Skip to main content

Advertisement

SpringerLink
Log in

Major histocompatibility complex variation and the evolution of resistance to amphibian chytridiomycosis

  • Review
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), has been implicated in population declines and species extinctions of amphibians around the world. Susceptibility to the disease varies both within and among species, most likely attributable to heritable immunogenetic variation. Analyses of transcriptional expression in hosts following their infection by Bd reveal complex responses. Species resistant to Bd generally show evidence of stronger innate and adaptive immune system responses. Major histocompatibility complex (MHC) class I and class II genes of some susceptible species are up-regulated following host infection by Bd, but resistant species show no comparable changes in transcriptional expression. Bd-resistant species share similar pocket conformations within the MHC-II antigen-binding groove. Among susceptible species, survivors of epizootics bear alleles encoding these conformations. Individuals with homozygous resistance alleles appear to benefit by enhanced resistance, especially in environmental conditions that promote pathogen virulence. Subjects that are repeatedly infected and subsequently cleared of Bd can develop an acquired immune response to the pathogen. Strong directional selection for MHC alleles that encode resistance to Bd may deplete genetic variation necessary to respond to other pathogens. Resistance to chytridiomycosis incurs life-history costs that require further study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Addis BR, Lowe WH, Hossack BR, Allendorf FW (2015) Population genetic structure and disease in montane boreal toads: more heterozygous individuals are more likely to be infected with amphibian chytrid. Conserv Genet 16:833–844

    Article  Google Scholar 

  • Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

  • Alford R, Richards S (1997) Lack of evidence for epidemic disease as an agent in the catastrophic decline of Australian rain forest frogs. Conserv Biol 11:1026–1029

  • An D, Waldman B (2016) Enhanced call effort in Japanese tree frogs infected by amphibian chytrid fungus. Biol Lett 12:20160018

  • Barribeau SM, Villinger J, Waldman B (2008) Major histocompatibility complex based resistance to a common bacterial pathogen of amphibians. PLoS One 3:e2692

    Article  PubMed  PubMed Central  Google Scholar 

  • Bataille A, Fong JJ, Cha M, Wogan GOU, Baek HJ, Lee H, Min M-S, Waldman B (2013) Genetic evidence for a high diversity and wide distribution of endemic strains of the pathogenic chytrid fungus Batrachochytrium dendrobatidis in wild Asian amphibians. Mol Ecol 22:4196–4209

  • Bataille A, Cashins SD, Grogan L, Skerratt LF, Hunter D, McFadden M, Scheele B, Brannelly LA, Macris A, Harlow PS, Bell S, Berger L, Waldman B (2015) Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation. Proc R Soc B 282:20143127

    Article  PubMed  PubMed Central  Google Scholar 

  • Berger L, Speare R, Daszak P, Green DE, Cunningham AA, Goggin CL, Slocombe R, Ragan MA, Hyatt AD, McDonald KR, Hines HB, Lips KR, Marantelli G, Parkes H (1998) Chytridiomycosis causes amphibian mortality associated with population declines in the rain forests of Australia and Central America. Proc Natl Acad Sci U S A 95:9031–9036

  • Berger L, Roberts AA, Voyles J, Longcore JE, Murray KA, Skerratt LF (2016) History and recent progress on chytridiomycosis in amphibians. Fungal Ecol 19:89–99

    Article  Google Scholar 

  • Beutler B, Rietschel ET (2003) Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 3:169–176

  • Blaustein AR, Romansic JM, Scheessele EA, Han BA, Pessier AP, Longcore JE (2005) Interspecific variation in susceptibility of frog tadpoles to the pathogenic fungus Batrachochytrium dendrobatidis. Conserv Biol 19:1460–1468

    Article  Google Scholar 

  • Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364:33–39

    Article  CAS  PubMed  Google Scholar 

  • Carey C, Bruzgul JE, Livo LJ, Walling ML, Kuehl KA, Dixon BF, Pessier AP, Alford RA, Rogers KB (2006) Experimental exposures of boreal toads (Bufo boreas) to a pathogenic chytrid fungus (Batrachochytrium dendrobatidis). EcoHealth 3:5–21

    Article  Google Scholar 

  • Carvalho T, Becker CG, Toledo LF (2017) Historical amphibian declines and extinctions in Brazil linked to chytridiomycosis. Proc R Soc B 284:20162254

  • Carver S, Bell BD, Waldman B (2010) Does chytridiomycosis disrupt amphibian skin function? Copeia 2010:487–495

