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Increased exposure to Plasmodium chabaudi antigens sustains cross-reactivity and avidity of antibodies binding Nippostrongylus brasiliensis: dissecting cross-phylum cross-reactivity in a rodent model


Mounting an antibody response capable of discriminating amongst and appropriately targeting different parasites is crucial in host defence. However, cross-reactive antibodies that recognize (bind to) multiple parasite species are well documented. We aimed to determine if a higher inoculating dose of one species, and thus exposure to larger amounts of antigen over a longer period of time, would fine-tune responses to that species and reduce cross-reactivity. Using the Plasmodium chabaudi chabaudi (Pcc)–Nippostrongylus brasiliensis (Nb) co-infection model in BALB/c mice, in which we previously documented cross-reactive antibodies, we manipulated the inoculating dose of Pcc across 4 orders of magnitude. We investigated antigen-specific and cross-reactive antibody responses against crude and defined recombinant antigens by enzyme linked immunosorbent assay, Western blot and antibody depletion assays. Contrary to our hypothesis that increasing exposure to Pcc would reduce cross-reactivity to Nb, we found evidence for increased avidity of a subpopulation of antibodies that recognized shared antigens. Western blot indicated proteins of apparent monomer molecular mass 28 and 98 kDa in both Nb and Pcc antigen preparations and also an Nb protein of similar size to recombinant Pcc antigen, merozoite surface protein-119. The implications of antibodies binding antigen from such phylogenetically distinct parasites are discussed.

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* Corresponding author: Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, King's Buildings, University of Edinburgh, Edinburgh, UK. E-mail:
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N. Acevedo and L. Caraballo (2011). IgE cross-reactivity between Ascaris lumbricoides and mite allergens: possible influences on allergic sensitization and asthma. Parasite Immunology 33, 309321.

A. H. Achtman , M. Khan , I. C. Maclennan and J. Langhorne (2003). Plasmodium chabaudi chabaudi infection in mice induces strong B cell responses and striking but temporary changes in splenic cell distribution. Journal of Immunology 171, 317324.

A. H. Achtman , R. Stephens , E. T. Cadman , V. Harrison and J. Langhorne (2007). Malaria-specific antibody responses and parasite persistence after infection of mice with Plasmodium chabaudi chabaudi. Parasite Immunology 29, 435444.

G. H. Beale , R. Carter and D. Walliker (1978). Genetics. In Rodent Malaria (eds. R. Killick-Kendrick and W. Peters ), 213244. Academic Press, London.

E. S. Bergmann-Leitner , E. H. Duncan and E. Angov (2009). MSP-1p42-specific antibodies impact growth and development of intra-erythrocytic parasites of Plasmodium falciparum. Malaria Journal 8, 183.

C. Bjorkman , K. Naslund , S. Stenlund , S. W. Maley , D. Buxton and A. Uggla (1999). An IgG avidity ELISA to discriminate between recent and chronic Neospora caninum infection. Journal of Veterinary Diagnostic Investigation 11, 4144.

A. Casadevall and L. A. Pirofski (2007). Antibody-mediated protection through cross-reactivity introduces a fungal heresy into immunological dogma. Infection and Immunity 75, 50745078.

S. I. Castillo-Mendez , C. A. Zago , L. R. Sardinha , A. P. Freitas Do Rosario , J. M. Alvarez and M. R. D'imperio Lima (2007). Characterization of the spleen B-cell compartment at the early and late blood-stage Plasmodium chabaudi malaria. Scandinavian Journal of Immunology 66, 309319.

D. D. Chaplin (2010). Overview of the immune response. Journal of Allergy and Clinical Immunology 125, S323.

M. R. D. Lima , J. M. Alvarez , G. C. Furtado , T. L. Kipnis , A. Coutinho and P. Minoprio (1996). Ig-isotype patterns of primary and secondary B cell responses to Plasmodium chabaudi chabaudi correlate with IFN-gamma and IL-4 cytokine production and with CD45RB expression by CD4(+) spleen cells. Scandinavian Journal of Immunology 43, 263270.

V. Diaz-Saez , G. Merino-Espinosa , M. Morales-Yuste , V. Corpas-Lopez , F. Pratlong , F. Morillas-Marquez and J. Martin-Sanchez (2014). High rates of Leishmania infantum and Trypanosoma nabiasi infection in wild rabbits (Oryctolagus cuniculus) in sympatric and syntrophic conditions in an endemic canine leishmaniasis area: epidemiological consequences. Veterinary Parasitology 202, 119127.

