Pathogen adaptations during host-pathogen co-evolution can cause the host balance between immunity and immunopathology to rapidly shift. However, little is known in natural disease systems about the immunological pathways optimised through the trade-off between immunity and self-damage. The evolutionary interaction between the conjunctival bacterial infection Mycoplasma gallisepticum (MG) and its avian host, the house finch (Haemorhous mexicanus), can provide insights into such adaptations in immune regulation. Here we use experimental infections to reveal immune variation in conjunctival tissue for house finches captured from four distinct populations differing in the length of their co-evolutionary histories with MG and their disease tolerance (defined as disease severity per pathogen load) in controlled infection studies. To differentiate contributions of host versus pathogen evolution, we compared house finch responses to one of two MG isolates: the original VA1994 isolate and a more evolutionarily derived one, VA2013. To identify differential gene expression involved in initiation of the immune response to MG, we performed 3'-end transcriptomic sequencing (QuantSeq) of samples from the infection site, conjunctiva, collected 3-days post-infection. In response to MG, we observed an increase in general pro-inflammatory signalling, as well as T-cell activation and IL17 pathway differentiation, associated with a decrease in the IL12/IL23 pathway signalling. The immune response was stronger in response to the evolutionarily derived MG isolate compared to the original one, consistent with known increases in MG virulence over time. The host populations differed namely in pre-activation immune gene expression, suggesting population-specific adaptations. Compared to other populations, finches from Virginia, which have the longest co-evolutionary history with MG, showed significantly higher expression of anti-inflammatory genes and Th1 mediators. This may explain the evolution of disease tolerance to MG infection in VA birds. We also show a potential modulating role of BCL10, a positive B- and T-cell regulator activating the NFKB signalling. Our results illuminate potential mechanisms of house finch adaptation to MG-induced immunopathology, contributing to understanding of the host evolutionary responses to pathogen-driven shifts in immunity-immunopathology trade-offs.

Department of Biological Sciences The University of Memphis Memphis TN United States

Department of Biological Sciences Virginia Tech Blacksburg VA United States

Department of Poultry Science The University of Georgia Athens GA United States

Department of Zoology Charles University Faculty of Science Prague Czechia

European Molecular Biology Laboratory Genomics Core Facility Heidelberg Germany

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Woolhouse ME, Webster JP, Domingo E, Charlesworth B, Levin BR. Biological and biomedical implications of the co-evolution of pathogens and their hosts. Nat Genet (2002) 32:569–77. doi: 10.1038/ng1202-569 PubMed DOI

Read AF. The evolution of virulence. Trends Microbiol (1994) 2:73–6. doi: 10.1016/0966-842X(94)90537-1 PubMed DOI

Bloom DE, Black S, Rappuoli R. Emerging infectious diseases: A proactive approach. Proc Natl Acad Sci (2017) 114:4055–9. doi: 10.1073/pnas.1701410114 PubMed DOI PMC

Cunningham AA, Daszak P, Wood JL. One Health, emerging infectious diseases and wildlife: two decades of progress? Philos Trans R Soc B Biol Sci (2017) 372:20160167. doi: 10.1098/rstb.2016.0167 PubMed DOI PMC

Hawley DM, Osnas EE, Dobson AP, Hochachka WM, Ley DH, Dhondt AA. Parallel patterns of increased virulence in a recently emerged wildlife pathogen. PloS Biol (2013) 11:e1001570. doi: 10.1371/journal.pbio.1001570 PubMed DOI PMC

Voyles J, Woodhams DC, Saenz V, Byrne AQ, Perez R, Rios-Sotelo G, et al. . Shifts in disease dynamics in a tropical amphibian assemblage are not due to pathogen attenuation. Science (2018) 359:1517–9. doi: 10.1126/science.aao4806 PubMed DOI

Langwig KE, Hoyt JR, Parise KL, Frick WF, Foster JT, Kilpatrick AM. Resistance in persisting bat populations after white-nose syndrome invasion. Philos Trans R Soc B Biol Sci (2017) 372:20160044. doi: 10.1098/rstb.2016.0044 PubMed DOI PMC

Alves JM, Carneiro M, Cheng JY, Lemos de Matos A, Rahman MM, Loog L, et al. . Parallel adaptation of rabbit populations to myxoma virus. Science (2019) 363:1319–26. doi: 10.1126/science.aau7285 PubMed DOI PMC

Graham AL, Allen JE, Read AF. Evolutionary causes and consequences of immunopathology. Annu Rev Ecol Evol Syst (2005) 36:373–97. doi: 10.1146/annurev.ecolsys.36.102003.152622 DOI