    Article  Google Scholar 

  • Cashins SD, Grogan LF, McFadden M, Hunter D, Harlow PS, Berger L, Skerratt LF (2013) Prior infection does not improve survival against the amphibian disease chytridiomycosis. PLoS One 8:e56747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins JP (2010) Amphibian decline and extinction: what we know and what we need to learn. Dis Aquat Org 92:93–99

  • Cresswell P, Ackerman AL, Giodini A, Peaper DR, Wearsch PA (2005) Mechanisms of MHC class I-restricted antigen processing and cross-presentation. Immunol Rev 207:145–157

  • Dai S, Crawford F, Marrack P, Kappler JW (2008) The structure of HLA-DR52c: comparison to other HLA-DRB3 alleles. Proc Natl Acad Sci U S A 105:11893–11897

  • Ellison AR, Savage AE, DiRenzo GV, Langhammer P, Lips KR, Zamudio KR (2014a) Fighting a losing battle: vigorous immune response countered by pathogen suppression of host defenses in the chytridiomycosis-susceptible frog Atelopus zeteki. G3 Genes Genom Genet 4:1275–1289

    CAS  Google Scholar 

  • Ellison AR, Tunstall T, DiRenzo GV, Hughey MC, Rebollar EA, Belden LK, Harris RN, Ibanez R, Lips KR, Zamudio KR (2014b) More than skin deep: functional genomic basis for resistance to amphibian chytridiomycosis. Genome Biol Evol 7:286–298

    Article  PubMed  PubMed Central  Google Scholar 

  • Farrer RA, Weinert LA, Bielby J, Garner TW, Balloux F, Clare F, Bosch J, Cunningham AA, Weldon C, du Preez LH, Anderson L, Kosakovsky Pond SL, Shahar-Golan R, Henk DA, Fisher MC (2011) Multiple emergences of genetically diverse amphibian-infecting chytrids include a globalized hypervirulent recombinant lineage. Proc Natl Acad Sci U S A 108:18732–18736

  • Fites JS, Ramsey JP, Holden WM, Collier SP, Sutherland DM, Reinert LK, Gayek AS, Dermody TS, Aune TM, Oswald-Richter K, Rollins-Smith LA (2013) The invasive chytrid fungus of amphibians paralyzes lymphocyte responses. Science 342:366–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fong JJ, Cheng TL, Bataille A, Pessier AP, Waldman B, Vredenburg VT (2015) Early 1900s detection of Batrachochytrium dendrobatidis in Korean amphibians. PLoS One 10:e0115656

  • Garner TWJ, Walker S, Bosch J, Leech S, Rowcliffe JM, Cunningham AA, Fisher MC (2009) Life history tradeoffs influence mortality associated with the amphibian pathogen Batrachochytrium dendrobatidis. Oikos 118:783–791

  • Goka K, Yokoyama J, Une Y, Kuroki T, Suzuki K, Nakahara M, Kobayashi A, Inaba S, Mizutani T, Hyatt AD (2009) Amphibian chytridiomycosis in Japan: distribution, haplotypes and possible route of entry into Japan. Mol Ecol 18:4757–4774

    Article  CAS  PubMed  Google Scholar 

  • Hayashi F, Smith KD, Ozinsky A, Hawn TR, Eugene CY, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103

    Article  CAS  PubMed  Google Scholar 

  • Hero J-M, Gillespie GR (1997) Epidemic disease and amphibian declines in Australia. Conserv Biol 11:1023–1025

  • Janeway CA, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

  • Knapp RA, Fellers GM, Kleeman PM, Miller DA, Vredenburg VT, Rosenblum EB, Briggs CJ (2016) Large-scale recovery of an endangered amphibian despite ongoing exposure to multiple stressors. Proc Natl Acad Sci U S A 113:11889–11894

  • Kolby JE, Daszak P (2016) The emerging amphibian fungal disease, chytridiomycosis: a key example of the global phenomenon of wildlife emerging infectious diseases. Microbiol Spectr 4:El10-0004-2015

    Google Scholar 

  • Kosch TA, Bataille A, Didinger C, Eimes JA, Rodriguez-Brenes S, Ryan MJ, Waldman B (2016) Major histocompatibility complex selection dynamics in pathogen-infected tungara frog (Physalaemus pustulosus) populations. Biol Lett 12:20160345

    Article  PubMed  Google Scholar 

  • Kosch TA, Eimes JA, Didinger C, Brannelly LA, Waldman B, Berger L, Skerratt LF (2017) Characterization of MHC class IA in the endangered southern corroboree frog. Immunogenetics 69:165–174