A. D. Douglas , A. R. Williams , E. Knuepfer , J. J. Illingworth , J. M. Furze , C. Crosnier , P. Choudhary , L. Y. Bustamante , S. E. Zakutansky , D. K. Awuah , D. G. Alanine , M. Theron , A. Worth , R. Shimkets , J. C. Rayner , A. A. Holder , G. J. Wright and S. J. Draper (2014). Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5. Journal of Immunology 192, 245258.

H. N. Eisen and A. K. Chakraborty (2010). Evolving concepts of specificity in immune reactions. Proceedings of the National Academy of Sciences of the United States of America 107, 2237322380.

K. J. Fairlie-Clarke , D. M. Shuker and A. L. Graham (2009). “Why do adaptive immune responses cross-react?”. Evolutionary Applications 2, 122131.

K. J. Fairlie-Clarke , T. J. Lamb , J. Langhorne , A. L. Graham and J. E. Allen (2010). Antibody isotype analysis of malaria-nematode co-infection: problems and solutions associated with cross-reactivity. BMC Immunology 11, 6.

A. Gonzalez-Fernandez and C. Milstein (1998). Low antigen dose favours selection of somatic mutants with hallmarks of antibody affinity maturation. Immunology 93, 149153.

A. L. Graham , T. J. Lamb , A. F. Read and J. E. Allen (2005). Malaria-filaria coinfection in mice makes malarial disease more severe unless filarial infection achieves patency. The Journal of Infectious Diseases 191, 410421.

M. F. Gurish , P. J. Bryce , H. Tao , A. B. Kisselgof , E. M. Thornton , H. R. Miller , D. S. Friend and H. C. Oettgen (2004). IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis. Journal of Immunology 172, 11391145.

M. Hensmann , C. Li , C. Moss , V. Lindo , F. Greer , C. Watts , S. A. Ogun , A. A. Holder and J. Langhorne (2004). Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response. European Journal of Immunology 34, 639648.

D. L. Hill , E. M. Eriksson , C. S. Li Wai Suen , C. Y. Chiu , V. Ryg-Cornejo , L. J. Robinson , P. M. Siba , I. Mueller , D. S. Hansen and L. Schofield (2013). Opsonising antibodies to P. falciparum merozoites associated with immunity to clinical malaria. PLoS ONE 8, e74627.

M. A. Hoeve , K. J. Mylonas , K. J. Fairlie-Clarke , S. M. Mahajan , J. E. Allen and A. L. Graham (2009). Plasmodium chabaudi limits early Nippostrongylus brasiliensis-induced pulmonary immune activation and Th2 polarization in co-infected mice. BMC Immunology 10, 60.

M. R. D. Lima , A. Bandeira , P. Falanga , A. A. Freitas , T. L. Kipnis , L. P. Dasilva and A. Coutinho (1991). Clonal analysis of lymphocyte-B responses to Plasmodium-chabaudi infection of normal and immunoprotected mice. International Immunology 3, 12071216.

M. M. Mota , K. N. Brown , V. E. Do Rosario , A. A. Holder and W. Jarra (2001). Antibody recognition of rodent malaria parasite antigens exposed at the infected erythrocyte surface: specificity of immunity generated in hyperimmune mice. Infection and Immunity 69, 25352541.

C. W. Naus , F. M. Jones , M. Z. Satti , S. Joseph , E. M. Riley , G. Kimani , J. K. Mwatha , C. H. Kariuki , J. H. Ouma , N. B. Kabatereine , B. J. Vennervald and D. W. Dunne (2003). Serological responses among individuals in areas where both schistosomiasis and malaria are endemic: cross-reactivity between Schistosoma mansoni and Plasmodium falciparum . The Journal of Infectious Diseases 187, 12721282.

H. H. Nguyen , M. Zemlin , Ii. Ivanov , J. Andrasi , C. Zemlin , H. L. Vu , R. Schelonka , H. W. Schroeder Jr. and J. Mestecky (2007). Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire. Journal of Virology 81, 93319338.

