Humans and other mammals mount vigorous immune assaults against helminth parasites, yet there are intriguing reports that the immune response can enhance rather than impair parasite development. It has been hypothesized that helminths, like many free-living organisms, should optimize their development and reproduction in response to cues predicting future life expectancy. However, immune-dependant development by helminth parasites has so far eluded such evolutionary explanation. By manipulating various arms of the immune response of experimental hosts, we show that filarial nematodes, the parasites responsible for debilitating diseases in humans like river blindness and elephantiasis, accelerate their development in response to the IL-5 driven eosinophilia they encounter when infecting a host. Consequently they produce microfilariae, their transmission stages, earlier and in greater numbers. Eosinophilia is a primary host determinant of filarial life expectancy, operating both at larval and at late adult stages in anatomically and temporally separate locations, and is implicated in vaccine-mediated protection. Filarial nematodes are therefore able to adjust their reproductive schedules in response to an environmental predictor of their probability of survival, as proposed by evolutionary theory, thereby mitigating the effects of the immune attack to which helminths are most susceptible. Enhancing protective immunity against filarial nematodes, for example through vaccination, may be less effective at reducing transmission than would be expected and may, at worst, lead to increased transmission and, hence, pathology.
References
[1]
Stearns S. C (1992) The evolution of life histories. Oxford: Oxford University Press. 249 p.
[2]
Roff D. A (2002) Life history evolution. Sunderland, Mass: Sinauer Associates. 527 p.
[3]
Weider L. J, Pijanowska J (1993) Plasticity of Daphnia life histories in response to chemical cues from predators. Oikos 67: 385–392.
[4]
Stibor H, Luning J (1994) Predator-induced phenotypic variation in the pattern of growth and reproduction in Daphnia hyalina (Crustacea: Cladocera). Funct Ecol 8: 97–101.
[5]
Bourdeau P. E (2010) Cue reliability, risk sensitivity and inducible morphological defense in a marine snail. Oecologia 162: 987–994.
[6]
Schlichting C, Pigliucci M (1998) Phenotypic evolution: a reaction norm perspective. Sunderland, Mass: Sinauer. 387 p.
[7]
West-Eberhard M. J (2003) Developmental plasticity and evolution. Oxford; New York: Oxford University Press. 794 p.
[8]
Hazel W, Smock R, Lively C. M (2004) The ecological genetics of conditional strategies. Am Nat 163: 888–900.
[9]
Scheiner S. M (1993) Genetics and evolution of phenotypic plasticity. Annu Rev Ecol Syst 24: 35–68.
[10]
Moran N. A (1992) The evolutionary maintenance of alternative phenotypes. Am Nat 139: 971–989.
[11]
Chevin L. M, Lande R, Mace G. M (2010) Adaptation, plasticity, and extinction in a changing environment: towards a predictive theory. PLoS Biol 8: e1000357. doi:10.1371/journal.pbio.1000357.
[12]
Lynch P. A, Grimm U, Read A. F (2008) How will public and animal health interventions drive life-history evolution in parasitic nematodes? Parasitology 135: 1599–1611.
[13]
Gemmill A. W, Skorping A, Read A. F (1999) Optimal timing of first reproduction in parasitic nematodes. J Evol Biol 12: 1148–1156.
[14]
Guinnee M. A, Gemmill A. W, Chan B. H, Viney M. E, Read A. F (2003) Host immune status affects maturation time in two nematode species–but not as predicted by a simple life-history model. Parasitology 127: 507–512.
[15]
Sorci G, Skarstein F, Morand S, Hugot J. P (2003) Correlated evolution between host immunity and parasite life histories in primates and oxyurid parasites. Proc R Soc Lond B Biol Sci 270: 2481–2484.
[16]
Bleay C, Wilkes C. P, Paterson S, Viney M. E (2009) The effect of infection history on the fitness of the gastrointestinal nematode Strongyloides ratti. Parasitology 136: 567–577.
[17]
Maizels R. M, Balic A, Gomez-Escobar N, Nair M, Taylor M. D, et al. (2004) Helminth parasites–masters of regulation. Immunol Rev 201: 89–116.
[18]
Taylor M. D, LeGoff L, Harris A, Malone E, Allen J. E, et al. (2005) Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol 174: 4924–4933.
[19]
Anthony R. M, Rutitzky L. I, Urban J. F. J, Stadecker M. J, Gause W. C (2007) Protective immune mechanisms in helminth infection. Nat Rev Immunol 7: 975–987.
[20]
Jackson J. A, Turner J. D, Rentoul L, Faulkner H, Behnke J. M, et al. (2004) T helper cell type 2 responsiveness predicts future susceptibility to gastrointestinal nematodes in humans. J Infect Dis 190: 1804–1811.
[21]
Quinnell R. J, Pritchard D. I, Raiko A, Brown A. P, Shaw M. A (2004) Immune responses in human necatoriasis: association between interleukin-5 responses and resistance to reinfection. J Infect Dis 190: 430–438.