    Article  CAS  PubMed  Google Scholar 

  • Lau Q, Igawa T, Komaki S, Satta Y (2016) Characterisation of major histocompatibility complex class I genes in Japanese Ranidae frogs. Immunogenetics 68:797–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurance WF, McDonald KR, Speare R (1996) Epidemic disease and the catastrophic decline of Australian rain forest frogs. Conserv Biol 10:406–413

    Article  Google Scholar 

  • Luquet E, Garner TW, Léna JP, Bruel C, Joly P, Lengagne T, Grolet O, Plénet S (2012) Genetic erosion in wild populations makes resistance to a pathogen more costly. Evolution 66:1942–1952

    Article  PubMed  Google Scholar 

  • Mak TW, Saunders ME, Jett BD (2014) The major histocompatibility complex. Primer to the immune response, 2nd edn. Academic Cell, Burlington, pp 143–159

    Google Scholar 

  • Martel A, Spitzen-van der Sluijs A, Blooi M, Bert W, Ducatelle R,  Fisher MC,Woeltjes A, Bosman W, Chiers K, Bossuyt F, Pasmans F (2013) Batrachochytrium salamandrivorans sp. nov. causes lethal chytridiomycosis in amphibians. Proc Natl Acad Sci U S A  110:15325–15329

  • Martel A, Blooi M, Adriaensen C, Van Rooij P, Beukema W, Fisher MC, Farrer RA, Schmidt BR, Tobler U, Goka K, Lips KR, Muletz C, Zamudio KR, Bosch J, Lotters S, Wombwell E, Garner TW, Cunningham AA, Spitzen-van der Sluijs A, Salvidio S, Ducatelle R, Nishikawa K, Nguyen TT, Kolby JE, Van Bocxlaer I, Bossuyt F, Pasmans F (2014) Wildlife disease. Recent introduction of a chytrid fungus endangers Western Palearctic salamanders. Science 346:630–631

    Article  CAS  PubMed  Google Scholar 

  • McMahon TA, Sears BF, Venesky MD, Bessler SM, Brown JM, Deutsch K, Halstead NT, Lentz G, Tenouri N, Young S, Civitello DJ, Ortega N, Fites JS, Reinert LK, Rollins-Smith LA, Raffel TR, Rohr JR (2014) Amphibians acquire resistance to live and dead fungus overcoming fungal immunosuppression. Nature 511:224–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci 114:347–360

    Article  PubMed  Google Scholar 

  • Morehouse EA, James TY, Ganley AR, Vilgalys R, Berger L, Murphy PJ, Longcore JE (2003) Multilocus sequence typing suggests the chytrid pathogen of amphibians is a recently emerged clone. Mol Ecol 12:395–403

    Article  CAS  PubMed  Google Scholar 

  • Myers JM, Ramsey JP, Blackman AL, Nichols AE, Minbiole KP, Harris RN (2012) Synergistic inhibition of the lethal fungal pathogen Batrachochytrium dendrobatidis: the combined effect of symbiotic bacterial metabolites and antimicrobial peptides of the frog Rana muscosa. J Chem Ecol 38:958–965

    Article  PubMed  Google Scholar 

  • Nowak MA, Tarczy-Hornoch K, Austyn JM (1992) The optimal number of major histocompatibility complex molecules in an individual. Proc Natl Acad Sci U S A 89:10896–10899

  • Pessier AP, Nichols DK, Longcore JE, Fuller MS (1999) Cutaneous chytridiomycosis in poison dart frogs (Dendrobates spp.) and White’s tree frogs (Litoria caerulea). J Vet Diagn Investig 11:194–199

  • Piertney SB, Oliver MK (2006) The evolutionary ecology of the major histocompatibility complex. Heredity 96:7–21

    CAS  PubMed  Google Scholar 

  • Poorten TJ, Rosenblum EB (2016) Comparative study of host response to chytridiomycosis in a susceptible and a resistant toad species. Mol Ecol 25:5663–5679

    Article  CAS  PubMed  Google Scholar 

  • Price SJ, Garner TW, Balloux F, Ruis C, Paszkiewicz KH, Moore K, Griffiths AG (2015) A de novo assembly of the common frog (Rana temporaria) transcriptome and comparison of transcription following exposure to Ranavirus and Batrachochytrium dendrobatidis. PLoS One 10:e0130500

