology 137, 311320.Google Scholar
Bishop, S. C. and Stear, M. J. (2003). Modeling of host genetics and resistance to infectious diseases: understanding and controlling nematode infections. Veterinary Parasitology 115, 147166.Google Scholar
Cable, J., Harris, P. D., Lewis, J. W. and Behnke, J. M. (2006). Molecular evidence that Heligmosomoides polygyrus from laboratory mice and wood mice are separate species. Parasitology 133, 111122.Google Scholar
Coles, G. C., Borgsteede, F. H. M. and Geerts, S. (1994). Anthelmintic-resistant nematodes in the EU. Parasitology Today 10, 288290.CrossRefGoogle Scholar
Cooke, G. S. and Hill, V. S. (2001). Genetics of susceptibility to human infectious disease. Nature Reviews Genetics 2, 967977.Google Scholar
Ekkens, M. J., Liu, Z., Liu, Q., Foster, A., Whitmire, J., Pesce, J., Sharpe, A. H., Urban, J. F. and Gause, W. C. (2002). Memory Th2 effector cells can develop in the absence of B7–1/B7-2, CD28 interactions, and effector Th cells after priming with an intestinal nematode parasite. Journal of Immunology 168, 63446351.CrossRefGoogle ScholarPubMed
Enriquez, F. J., Brooks, B. O., Cypess, R. H., David, C. S. and Wassom, D. L. (1988). Nematospiroides dubius: two H-2 -linked genes influence levels of resistance to infection in mice. Experimental Parasitology 67, 221226.CrossRefGoogle ScholarPubMed
Fumagalli, M., Pozzoli, U., Cagliani, R., Comi, G. P., Bresolin, N., Clerici, M. and Sironi, M. (2010). The landscape of human genes involved in the immune response to parasitic worms. BMC Evolutionary Biology 10, 264.Google Scholar
Gause, W. C., Lu, P., Zhou, X. D., Chen, S-J, Madden, K. B., Morris, S. C., Linsley, P. S., Finkelman, F. D. and Urban, J. F. (1996). H. polygyrus: B7-independence of the secondary type 2 response. Experimental Parasitology 84, 264273.Google Scholar
Gause, W. C., Chen, S. J., Greenwald, R. J., Halvorson, M. J., Lu, P., di Zhou, X., Morris, S. C., Lee, K. P., June, C. H., Finkelman, F. D., Urban, J. F. and Abe, R. (1997). CD28 dependence of T cell differentiation to IL-4 production varies with the particular Type 2 immune response. Journal of Immunology 158, 40824087.Google Scholar
Gilleard, J. S. (2006). Understanding anthelmintic resistance: the need for genomics and genetics. International Journal for Parasitology 36, 12271239.Google Scholar
Golbar, H. M., Izawa, T., Juniantito, V., Ichikawa, C., Tanaka, M., Kuwamura, M. and Yamate, J. (2013). Immunohistochemical characterization of macrophages and myofibroblasts in fibrotic liver lesions due to Fasciola infection in cattle. Journal of Veterinary Medical Science 75, 857865.Google Scholar
Goodhead, I., Archibald, A., Amwayi, P., Brass, A., Gibson, J., Hall, N., Hughes, M. A., Limo, M., Iraqi, F., Kemp, S. J. and Noyes, H. A. (2010). A comprehensive genetic analysis of candidate genes regulating response to Trypanosoma congolense infection in mice. PLoS Neglected Tropical Diseases 4, e880.Google Scholar
Greenwald, R. J., Lu, P., Halvorson, M. J., Zhou, X-D, Chen, S-J, Madden, K. B., Perrin, P. J., Morris, S. C., Finkelman, F. D., Peach, R., Linsley, P. S., Urban, J. F. Jr. and Gause, W. C. (1997). Effects of blocking B7–1 and B7–2 interactions during a Type 2 in vivo immune response. Journal of Immunology 158, 40884096.Google Scholar
Harris, N. L., Peach, R. J. and Ronchese, F. (1999). Ctla4-Ig inhibits optimal T helper 2 cell development but not protective immunity or memory response to Nippostrongylus brasiliensis . European Journal of Immunology 29, 311316.3.0.CO;2-B>CrossRefGoogle ScholarPubMed
Harris, N. L., Spoerri, I., Schopfer, J. F., Nembrini, C., Merky, P., Massacand, J., Urban, J. F. Jr., Lamarre, A., Burki, K., Odermatt, B., Zinkernagel, R. M. and Macpherson, A. J. (2006). Mechanisms of neonatal mucosal antibody protection. Journal of Immunology 177, 62566262.Google Scholar
Harris, N. L., Pleass, R. and Behnke, J. M. (2014). Understanding the role of antibodies in murine infections with Heligmosomoides (polygyrus) bakeri: 35 years ago, now and 35 years ahead. Parasite Immunology 35, 115124.Google Scholar