N. E. Nieuwenhuizen , J. M. Meter , W. G. Horsnell , J. C. Hoving , L. Fick , M. F. Sharp , M. G. Darby , S. P. Parihar , F. Brombacher and A. L. Lopata (2013). A cross-reactive monoclonal antibody to nematode haemoglobin enhances protective immune responses to Nippostrongylus brasiliensis . Plos Neglected Tropical Diseases 7, e2395.

Z. Pancer and M. D. Cooper (2006). The evolution of adaptive immunity. Annual Review of Immunology 24, 497518.

A. B. Pedersen and A. Fenton (2007). Emphasizing the ecology in parasite community ecology. Trends in Ecology and Evolution 22, 133139.

T. N. Petney and R. H. Andrews (1998). Multiparasite communities in animals and humans: frequency, structure and pathogenic significance. International Journal of Parasitology 28, 377393.

C. Pierrot , S. Wilson , H. Lallet , S. Lafitte , F. M. Jones , W. Daher , M. Capron , D. W. Dunne and J. Khalife (2006). Identification of a novel antigen of Schistosoma mansoni shared with Plasmodium falciparum and evaluation of different cross-reactive antibody subclasses induced by human schistosomiasis and malaria. Infection and Immunity 74, 33473354.

M. Rieck , A. Arechiga , S. Onengut-Gumuscu , C. Greenbaum , P. Concannon and J. H. Buckner (2007). Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. Journal of Immunology 179, 47044710.

J. Sotillo , A. Sanchez-Flores , C. Cantacessi , Y. Harcus , D. Pickering , T. Bouchery , M. Camberis , S. C. Tang , P. Giacomin , J. Mulvenna , M. Mitreva , M. Berriman , G. Legros , R. M. Maizels and A. Loukas (2014). Secreted proteomes of different developmental stages of the gastrointestinal nematode Nippostrongylus brasiliensis . Molecular and Cell Proteomics 13, 27362751

Z. Su and M. M. Stevenson (2002). IL-12 is required for antibody-mediated protective immunity against blood-stage Plasmodium chabaudi AS malaria infection in mice. Journal of Immunology 168, 13481355.

D. M. Tarlinton and K. G. Smith (2000). Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre. Immunology Today 21, 436441.

R. Timms , N. Colegrave , B. H. Chan and A. F. Read (2001). The effect of parasite dose on disease severity in the rodent malaria Plasmodium chabaudi. Parasitology 123, 111.

K. M. Toellner , W. E. Jenkinson , D. R. Taylor , M. Khan , D. M. Sze , D. M. Sansom , C. G. Vinuesa and I. C. Maclennan (2002). Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers. Journal of Experimental Medicine 195, 383389.

S. Tonegawa (1983). Somatic generation of antibody diversity. Nature 302, 575581.

A. Van Remoortere , C. M. Bank , A. K. Nyame , R. D. Cummings , A. M. Deelder and I. Van Die (2003). Schistosoma mansoni-infected mice produce antibodies that cross-react with plant, insect, and mammalian glycoproteins and recognize the truncated biantennaryN-glycan Man3GlcNAc2-R. Glycobiology 13, 217225.

F. Wang , S. Sen , Y. Zhang , I. Ahmad , X. Zhu , I. A. Wilson , V. V. Smider , T. J. Magliery and P. G. Schultz (2013). Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation. Proceedings of the National Academy of Sciences of the United States of America 110, 42614266.

Y. Wang , G. Huang , J. Wang , H. Molina , D. D. Chaplin and Y. X. Fu (2000). Antigen persistence is required for somatic mutation and affinity maturation of immunoglobulin. European Journal of Immunology 30, 22262234.

W. P. Weidanz , J. M. Batchelder , P. Flaherty , G. Lafleur , C. Wong and H. C. Van der Heyde (2005). Plasmodium chabaudi adami: use of the B-cell-deficient mouse to define possible mechanisms modulating parasitemia of chronic malaria. Experimental Parasitology 111, 97104.

B. X. Xu and M. R. Powell (1991). Carbohydrate epitopes are responsible for antibody cross-reactivity in Trypanosoma cruzi-infected mice. Journal of Parasitology 77, 808810.

J. Yin , A. E. T. Beuscher , S. E. Andryski , R. C. Stevens and P. G. Schultz (2003). Structural plasticity and the evolution of antibody affinity and specificity. Journal of Molecular Biology 330, 651656.

T. D. Chan and R. Brink (2012). Affinity-based selection and the germinal center response. Immunological Reviews 247, 1123.

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