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramirez-Garces D, Camborde L, Pel MJ, Jauneau A, Martinez Y, Neant I, Leclerc C, Moreau M, Dumas B, Gaulin E (2016) CRN13 candidate effectors from plant and animal eukaryotic pathogens are DNA-binding proteins which trigger host DNA damage response. New Phytol 210:602–617

    Article  CAS  PubMed  Google Scholar 

  • Ramsey JP, Reinert LK, Harper LK, Woodhams DC, Rollins-Smith LA (2010) Immune defenses against Batrachochytrium dendrobatidis, a fungus linked to global amphibian declines, in the South African clawed frog, Xenopus laevis. Infect Immun 78:3981–3992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richmond JQ, Savage AE, Zamudio KR, Rosenblum EB (2009) Toward immunogenetic studies of amphibian chytridiomycosis: linking innate and acquired immunity. Bioscience 59:311–320

    Article  Google Scholar 

  • Robert J, Ohta Y (2009) Comparative and developmental study of the immune system in Xenopus. Dev Dynam 238:1249–1270

    Article  CAS  Google Scholar 

  • Rodriguez D, Becker CG, Pupin NC, Haddad CF, Zamudio KR (2014) Long-term endemism of two highly divergent lineages of the amphibian-killing fungus in the Atlantic Forest of Brazil. Mol Ecol 23:774–787

    Article  CAS  PubMed  Google Scholar 

  • Rollins-Smith LA (1998) Metamorphosis and the amphibian immune system. Immunol Rev 166:221–230

  • Rollins-Smith LA (2009) The role of amphibian antimicrobial peptides in protection of amphibians from pathogens linked to global amphibian declines. Biochim Biophys Acta 1788:1593–1599

    Article  CAS  PubMed  Google Scholar 

  • Rollins-Smith LA (2017) Amphibian immunity-stress, disease, and climate change. Dev Comp Immunol 66:111–119

  • Rollins-Smith LA, Conlon JM (2005) Antimicrobial peptide defenses against chytridiomycosis, an emerging infectious disease of amphibian populations. Dev Comp Immunol 29:589–598

    Article  CAS  PubMed  Google Scholar 

  • Rollins-Smith LA, Ramsey JP, Reinert LK, Woodhams DC, Livo LJ, Carey C (2009) Immune defenses of Xenopus laevis against Batrachochytrium dendrobatidis. Front Biosci 1:68–91

    Article  Google Scholar 

  • Rollins-Smith LA, Ramsey JP, Pask JD, Reinert LK, Woodhams DC (2011) Amphibian immune defenses against chytridiomycosis: impacts of changing environments. Integr Comp Biol 51:552–562

    Article  CAS  PubMed  Google Scholar 

  • Rosenblum EB, Poorten TJ, Settles M, Murdoch GK, Robert J, Maddox N, Eisen MB (2009) Genome-wide transcriptional response of Silurana (Xenopus) tropicalis to infection with the deadly chytrid fungus. PLoS One 4:e6494

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosenblum EB, Poorten TJ, Settles M, Murdoch GK (2012) Only skin deep: shared genetic response to the deadly chytrid fungus in susceptible frog species. Mol Ecol 21:3110–3120

    Article  PubMed  Google Scholar 

  • Savage AE, Zamudio KR (2011) MHC genotypes associate with resistance to a frog-killing fungus. Proc Natl Acad Sci U S A 108:16705–16710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savage AE, Zamudio KR (2016) Adaptive tolerance to a pathogenic fungus drives major histocompatibility complex evolution in natural amphibian populations. Proc R Soc B 283:20153115

    Article  PubMed  PubMed Central  Google Scholar 

  • Scheele BC, Skerratt LF, Grogan LF, Hunter DA, Clemann N, McFadden M, Newell D, Hosking CJ, Gillespie GR, Heard GW, Brannelly L, Roberts AA, Berger L (2017) After the epidemic: ongoing declines, stablizations and recoveries in amphibians afflicted by chytridiomycosis. Biol Conserv 206:37–46

  • Slade RW (1992) Limited MHC polymorphism in the southern elephant seal: implications for MHC evolution and marine mammal population biology. Proc R Soc B 249:163–171

    Article  CAS  PubMed  Google Scholar 

  • Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC (1994) Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368:215–221

    Article  CAS  PubMed  Google Scholar 

  • Stice MJ, Briggs CJ (2010) Immunization is ineffective at preventing infection and mortality due to the amphibian chytrid fungus Batrachochytrium dendrobatidis. J Wildl Dis 46:70–77