[22]
Saeftel M, Arndt M, Specht S, Volkmann L, Hoerauf A (2003) Synergism of gamma interferon and interleukin-5 in the control of murine filariasis. Infect Immun 71: 6978–6985.
[23]
Faulkner H, Turner J, Kamgno J, Pion S. D, Boussinesq M, et al. (2002) Age- and infection intensity-dependent cytokine and antibody production in human trichuriasis: the importance of IgE. J Infect Dis 185: 665–672.
[24]
Amiri P, Locksley R. M, Parslow T. G, Sadick M, Rector E, et al. (1992) Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature 356: 604–607.
[25]
Dunne D. W, Hassounah O, Musallam R, Lucas S, Pepys M. B, et al. (1983) Mechanisms of Schistosoma mansoni egg excretion: parasitological observations in immunosuppressed mice reconstituted with immune serum. Parasite Immunol 5: 47–60.
[26]
Davies S. J, Grogan J. L, Blank R. B, Lim K. C, Locksley R. M, et al. (2001) Modulation of blood fluke development in the liver by hepatic CD4+ lymphocytes. Science 294: 1358–1361.
[27]
Blank R. B, Lamb E. W, Tocheva A. S, Crow E. T, Lim K. C, et al. (2006) The common gamma chain cytokines interleukin (IL)-2 and IL-7 indirectly modulate blood fluke development via effects on CD4+ T cells. J Infect Dis 194: 1609–1616.
[28]
Henderson N. G, Stear M. J (2006) Eosinophil and IgA responses in sheep infected with Teladorsagia circumcincta. Vet Immunol Immunopathol 112: 62–66.
[29]
Babu S, Shultz L. D, Rajan T. V (1999) T cells facilitate Brugia malayi development in TCRalpha(null) mice. Exp Parasitol 93: 55–57.
[30]
Babu S, Porte P, Klei T. R, Shultz L. D, Rajan T. V (1998) Host NK cells are required for the growth of the human filarial parasite Brugia malayi in mice. J Immunol 161: 1428–1432.
[31]
Babayan S, Ungeheuer M, Martin C, Attout T, Belnoue E, et al. (2003) Resistance and susceptibility to filarial infection with Litomosoides sigmodontis are associated with early differences in parasite development and in localized immune reactions. Infect Immun 71: 6820–6829.
[32]
Martin C, Le Goff L, Ungeheuer M. N, Vuong P. N, Bain O (2000) Drastic reduction of a filarial infection in eosinophilic interleukin-5 transgenic mice. Infect Immun 68: 3651–3656.
[33]
Martin C, Al-Qaoud K. M, Ungeheuer M. N, Paehle K, Vuong P. N, et al. (2000) IL-5 is essential for vaccine-induced protection and for resolution of primary infection in murine filariasis. Medical Microbiology and Immunology 189: 67–74.
[34]
Gandon S, Day T (2008) Evidences of parasite evolution after vaccination. Vaccine 26: Suppl 3C4–7.
[35]
Allen J. E, Adjei O, Bain O, Hoerauf A, Hoffmann W. H, et al. (2008) Of mice, cattle, and humans: the immunology and treatment of river blindness. PLoS Negl Trop Dis 2: e217. doi:10.1371/journal.pntd.0000217.
[36]
de Almeida A. B, Freedman D. O (1999) Epidemiology and immunopathology of bancroftian filariasis. Microbes Infect 1: 1015–1022.
[37]
Hoerauf A, Satoguina J, Saeftel M, Specht S (2005) Immunomodulation by filarial nematodes. Parasite Immunol 27: 417–429.
[38]
Herbert D. R, Lee J. J, Lee N. A, Nolan T. J, Schad G. A, et al. (2000) Role of IL-5 in innate and adaptive immunity to larval Strongyloides stercoralis in mice. J Immunol 165: 4544–4551.
[39]
Volkmann L, Bain O, Saeftel M, Specht S, Fischer K, et al. (2003) Murine filariasis: interleukin 4 and interleukin 5 lead to containment of different worm developmental stages. Med Microbiol Immunol 192: 23–31.
[40]
Specht S, Saeftel M, Arndt M, Endl E, Dubben B, et al. (2006) Lack of eosinophil peroxidase or major basic protein impairs defense against murine filarial infection. Infect Immun 74: 5236–5243.
[41]
Giacomin P. R, Gordon D. L, Botto M, Daha M. R, Sanderson S. D, et al. (2008) The role of complement in innate, adaptive and eosinophil-dependent immunity to the nematode Nippostrongylus brasiliensis. Mol Immunol 45: 446–455.
[42]
Rainbird M. A, Macmillan D, Meeusen E. N (1998) Eosinophil-mediated killing of Haemonchus contortus larvae: effect of eosinophil activation and role of antibody, complement and interleukin-5. Parasite Immunol 20: 93–103.