Seal S, Dharmarajan G, Khan I. Evolution of pathogen tolerance and emerging infections: A missing experimental paradigm. Elife (2021) 10:e68874. doi: 10.7554/eLife.68874 PubMed DOI PMC

Boots M, Bowers RG. Three mechanisms of host resistance to microparasites—avoidance, recovery and tolerance—show different evolutionary dynamics. J Theor Biol (1999) 201:13–23. doi: 10.1006/jtbi.1999.1009 PubMed DOI

Råberg L, Sim D, Read AF. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science (2007) 318:812–4. doi: 10.1126/science.1148526 PubMed DOI

Miller MR, White A, Boots M. The evolution of parasites in response to tolerance in their hosts: the good, the bad, and apparent commensalism. Evolution (2006) 60:945–56. doi: 10.1111/j.0014-3820.2006.tb01173.x PubMed DOI

Little TJ, Shuker DM, Colegrave N, Day T, Graham AL. The coevolution of virulence: tolerance in perspective. PloS Pathog (2010) 6:e1001006. doi: 10.1371/journal.ppat.1001006 PubMed DOI PMC

Henschen AE, Adelman JS. What does tolerance mean for animal disease dynamics when pathology enhances transmission? Integr Comp Biol (2019) 59:1220–30. doi: 10.1093/icb/icz065 PubMed DOI

Ruden RM, Adelman JS. Disease tolerance alters host competence in a wild songbird. Biol Lett (2021) 17:20210362. doi: 10.1098/rsbl.2021.0362 PubMed DOI PMC

Savage AE, Zamudio KR. Adaptive tolerance to a pathogenic fungus drives major histocompatibility complex evolution in natural amphibian populations. Proc R Soc B Biol Sci (2016) 283:20153115. doi: 10.1098/rspb.2015.3115 PubMed DOI PMC

Atkinson CT, Saili KS, Utzurrum RB, Jarvi SI. Experimental evidence for evolved tolerance to avian malaria in a wild population of low elevation Hawai ‘i ‘Amakihi (Hemignathus virens). EcoHealth (2013) 10:366–75. doi: 10.1007/s10393-013-0899-2 PubMed DOI

Weber JN, Steinel NC, Peng F, Shim KC, Lohman BK, Fuess LE, et al. . Evolutionary gain and loss of a pathological immune response to parasitism. Science (2022) 377:1206–11. doi: 10.1126/science.abo3411 PubMed DOI PMC

Henschen AE, Vinkler M, Langager MM, Rowley AA, Dalloul RA, Hawley DM, et al. . Rapid adaptation to a novel pathogen through disease tolerance in a wild songbird. PloS Pathog (2023) 19:e1011408. doi: 10.1371/journal.ppat.1011408 PubMed DOI PMC

Vinkler M, Fiddaman SR, Těšický M, O’Connor EA, Savage AE, Lenz TL, et al. . Understanding the evolution of immune genes in jawed vertebrates. J Evol Biol (2023) 36:847–73. doi: 10.1111/jeb.14181 PubMed DOI PMC

Ley DH. Mycoplasma gallisepticum infection. In: Saif YM, editor. Diseases of poultry (12th ed). Ames, IA, USA: Blackwell Publishing; (2008) pp. 807–834.

Ferguson-Noel N, Armour NK, Noormohammadi AH, El-Gazzar M, Bradbury JM. Mycoplasmosis. Dis Poult (2020), 907–65. doi: 10.1002/9781119371199.ch21 DOI

Ley DH, Berkhoff JE, McLaren JM. Mycoplasma gallisepticum Isolated from House Finches (Carpodacus mexicanus) with Conjunctivitis. Avian Dis (1996) 40:480. doi: 10.2307/1592250 PubMed DOI

Dhondt AA, Altizer S, Cooch EG, Davis AK, Dobson A, Driscoll MJL, et al. . Dynamics of a novel pathogen in an avian host: Mycoplasmal conjunctivitis in house finches. Acta Trop (2005) 94:77–93. doi: 10.1016/j.actatropica.2005.01.009 PubMed DOI

Faustino CR, Jennelle CS, Connolly V, Davis AK, Swarthout EC, Dhondt AA, et al. . Mycoplasma gallisepticum infection dynamics in a house finch population: seasonal variation in survival, encounter and transmission rate. J Anim Ecol (2004) 73:651–69. doi: 10.1111/j.0021-8790.2004.00840.x DOI

Hochachka WM, Dhondt AA. Density-dependent decline of host abundance resulting from a new infectious disease. Proc Natl Acad Sci (2000) 97:5303–6. doi: 10.1073/pnas.080551197 PubMed DOI PMC

