, Volume 15, Issue 2, pp 360–371 | Cite as

Parasite Tolerance and Host Competence in Avian Host Defense to West Nile Virus

  • Sarah C. Burgan
  • Stephanie S. Gervasi
  • Lynn B. MartinEmail author
Original Contribution


Competence, or the propensity of a host to transmit parasites, is partly underlain by host strategies to cope with infection (e.g., resistance and tolerance). Resistance represents the ability of hosts to prevent or clear infections, whereas tolerance captures the ability of individuals to cope with a given parasite burden. Here, we investigated (1) whether one easy-to-measure form of tolerance described well the dynamic relationships between host health and parasite burden, and (2) whether individual resistance and tolerance to West Nile virus (WNV) were predictable from single cytokine measures. We exposed house sparrows (HOSP) to WNV and measured subsequent changes in host performance, viral burden, and cytokine expression. We then used two novel approaches (one complex, one simpler) to estimate tolerance within-individual HOSP using four separate host performance traits. We lastly investigated changes in the expression of pro-inflammatory cytokine interferon-γ (IFN-γ) and anti-inflammatory cytokine interleukin-10 (IL-10). Both approaches to estimating tolerance were equivalent among WNV-infected HOSP; thus, an easy-to-measure tolerance estimation may be successfully applied in field studies. Constitutive expression of IFN-γ and IL-10 were predictive of resistance and tolerance to WNV, implicating these cytokines as viable biomarkers of host competence to WNV.


behavior biomarkers competence disease methodology transmission 



We thank Drs. Thomas Unnasch and Hassan Hassan for their support on the WNV grant conceiving of this work, and Dr. Laura Schoenle for her help and advice in developing the position method of estimating tolerance. We also appreciate the assistance of Dr. Amber Brace, Holly Kilvitis, and the rest of the Martin and Unnasch labs for their support and feedback. This work was supported by the National Science Foundation’s Division of Integrative Organismal Systems [1257773 to LBM], the American Ornithologists Union [AOU Award to SCB], Sigma-Xi [Grants-in-Aid of Research to SCB], the Porter Family Foundation [Porter Award to SCB] and the Animal Behavior Society [ABS Student Research Grant to SCB].

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Data Availability

Data will be made publically available from the Dryad Digital Repository.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Supplementary material

10393_2018_1332_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 kb)
10393_2018_1332_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 12 kb)