    Article  PubMed  Google Scholar 

  • Talley BL, Muletz CR, Vredenburg VT, Fleischer RC, Lips KR (2015) A century of Batrachochytrium dendrobatidis in Illinois amphibians (1888–1989). Biol Conserv 182:254–261

    Article  Google Scholar 

  • Taylor SK, Williams ES, Thorne ET, Mills KW, Withers DI, Pier AC (1999) Causes of mortality of the Wyoming toad. J Wildl Dis 35:49–57

  • Teacher AG, Garner TW, Nichols RA (2009) Evidence for directional selection at a novel major histocompatibility class I marker in wild common frogs (Rana temporaria) exposed to a viral pathogen (Ranavirus). PLoS One 4:e4616

    Article  PubMed  PubMed Central  Google Scholar 

  • Tracy KE, Kiemnec-Tyburczy KM, Dewoody JA, Parra-Olea G, Zamudio KR (2015) Positive selection drives the evolution of a major histocompatibility complex gene in an endangered Mexican salamander species complex. Immunogenetics 67:323–335

    Article  CAS  PubMed  Google Scholar 

  • Van Rooij P, Martel A, D'Herde K, Brutyn M, Croubels S, Ducatelle R, Haesebrouck F, Pasmans F (2012) Germ tube mediated invasion of Batrachochytrium dendrobatidis in amphibian skin is host dependent. PLoS One 7:e41481

  • Voyles J, Young S, Berger L, Campbell C, Voyles WF, Dinudom A, Cook D, Webb R, Alford RA, Skerratt LF, Speare R (2009) Pathogenesis of chytridiomycosis, a cause of catastrophic amphibian declines. Science 326:582–585

  • Wake DB (1991) Declining amphibian populations. Science 253:860

    Article  CAS  PubMed  Google Scholar 

  • Wake DB, Vredenburg VT (2008) Are we in the midst of the sixth mass extinction? A view from the world of amphibians. Proc Natl Acad Sci U S A 105(Suppl 1):11466–11473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waldman B, Tocher M (1998) Behavioral ecology, genetic diversity, and declining amphibian populations. In: Caro T (ed) Behavioral ecology and conservation biology. Oxford University Press, New York, pp 394–443

    Google Scholar 

  • Wegner K, Reusch T, Kalbe M (2003) Multiple parasites are driving major histocompatibility complex polymorphism in the wild. J Evol Biol 16:224–232

    Article  CAS  PubMed  Google Scholar 

  • Woodhams DC, Ardipradja K, Alford RA, Marantelli G, Reinert LK, Rollins-Smith LA (2007) Resistance to chytridiomycosis varies among amphibian species and is correlated with skin peptide defenses. Anim Conserv 10:409–417

    Article  Google Scholar 

  • Woodhams DC, Bell SC, Bigler L, Caprioli RM, Chaurand P, Lam BA, Reinert LK, Stalder U, Vazquez VM, Schliep K, Hertz A, Rollins-Smith LA (2016) Life history linked to immune investment in developing amphibians. Conserv Physiol 4:cow025

  • Young S, Whitehorn P, Berger L, Skerratt LF, Speare R, Garland S, Webb R (2014) Defects in host immune function in tree frogs with chronic chytridiomycosis. PLoS One 9:e107284

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu R, Chen ZY, Wang J, Yuan JD, Liao XY, Gui JF, Zhang QY (2014) Extensive diversification of MHC in Chinese giant salamanders Andrias davidianus (Anda-MHC) reveals novel splice variants. Dev Comp Immunol 42:311–322

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Arnaud Bataille and Ramasamy Dhamodharan for comments on the manuscript. Arnaud Bataille prepared Fig. 1. Our research is supported by grants (to B.W.) from the National Research Foundation of Korea (2015R1D1A1A01057282) funded by the government of the Republic of Korea (MOE), the National Geographic Foundation for Science and Exploration, and the Seoul National University R&D Foundation.

Author information

Authors and Affiliations

  1. Laboratory of Behavioral and Population Ecology, School of Biological Sciences, Seoul National University, Seoul, 08826, South Korea

    Minjie Fu & Bruce Waldman

Authors
  1. Minjie Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce Waldman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce Waldman.

Additional information

This article is published in the Special Issue MHC Genes and Their Ligands in Health and Disease with Editor Prof. Ronald Bontrop.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, M., Waldman, B. Major histocompatibility complex variation and the evolution of resistance to amphibian chytridiomycosis. Immunogenetics 69, 529–536 (2017). https://doi.org/10.1007/s00251-017-1008-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-017-1008-4

Keywords

Search

Navigation