Staley M, Bonneaud C, McGraw KJ, Vleck CM, Hill GE. Detection of Mycoplasma gallisepticum in house finches (Haemorhous mexicanus) from Arizona. Avian Dis (2018) 62:14–7. doi: 10.1637/11610-021317-Reg.1 PubMed DOI

Ley DH, Hawley DM, Geary SJ, Dhondt AA. House Finch (Haemorhous mexicanus) Conjunctivitis, and Mycoplasma spp. Isolated from North American Wild Birds, 1994–2015. J Wildl Dis (2016) 52:669–73. doi: 10.7589/2015-09-244 PubMed DOI PMC

Grodio JL, Hawley DM, Osnas EE, Ley DH, Dhondt KV, Dhondt AA, et al. . Pathogenicity and immunogenicity of three Mycoplasma gallisepticum isolates in house finches (Carpodacus mexicanus). Vet Microbiol (2012) 155:53–61. doi: 10.1016/j.vetmic.2011.08.003 PubMed DOI

Hawley DM, Dhondt KV, Dobson AP, Grodio JL, Hochachka WM, Ley DH, et al. . Common garden experiment reveals pathogen isolate but no host genetic diversity effect on the dynamics of an emerging wildlife disease: Host genetic diversity and disease resistance. J Evol Biol (2010) 23:1680–8. doi: 10.1111/j.1420-9101.2010.02035.x PubMed DOI

Hill GE, Farmer KL. Carotenoid-based plumage coloration predicts resistance to a novel parasite in the house finch. Naturwissenschaften (2005) 92:30–4. doi: 10.1007/s00114-004-0582-0 PubMed DOI

Adelman JS, Kirkpatrick L, Grodio JL, Hawley DM. House Finch Populations Differ in Early Inflammatory Signaling and Pathogen Tolerance at the Peak of Mycoplasma gallisepticum Infection. Am Nat (2013) 181:674–89. doi: 10.1086/670024 PubMed DOI

Razin S, Yogev D, Naot Y. Molecular biology and pathogenicity of mycoplasmas. Microbiol Mol Biol Rev (1998) 62:63. doi: 10.1128/MMBR.62.4.1094-1156.1998 PubMed DOI PMC

Atkinson TP, Waites KB. Mycoplasma pneumoniae infections in childhood. Pediatr Infect Dis J (2014) 33:92–4. doi: 10.1097/INF.0000000000000171 PubMed DOI

Hawley DM, Thomason CA, Aberle MA, Brown R, Adelman JS. High virulence is associated with pathogen spreadability in a songbird–bacterial system. R Soc Open Sci (2023) 10:220975. doi: 10.1098/rsos.220975 PubMed DOI PMC

Vinkler M, Leon AE, Kirkpatrick L, Dalloul RA, Hawley DM. Differing house finch cytokine expression responses to original and evolved isolates of Mycoplasma gallisepticum . Front Immunol (2018) 9:13. doi: 10.3389/fimmu.2018.00013 PubMed DOI PMC

Bonneaud C, Balenger SL, Russell AF, Zhang J, Hill GE, Edwards SV. Rapid evolution of disease resistance is accompanied by functional changes in gene expression in a wild bird. Proc Natl Acad Sci (2011) 108:7866–71. doi: 10.1073/pnas.1018580108 PubMed DOI PMC

Bonneaud C, Balenger SL, Zhang J, Edwards SV, Hill GE. Innate immunity and the evolution of resistance to an emerging infectious disease in a wild bird. Mol Ecol (2012) 21:2628–39. doi: 10.1111/j.1365-294X.2012.05551.x PubMed DOI

Pyle P. Molt limits in North American passerines. North Am Bird Bander (1997) 22:49–89.

Fleming-Davies AE, Williams PD, Dhondt AA, Dobson AP, Hochachka WM, Leon AE, et al. . Incomplete host immunity favors the evolution of virulence in an emergent pathogen. Science (2018) 359:1030–3. doi: 10.1126/science.aao2140 PubMed DOI PMC

Corley SM, Troy NM, Bosco A, Wilkins MR. QuantSeq. 3′ Sequencing combined with Salmon provides a fast, reliable approach for high throughput RNA expression analysis. Sci Rep (2019) 9:18895. doi: 10.1038/s41598-019-55434-x PubMed DOI PMC

Jarvis S, Birsa N, Secrier M, Fratta P, Plagnol V. A comparison of low read depth quantSeq 3′ Sequencing to total RNA-seq in FUS mutant mice. Front Genet (2020) 11:562445. doi: 10.3389/fgene.2020.562445 PubMed DOI PMC

Moll P, Ante M, Seitz A, Reda T. QuantSeq 3′ mRNA sequencing for RNA quantification. Nat Methods (2014) 11:i–iii. doi: 10.1038/nmeth.f.376 DOI