  1. Adelman JS, Bentley GE, Wingfield JC, Martin LB, Hau M, et al. (2010) Population differences in fever and sickness behaviors in a wild passerine: a role for cytokines. Journal of Experimental Biology 213:4099–4109CrossRefPubMedGoogle Scholar
  2. Adelman JS and Hawley DM (2017) Tolerance of infection: a role for animal behavior, potential immune mechanisms, and consequences for parasite transmission. Hormones and Behavior 88:79–86CrossRefPubMedGoogle Scholar
  3. Adelman JS, Kirkpatrick L, Grodio JL, Hawley DM et al. (2013) House finch populations differ in early inflammatory signaling and pathogen tolerance at the peak of mycoplasma gallisepticum infection. The American Naturalist 181:674–689CrossRefPubMedGoogle Scholar
  4. Ayres JS and Schneider DS (2012) Tolerance of infections. Annual Review of Immunology 30:271–294CrossRefPubMedGoogle Scholar
  5. Bai FW, Town T, Qian F, Wang PH, Kamanaka M, Connolly TM, Gate D, Montgomery RR, Flavell RA, Fikrig E et al. (2009) Il-10 signaling blockade controls murine west nile virus infection. PLoS Pathogens 5:e1000610CrossRefPubMedPubMedCentralGoogle Scholar
  6. Barron DG, Gervasi SS, Pruitt JN, and Martin LB (2015) Behavioral competence: how host behaviors can interact to influence parasite transmission risk. Current Opinion in Behavioral Sciences 6:35–40CrossRefGoogle Scholar
  7. Bates D, Maechler M, Bolker B, Walker S et al. (2015) Fitting linear mixed-effects models using lme4. Journal of Statistical Software 67:1–48CrossRefGoogle Scholar
  8. Best A, White A, Boots M et al. (2014) The coevolutionary implications of host tolerance. Evolution 68:1426–1435CrossRefPubMedGoogle Scholar
  9. Boots M (2008) Fight or learn to live with the consequences?. Trends in Ecology & Evolution 23:248–250CrossRefGoogle Scholar
  10. Brien JD, Lazear HM, Diamond MS et al. (2013) Propagation, quantification, detection, and storage of west nile virus. In Current protocols in microbiology. Hoboken: WileyGoogle Scholar
  11. Burgan SC, Gervasi SS, Johnson L, and Martin LB (in review) Tolerance and competence: how technique affects inference across ecological scales.Google Scholar
  12. Byrne SN, Halliday GM, Johnston LJ, King NJ et al. (2001) Interleukin-1beta; but not tumor necrosis factor is involved in west nile virus-induced langerhans cell migration from the skin in c57bl/6 mice. Journal of investigative dermatology 117:702–709CrossRefPubMedGoogle Scholar
  13. Cator L (2017) Malaria altering host attractiveness and mosquito feeding. Trends in Parasitology 33:338CrossRefPubMedGoogle Scholar
  14. Coon CaC, Brace AJ, Mcwilliams SR, Mccue MD, Martin LB et al. (2014) Introduced and native congeners use different resource allocation strategies to maintain performance during infection. Physiological and Biochemical Zoology 87:559–567CrossRefGoogle Scholar
  15. Cornet S, Nicot A, Rivero A, Gandon S et al. (2013) Malaria infection increases bird attractiveness to uninfected mosquitoes. Ecology Letters 16:323–329CrossRefPubMedGoogle Scholar
  16. De Roode JC and Altizer S (2010) Host-parasite genetic interactions and virulence-transmission relationships in natural populations of monarch butterflies. Evolution 64:502–514CrossRefPubMedGoogle Scholar
  17. Del Amo J, Llorente F, Perez-Ramirez E, Soriguer RC, Figuerola J, Nowotny N, Jimenez-Clavero MA et al. (2014) Experimental infection of house sparrows (passer domesticus) with west nile virus strains of lineages 1 and 2. Veterinary Microbiology 172:542–547CrossRefPubMedGoogle Scholar
  18. Diamond MS, Shrestha B, Marri A, Mahan D, Engle M et al. (2003) B cells and antibody play critical roles in the immediate defense of disseminated infection by west nile encephalitis virus. Journal of Virology 77:2578–2586CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dinarello CA (2000) Proinflammatory cytokines. Chest 118:503–508CrossRefPubMedGoogle Scholar