Hunter, K., Rainbow, D., Plagnol, V., Todd, J. A., Peterson, L. B. and Wicker, L. S. (2007). Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes. Journal of Immunology 179, 83418349.Google Scholar
Hurst, R. J. M. and Else, K. J. (2013). Trichuris muris research revisited: a journey through time. Parasitology 140, 13251339.Google Scholar
Iraqi, F., Clapcott, S. J., Kumar, P., Haley, C. S., Kemp, S. J. and Teale, A. (2000). Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines. Mammalian Genome 11, 645648.CrossRefGoogle ScholarPubMed
Iraqi, F. A., Behnke, J. M., Menge, D. M., Lowe, A., Teale, A. J., Gibson, J. P., Baker, L. R. and Wakelin, D. (2003). Chromosomal regions controlling resistance to gastro-intestinal nematode infections in mice. Mammalian Genome 14, 184191.CrossRefGoogle ScholarPubMed
Jackson, F., Jackson, E. and Coop, R. L. (1992). Evidence of multiple resistance in a strain of Teladorsagia (Ostertagia) circumcincta isolated from goats in Scotland. Research in Veterinary Science 53, 371374.Google Scholar
Jones, C. E. and Rubin, R. (1974). Nematospiroides dubius: mechanisms of host immunity. I. Parasite counts, histopathology and serum transfer involving orally or subcutaneously sensitized mice. Experimental Parasitology 35, 434452.Google Scholar
Kaplan, R. M. (2004). Drug resistance in nematodes of veterinary importance. Trends in Parasitology 20, 477481.Google Scholar
Keane, O. M., Dodds, K. G., Crawford, A. M. and McEwan, J. C. (2008). Identifying genes for intestinal nematode resistance using transcriptional profiling. Developmental Biology 132, 205212.Google Scholar
Kemp, S. J., Iraqi, F., Darvasi, A., Soller, M. and Teale, A. J. (1997). Localization of genes controlling resistance to trypanosomiasis in mice. Nature Genetics 16, 194196.Google Scholar
Klementowicz, J. E., Travis, M. A. and Grencis, R. K. (2012). Trichuris muris: a model of gastrointestinal parasite infection. Seminars in Immunopathology 34, 815828.Google Scholar
Kloosterman, A., Parmentier, H. K. and Ploeger, H. W. (1992). Breeding cattle and sheep for resistance to gastrointestinal nematodes. Parasitology Today 8, 330335.Google Scholar
Kwiatkowski, D. P. (2005). How malaria has affected the human genome and what human genetics can teach us about malaria. American Journal of Human Genetics 77, 171192.Google Scholar
Levison, S. E., Fisher, P., Hankinson, J., Zeef, L., Eyre, S., Ollier, W., McLaughlin, J. T., Brass, A., Grencis, R. and Pennock, J. (2013). Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation. BMC Genomics 14, 127.Google Scholar
Liu, S. K. (1965). Pathology of Nematospiroides dubius. II Reinfections in Webster mice. Experimental Parasitology 17, 136147.Google Scholar
Liu, Q., Kreider, T., Bowdridge, S., Liu, Z., Song, Y., Gaydo, A. G., Urban, J. F. Jr. and Gause, W. C. (2010). B cells have distinct roles in host protection against different nematode parasites. Journal of Immunology 184, 52135223.Google Scholar
Lu, P., di Zhou, X., Chen, S.-J., Moorman, M., Morris, S. C., Finkelman, F. D., Linsley, P., Urban, J. F. and Gause, W. C. (1994). CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite. Journal of Experimental Medicine 180, 693698.CrossRefGoogle Scholar
Maier, L. M. and Wicker, L. S. (2005). Genetic susceptibility to type 1 diabetes. Current Opinion in Immunology 17, 601608.CrossRefGoogle ScholarPubMed
Makino, S., Kunimoto, K., Muraoka, Y., Mizushima, Y., Katagiri, K. and Tochino, Y. (1980). Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29, 113.Google Scholar
McCoy, K. D., Stoel, M., Stettler, R., Merky, P., Fink, P., Senn, B. M., Schaer, C., Massacand, J., Odermatt, B., Oettgen, H. C., Zinkernagel, R. M., Bos, N. A., Hengartner, H., MacPherson, A. J. and Harris, N. L. (2008). Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection. Cell Host Microbe 4, 362373.Google Scholar
Menge, D. M., Behnke, J. M., Lowe, A., Gibson, J. P., Iraqi, F. A., Baker, L. and Wakelin, D. (2003). Mapping of chromosomal regions influencing immunological responses to gastrointestinal nematode infections in mice. Parasite Immunology 25, 341349.CrossRefGoogle ScholarPubMed