[43]
Simons J. E, Rothenberg M. E, Lawrence R. A (2005) Eotaxin-1-regulated eosinophils have a critical role in innate immunity against experimental Brugia malayi infection. Eur J Immunol 35: 189–197.
[44]
Babayan S. A, Attout T, Harris A, Taylor M. D, Le Goff L, et al. (2006) Vaccination against filarial nematodes with irradiated larvae provides long-term protection against the third larval stage but not against subsequent life cycle stages. Int J Parasitol 36: 903–914.
[45]
Le Goff L, Loke P, Ali H. F, Taylor D. W, Allen J. E (2000) Interleukin-5 is essential for vaccine-mediated immunity but not innate resistance to a filarial parasite. Infect Immun 68: 2513–2517.
[46]
Lee J. J, Dimina D, Macias M. P, Ochkur S. I, McGarry M. P, et al. (2004) Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305: 1773–1776.
[47]
Babayan S, Attout T, Specht S, Hoerauf A, Snounou G, et al. (2005) Increased early local immune responses and altered worm development in high-dose infections of mice susceptible to the filaria Litomosoides sigmodontis. Med Microbiol Immunol 194: 151–162.
[48]
Marechal P, Le Goff L, Petit G, Diagne M, Taylor D. W, et al. (1996) The fate of the filaria Litomosoides sigmodontis in susceptible and naturally resistant mice. Parasite 3: 25–31.
[49]
Foster P. S, Mould A. W, Yang M, Mackenzie J, Mattes J, et al. (2001) Elemental signals regulating eosinophil accumulation in the lung. Int J Parasitol 179: 173–181.
[50]
Grimaldi J. C, Yu N. X, Grunig G, Seymour B. W, Cottrez F, et al. (1999) Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3). J Leukoc Biol 65: 846–853.
[51]
Le Goff L, Lamb T. J, Graham A. L, Harcus Y, Allen J. E (2002) IL-4 is required to prevent filarial nematode development in resistant but not susceptible strains of mice. Int J Parasitol 32: 1277–1284.
[52]
Martin C, Saeftel M, Vuong P. N, Babayan S. A, Fischer K, et al. (2001) B-cell deficiency suppresses vaccine-induced protection against murine filariasis but does not increase the recovery rate for primary infection. Infect Immun 69: 7067–7073.
[53]
Horikawa K, Takatsu K (2006) Interleukin-5 regulates genes involved in B-cell terminal maturation. Immunology 118: 497–508.
[54]
Al-Qaoud K. M, Pearlman E, Hartung T, Klukowski J, Fleischer B, et al. (2000) A new mechanism for IL-5-dependent helminth control: neutrophil accumulation and neutrophil-mediated worm encapsulation in murine filariasis are abolished in the absence of IL-5. Int Immunol 12: 899–908.
[55]
Karanja D. M, Colley D. G, Nahlen B. L, Ouma J. H, Secor W. E (1997) Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections. Am J Trop Med Hyg 56: 515–521.
[56]
Lamb E. W, Crow E. T, Lim K. C, Liang Y. S, Lewis F. A, et al. (2007) Conservation of CD4+ T cell-dependent developmental mechanisms in the blood fluke pathogens of humans. Int J Parasitol 37: 405–415.
[57]
Bateson P, Barker D, Clutton-Brock T, Deb D, D'Udine B, et al. (2004) Developmental plasticity and human health. Nature 430: 419–421.
[58]
Sultan S. E (2007) Development in context: the timely emergence of eco-devo. Trends Ecol Evol 22: 575–582.
[59]
de Almeida A. B, Maia e Silva M. C, Maciel M. A, Freedman D. O (1996) The presence or absence of active infection, not clinical status, is most closely associated with cytokine responses in lymphatic filariasis. J Infect Dis 173: 1453–1459.
[60]
Thomas F, Brown S. P, Sukhdeo M, Renaud F (2002) Understanding parasite strategies: a state-dependent approach? Trends in Parasitology 18: 387–390.
[61]
Van Buskirk J, Steiner U. K (2009) The fitness costs of developmental canalization and plasticity. J Evol Biol 22: 852–860.
[62]
Gandon S, Day T (2007) The evolutionary epidemiology of vaccination. J R Soc Interface 4: 803–817.
[63]
Chandler A. C (1931) New genera and species of nematode worms. Proc US Nat Hist Mus 78: 1–11.
[64]
Diagne M, Petit G, Liot P, Cabaret J, Bain O (1990) The filaria Litomosoides galizai in mites; microfilarial distribution in the host and regulation of the transmission. Ann Parasitol Hum Comp 65: 193–199.
[65]
Bain O, Wanji S, Vuong P. N, Marechal P, Le Goff L, et al. (1994) Larval biology of six filariae of the sub-family Onchocercinae in a vertebrate host. Parasite 1: 241–254.
[66]
Ihaka R, Gentleman R (1996) R: A language for data analysis and graphics. Journal of Computational and Graphical Statistics 5: 299–314.