  20. Doeschl-Wilson AB, Bishop SC, Kyriazakis I, Villanueva B et al. (2012) Novel methods for quantifying individual host response to infectious pathogens for genetic analyses. Frontiers in Genetics 3:266PubMedPubMedCentralGoogle Scholar
  21. Duggal NK, Bosco-Lauth A, Bowen RA, Wheeler SS, Reisen WK, Felix TA, Mann BR, Romo H, Swetnam DM, Barrett ADT, Brault AC et al. (2014) Evidence for co-evolution of west nile virus and house sparrows in North America. PLoS Negl Trop Dis 8:e3262CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, Ogarra A et al. (1991) Il-10 inhibits cytokine production by activated macrophages. Journal of Immunology 147:3815–3822Google Scholar
  23. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR et al. (1993) An essential role for interferon gamma in resistance to mycobacterium tuberculosis infection. The Journal of Experimental Medicine 178:2249–2254CrossRefPubMedGoogle Scholar
  24. Fox J and Weisberg S (2011) An {r} companion to applied regression, 2nd edn., Thousand Oaks: Sage.Google Scholar
  25. Gazzinelli RT, Oswald IP, James SL, Sher A et al. (1992) Il-10 inhibits parasite killing and nitrogen-oxide production by IFN-gamma-activated macrophages. Journal of Immunology 148:1792–1796Google Scholar
  26. Gervasi SS, Burgan SC, Hofmeister E, Unnasch TR, Martin LB et al. (2017) Stress hormones predict a host superspreader phenotype in the west nile virus system. Proceedings of the Royal Society B: Biological Sciences 284:20171090Google Scholar
  27. Gervasi SS, Civitello DJ, Kilvitis HJ, Martin LB et al. (2015) The context of host competence: a role for plasticity in host–parasite dynamics. Trends in Parasitology 31:419–425CrossRefPubMedPubMedCentralGoogle Scholar
  28. Gopinath S, Lichtman JS, Bouley DM, Elias JE, Monack DM (2014) Role of disease-associated tolerance in infectious superspreaders. Proceedings of the National Academy of Sciences of the United States of America 111:15780–15785CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gosler AG (1991) On the use of greater covert moult and pectoral muscle as measures of condition in passerines with data for the great tit parus major. Bird Study 38:1–9CrossRefGoogle Scholar
  30. Govorkova EA, Murti G, Meignier B, De Taisne C, Webster RG et al. (1996) African green monkey kidney (vero) cells provide an alternative host cell system for influenza a and b viruses. Journal of Virology 70:5519–5524PubMedPubMedCentralGoogle Scholar
  31. Graham AL, Shuker DM, Pollitt LC, Auld SKJR, Wilson AJ, and Little TJ (2011) Fitness consequences of immune responses: Strengthening the empirical framework for ecoimmunology. Functional Ecology 25:5-17CrossRefGoogle Scholar
  32. Han BA, Kramer AM, Drake JM et al. (2016) Global patterns of zoonotic disease in mammals. Trends in Parasitology PubMedPubMedCentralCrossRefGoogle Scholar
  33. Harrell Jr. FE, Dupont C, et al. (2008) “Hmisc: Harrell miscellaneous.” R package version 3.2Google Scholar
  34. Hayward AD, Nussey DH, Wilson AJ, Berenos C, Pilkington JG, Watt KA, Pemberton JM, and Graham AL (2014) Natural selection on individual variation in tolerance of gastrointestinal nematode infection. PLoS Biology 12:e1001917Google Scholar
  35. Keesing F, Holt RD, Ostfeld RS et al.(2006) Effects of species diversity on disease risk. Ecology Letters 9:485–498CrossRefPubMedGoogle Scholar
  36. Kilpatrick AM, Ladeau SL, Marra PP et al. (2007) Ecology of west nile virus transmission and its impact on birds in the western hemisphere. The Auk 124:1121–1136CrossRefGoogle Scholar