Pritchard, D. I., Williams, D. J. L., Behnke, J. M. and Lee, T. D. G. (1983). The role of IgG1 hypergammaglobulinemia in immunity to the gastrointestinal nematode Nematospiroides dubius. The immunochemical purification, antigen-specificity and in vivo anti-parasite effect of IgG1 from immune serum. Immunology 49, 353365.Google Scholar
Quinnell, R. J. (2003). Genetics of susceptibility to human helminth infection. International Journal for Parasitology 33, 12191231.CrossRefGoogle ScholarPubMed
Ramensky, V., Bork, P. and Sunyaev, S. (2002). Human non-synonymous SNPs: server and survey. Nucleic Acids Research 30, 38943900.Google Scholar
Redpath, S. A., van der Werf, N., Cervera, A. M., MacDonald, A. S., Gray, D., Maizels, R. M. and Taylor, M. D. (2013). ICOS controls Foxp3+ regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. European Journal of Immunology 43, 705715.Google Scholar
Saunders, K. A., Raine, T., Cooke, A. and Lawrence, C. E. (2007). Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infection and Immunity 75, 397407.Google Scholar
Scales, H. E., Ierna, M. X., Gutierrez-Ramos, J-C., Coyle, A. J., Garside, P. and Lawrence, C. E. (2004). Effect of inducible costimulator blockade on the pathological and protective immune responses induced by the gastrointestinal helminth Trichinella spiralis . European Journal of Immunology 34, 28542862.Google Scholar
Stear, M. J., Doligalska, M. and Donskow-Schmelter, K. (2007). Alternatives to anthelmintics for the control of nematodes in livestock. Parasitology 134, 139151.Google Scholar
Stumpf, M., Zhou, X. and Bluestone, J. A. (2013). The B7-independent isoform of CTLA-4 functions to regulate autoimmune diabetes. Journal of Immunology 190, 961969.CrossRefGoogle ScholarPubMed
Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., Cooke, M. P., Walker, J. R. and Hogenesch, J. B. (2004). A gene atlas of the mouse and human protein-encoding transcriptomes. Proceeding of the National Academy of Sciences, USA 101, 60626067.CrossRefGoogle ScholarPubMed
Suzuki, T., Ishih, A., Kino, H., Muregi, F. W., Takabayashi, S., Nishikawa, T., Takagi, H. and Terada, M. (2006). Chromosomal mapping of host resistance loci to Trichinella spiralis nematode infection in rats. Immunogenetics 58, 2630.Google Scholar
van Wyk, J. A. (1990). Occurrence and dissemination of anthelmintic resistance in South Africa, and management of resistant worm strains. In Resistance of Parasites to Antiparasitic Drugs (ed. Boray, J. C., Martin, P. J. and Roush, R. T.), pp. 103114. MSD, AGVET, Raway, NJ.Google Scholar
Vieira Benavides, M., Sonstegard, T. S., Kemp, S., Mugambi, J. M., Gibson, J., Baker, R. L., Hanotte, O., Marshall, K. and Van Tassell, C. (2014). Identification of single nucleotide polymorphisms associated with gastrointestinal parasite resistance in a Red Maasai x Dorper backcross population. PLoS ONE. In press.Google Scholar
Williams-Blangero, S., VandeBerg, J. L., Subedi, J., Aivaliotis, M. J., Rai, D. R., Upadhayay, R. P., Jha, B. and Blangero, J. (2002). Genes on chromosomes 1 and 13 have significant effects on Ascaris infection. Proceeding of the National Academy of Sciences, USA 99, 55335538.Google Scholar
Wrigley, J., McArthur, M., McKenna, P. B. and Mariadas, B. (2006). Resistance to a triple combination of broad-spectrum anthelmintics in naturally-acquired Ostertagia circumcincta infections in sheep. New Zealand Veterinary Journal 54, 4749.Google Scholar
Wu, Z., Nagano, I. and Takahashi, Y. (2008). Candidate genes responsible for common and different pathology of infected muscle tissues between Trichinella spiralis and T. pseudospiralis infection. Parasitology International 57, 368378.Google Scholar
Yamanouchi, J., Rainbow, D., Serra, P., Howlett, S., Hunter, K., Garner, V. E. S., Gonzalez-Munroz, A., Clark, J., Veijola, R., Cubbon, R., Chen, S.-L., Rosa, R., Cumiskey, A. M., Serreze, D. V., Gregory, S., Rogers, J., Lyons, P. A., Healy, B., Smink, L. J., Todd, J. A., Peterson, L. B., Wicker, L. S. and Santamaria, P. (2007). Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nature Genetics 39, 329337.Google Scholar