  37. Kilpatrick AM and Pape WJ (2013) Predicting human west nile virus infections with mosquito surveillance data. American Journal of Epidemiology PubMedCentralCrossRefPubMedGoogle Scholar
  38. Kilpatrick AM, Peters RJ, Dupuis AP, Jones MJ, Marra PP, Kramer LD et al.(2013) Predicted and observed mortality from vector-borne disease in small songbirds. Biological Conservation 165:79–85CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kokordelis P, Krämer B, Körner C, Boesecke C, Voigt E, Ingiliz P, Glässner A, Eisenhardt M, Wolter F, Kaczmarek D, Nischalke HD, Rockstroh JK, Spengler U, Nattermann J et al.(2014) An effective interferon-gamma-mediated inhibition of hepatitis c virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis c in human immunodeficiency virus-positive patients. Hepatology 59:814–827CrossRefPubMedGoogle Scholar
  40. Komar N, Langevin S, Hinten S, Nemeth N, Edwards E, Hettler D, Davis B, Bowen R, Bunning M et al. (2003) Experimental infection of north american birds with the new york 1999 strain of west nile virus. Emerging Infectious Diseases 9:311–322CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kramer LD, Li J, Shi P-Y et al. (2007) West nile virus. The Lancet Neurology 6:171–181CrossRefPubMedGoogle Scholar
  42. Kutzer MaM and Armitage SaO (2016) Maximising fitness in the face of parasites: a review of host tolerance. Zoology 119:281–289CrossRefGoogle Scholar
  43. Lanciotti RS, Kerst AJ, Nasci RS, Godsey MS, Mitchell CJ, Savage HM, Komar N, Panella NA, Allen BC, Volpe KE, Davis BS, Roehrig JT (2000) Rapid detection of west nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a taqman reverse transcriptase-pcr assay. Journal of Clinical Microbiology 38:4066–4071PubMedGoogle Scholar
  44. Langsrud Ø (2003) Anova for unbalanced data: use type II instead of type III sums of squares. Statistics and Computing 13:163–167CrossRefGoogle Scholar
  45. Lim SM, Koraka P, Osterhaus ADME, and Martina BEE (2011) West nile virus: immunity and pathogenesis. Viruses-Basel 3:811–828CrossRefGoogle Scholar
  46. Little TJ, Shuker DM, Colegrave N, Day T, Graham AL et al. (2010) The coevolution of virulence: tolerance in perspective. PLoS Pathogens 6:e1001006Google Scholar
  47. Lloyd-Smith JO, Schreiber SJ, Kopp PE, Getz WM et al. (2005) Superspreading and the effect of individual variation on disease emergence. Nature 438:355–359CrossRefPubMedGoogle Scholar
  48. Logiudice K, Ostfeld RS, Schmidt KA, Keesing F et al. (2003) The ecology of infectious disease: Effects of host diversity and community composition on lyme disease risk. Proceedings of the National Academy of Sciences of the United States of America 100:567–571CrossRefPubMedPubMedCentralGoogle Scholar
  49. Long GH, Chan BHK, Allen JE, Read AF, Graham AL et al. (2008) Blockade of tnf receptor 1 reduces disease severity but increases parasite transmission during plasmodium chabaudi chabaudi infection. International Journal for Parasitology 38:1073–1081CrossRefPubMedGoogle Scholar
  50. Mandl JN, Ahmed R, Barreiro LB, Daszak P, Epstein JH, Virgin HW, Feinberg MB et al. (2015) Reservoir host immune responses to emerging zoonotic viruses. Cell 160:20–35CrossRefPubMedGoogle Scholar
  51. Martin LB, Brace AJ, Urban A, Coon CaC, Liebl AL et al. (2012) Does immune suppression during stress occur to promote physical performance? Journal of Experimental Biology 215:4097–4103CrossRefPubMedGoogle Scholar
  52. Martin LB, Burgan SC, Adelman JS, Gervasi SS (2016) Host competence: an organismal trait to integrate immunology and epidemiology. Integrative and Comparative Biology CrossRefPubMedGoogle Scholar
  53. Mckinnon EA, Rotenberg JA, Stutchbury BJM et al. (2015) Seasonal change in tropical habitat quality and body condition for a declining migratory songbird. Oecologia 179:363–375CrossRefPubMedGoogle Scholar
  54. Medzhitov R, Schneider DS, Soares MP et al. (2012) Disease tolerance as a defense strategy. Science 335:936–941CrossRefPubMedPubMedCentralGoogle Scholar
  55. Metcalfe NB and Ure SE (1995) Diurnal variation in flight performance and hence potential predation risk in small birds. Proceedings of the Royal Society of London B: Biological Sciences 261:395–400CrossRefGoogle Scholar
  56. Muñoz J, Ruiz S, Soriguer R, Alcaide M, Viana DS, Roiz D, Vázquez A, Figuerola J et al. (2012) Feeding patterns of potential west nile virus vectors in south-west spain. PLoS ONE 7:e39549CrossRefPubMedPubMedCentralGoogle Scholar
  57. Nemeth N, Young G, Ndaluka C, Bielefeldt-Ohmann H, Komar N, Bowen R et al. (2009a) Persistent west nile virus infection in the house sparrow (passer domesticus). Archives of Virology 154:783–789CrossRefPubMedGoogle Scholar
  58. Nemeth NM, Oesterle PT, Bowen RA et al. (2009b) Humoral immunity to west nile virus is long-lasting and protective in the house sparrow (passer domesticus). American Journal of Tropical Medicine and Hygiene 80:864–869CrossRefPubMedGoogle Scholar
  59. O’brien VA, Meteyer CU, Ip HS, Long RR, Brown CR et al. (2010a) Pathology and virus detection in tissues of nestling house sparrows naturally infected with buggy creek virus (togaviridae). Journal of Wildlife Diseases 46:23–32Google Scholar
  60. O’brien VA, Meteyer CU, Reisen WK, Ip HS, Brown CR et al. (2010b) Prevalence and pathology of west nile virus in naturally infected house sparrows, western nebraska, 2008. American Journal of Tropical Medicine and Hygiene 82:937–944Google Scholar
  61. Opal SM and Depalo VA (2000) Anti-inflammatory cytokines. Chest 117:1162–1172CrossRefPubMedGoogle Scholar
  62. Ostfeld RS and Keesing F (2000) Biodiversity and disease risk: the case of lyme disease biodiversidad y riesgo de enfermedades: El caso de la enfermedad de lyme. Conservation Biology 14:722–728CrossRefGoogle Scholar
  63. Owen-Ashley NT and Wingfield JC (2007) Acute phase responses of passerine birds: characterization and seasonal variation. Journal of Ornithology 148:583–591CrossRefGoogle Scholar
  64. Papin JF, Vahrson W, Larson L, Dittmer DP et al. (2010) Genome-wide real-time pcr for west nile virus reduces the false-negative rate and facilitates new strain discovery. Journal of Virological Methods 169:103–111CrossRefPubMedPubMedCentralGoogle Scholar
  65. Paull SH, Song S, Mcclure KM, Sackett LC, Kilpatrick AM, Johnson PTJ et al. (2012) From superspreaders to disease hotspots: linking transmission across hosts and space. Frontiers in Ecology and the Environment 10:75–82CrossRefPubMedPubMedCentralGoogle Scholar
  66. R Core Team (2015) R: a language and environment for statistical computing. In R Foundation for Statistical Computing (Team, C., ed).Google Scholar
  67. Raberg L, Graham AL, Read AF et al. (2009) Decomposing health: Tolerance and resistance to parasites in animals. Philosophical Transactions of the Royal Society B-Biological Sciences 364:37–49CrossRefGoogle Scholar
  68. Raberg L, Sim D, Read AF et al. (2007) Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318:812–814CrossRefPubMedGoogle Scholar
  69. Raffel TR, Martin LB, Rohr JR (2008) Parasites as predators: unifying natural enemy ecology. Trends in Ecology & Evolution 23:610–618CrossRefGoogle Scholar
  70. Regoes RR, Mclaren PJ, Battegay M, Bernasconi E, Calmy A, Gunthard HF, Hoffmann M, Rauch A, Telenti A, Fellay J, Study SHC et al. (2014) Disentangling human tolerance and resistance against hiv. PLoS Biology 12:e1001951Google Scholar
  71. Rizzoli A, Bolzoni L, Chadwick EA, Capelli G, Montarsi F, Grisenti M, De La Puente JM, Muñoz J, Figuerola J, Soriguer R, Anfora G, Di Luca M, Rosà R et al.(2015) Understanding west nile virus ecology in europe: culex pipiens host feeding preference in a hotspot of virus emergence. Parasites & Vectors 8:1–13CrossRefGoogle Scholar
  72. Rohr JR, Raffel TR, and Hall CA (2010) Developmental variation in resistance and tolerance in a multi-host-parasite system. Functional Ecology 24:1110-1121CrossRefGoogle Scholar
  73. Samuel MA and Diamond MS (2006) Pathogenesis of west nile virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. Journal of Virology 80:9349–9360CrossRefPubMedPubMedCentralGoogle Scholar
  74. Schneider DS (2011) Tracing personalized health curves during infections. PLoS Biology 9:e1001158CrossRefPubMedPubMedCentralGoogle Scholar
  75. Sears BF, Rohr JR, Allen JE, Martin LB et al. (2011) The economy of inflammation: When is less more? Trends in Parasitology 27:382–387CrossRefPubMedGoogle Scholar
  76. Shrestha B, Wang T, Samuel MA, Whitby K, Craft J, Fikrig E, Diamond MS et al. (2006) Gamma interferon plays a crucial early antiviral role in protection against west nile virus infection. Journal of Virology 80:5338–5348CrossRefPubMedPubMedCentralGoogle Scholar
  77. Simms EL (2000) Defining tolerance as a norm of reaction. Evolutionary Ecology 14:563–570CrossRefGoogle Scholar
  78. Stowe KA, Marquis RJ, Hochwender CG, Simms EL et al. (2000) The evolutionary ecology of tolerance to consumer damage. Annual Review of Ecology and Systematics 31:565–595CrossRefGoogle Scholar
  79. Suzuki Y, Orellana M, Schreiber R, Remington J et al. (1988) Interferon-gamma: the major mediator of resistance against toxoplasma Gondii. Science 240:516–518CrossRefPubMedGoogle Scholar
  80. Tracey KJ and Cerami A (1993) Tumor necrosis factor, other cytokines and disease. Annual Review of Cell Biology 9:317–343CrossRefPubMedGoogle Scholar
  81. Vale PF, Mcnally L, Doeschl-Wilson A, King KC, Popat R, Domingo-Sananes MR, Allen JE, Soares MP, Kümmerli R et al. (2016) Beyond killing: can we find new ways to manage infection? Evolution, Medicine, and Public Health 2016:148–157CrossRefPubMedPubMedCentralGoogle Scholar
  82. Vanderwaal KL and Ezenwa VO (2016) Heterogeneity in pathogen transmission: mechanisms and methodology. Functional Ecology CrossRefGoogle Scholar
  83. Venables WN and Ripley BD (2002) Modern applied statistics with s. Berlin: SpringerGoogle Scholar
  84. Wang T, Scully E, Yin Z, Kim JH, Wang S, Yan J, Mamula M, Anderson JF, Craft J, Fikrig E et al. (2003) Ifn-γ-producing γδ t cells help control murine west nile virus infection. The Journal of Immunology 171:2524–2531CrossRefPubMedGoogle Scholar
  85. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA et al. (2004) Toll-like receptor 3 mediates west nile virus entry into the brain causing lethal encephalitis. Nature Medicine 10:1366–1373CrossRefPubMedGoogle Scholar
  86. Wheeler SS, Vineyard MP, Woods LW, Reisen WK et al. (2012) Dynamics of west nile virus persistence in house sparrows (passer domesticus). PLoS Neglected Tropical Diseases 6:e1860Google Scholar
  87. Woolhouse MEJ, Dye C, Etard J-F, Smith T, Charlwood JD, Garnett GP, Hagan P, Hii JLK, Ndhlovu PD, Quinnell RJ, Watts CH, Chandiwana SK, Anderson RM et al. (1997) Heterogeneities in the transmission of infectious agents: implications for the design of control programs. Proceedings of the National Academy of Sciences 94:338–342CrossRefGoogle Scholar

Copyright information

© EcoHealth Alliance 2018

Authors and Affiliations

  • Sarah C. Burgan
    • 1
  • Stephanie S. Gervasi
    • 2
  • Lynn B. Martin
    • 1
    Email author
  1. 1.Department of Integrative BiologyUniversity of South FloridaTampaUSA
  2. 2.Monell Chemical Senses CenterPhiladelphiaUSA

Personalised recommendations