Zhong S, Joung J-G, Zheng Y, Chen Y, Liu B, Shao Y, et al. . High-throughput illumina strand-specific RNA sequencing library preparation. Cold Spring Harb Protoc (2011) pdb–prot5652. doi: 10.1093/nar/gkaa942 PubMed DOI

Ma F, Fuqua BK, Hasin Y, Yukhtman C, Vulpe CD, Lusis AJ, et al. . A comparison between whole transcript and 3’ RNA sequencing methods using Kapa and Lexogen library preparation methods. BMC Genomics (2019) 20:9. doi: 10.1186/s12864-018-5393-3 PubMed DOI PMC

Howe KL, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Amode MR, et al. . Ensembl 2021. Nucleic Acids Res (2021) 49:D884–91. doi: 10.1093/nar/gkaa942 PubMed DOI PMC

Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics (2014) 30:2114–20. doi: 10.1093/bioinformatics/btt656 PubMed DOI PMC

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. . STAR: ultrafast universal RNA-seq aligner. Bioinformatics (2013) 29:15–21. doi: 10.1093/nar/gkv007 PubMed DOI PMC

Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics (2014) 30:923–30. doi: 10.1093/bioinformatics/btt656 PubMed DOI

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. . limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res (2015) 43:e47–7. doi: 10.1093/nar/gkv007 PubMed DOI PMC

Team RC . R: A language and environment for statistical computing. R Foundation for Statistical Computing; (2020).

Ge SX, Jung D, Yao R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics (2020) 36:2628–9. doi: 10.1093/bioinformatics/btz931 PubMed DOI PMC

Kaspers B, Schat KA, Göbel T, Vervelde L. Avian immunology. London, UK: Academic Press; (2021).

Culhane AC, Perriere G, Considine EC, Cotter TG, Higgins DG. Between-group analysis of microarray data. Bioinformatics (2002) 18:1600–8. doi: 10.1073/pnas.0509592103 PubMed DOI

Wu R, Kang R, Tang D. Mitochondrial ACOD1/IRG1 in infection and sterile inflammation. J Intensive Med (2022) 2(2):78–88. doi: 10.1016/j.jointm.2022.01.001 PubMed DOI PMC

Guo D, Dong W, Cong Y, Liu Y, Liang Y, Ye Z, et al. . LIF aggravates pulpitis by promoting inflammatory response in macrophages. Inflammation (2024) 47:307–22. doi: 10.1007/s10753-023-01910-6 PubMed DOI

Inagaki T, Moschetta A, Lee Y-K, Peng L, Zhao G, Downes M, et al. . Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci (2006) 103:3920–5. doi: 10.3389/fimmu.2019.01172 PubMed DOI PMC

Guyon A. CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems. Front Cell Neurosci (2014) 8:65. doi: 10.2147/OTT.S237162 PubMed DOI PMC

Wu R, Chen F, Wang N, Tang D, Kang R. ACOD1 in immunometabolism and disease. Cell Mol Immunol (2020) 17:822–33. doi: 10.1038/s41423-020-0489-5 PubMed DOI PMC

Lee Y, Clinton J, Yao C, Chang SH. Interleukin-17D promotes pathogenicity during infection by suppressing CD8 T cell activity. Front Immunol (2019) 10:1172. doi: 10.1128/IAI.01356-12 PubMed DOI PMC

Zhu C, Chen X, Guan G, Zou C, Guo Q, Cheng P, et al. . IFI30 is a novel immune-related target with predicting value of prognosis and treatment response in glioblastoma. OncoTargets Ther (2020) 13:1129. doi: 10.3389/fimmu.2020.628804 PubMed DOI PMC

Chen Y, Zhao H, Feng Y, Ye Q, Hu J, Guo Y, et al. . Pan-cancer analysis of the associations of TGFBI expression with prognosis and immune characteristics. Front Mol Biosci (2021) 8:745649. doi: 10.3389/fmolb.2021.745649 PubMed DOI PMC

de Almeida LA, Macedo GC, Marinho FA, Gomes MT, Corsetti PP, Silva AM, et al. . Toll-like receptor 6 plays an important role in host innate resistance to Brucella abortus infection in mice. Infect Immun (2013) 81:1654–62. doi: 10.1016/j.dci.2016.01.008 PubMed DOI PMC

Kulappu Arachchige SN, Young ND, Kanci Condello A, Omotainse OS, Noormohammadi AH, Wawegama NK, et al. . Transcriptomic analysis of long-term protective immunity induced by vaccination with Mycoplasma gallisepticum strain ts-304. Front Immunol (2021) 11:628804. doi: 10.1016/S0167-4889(01)00166-5 PubMed DOI PMC

Beaudet J, Tulman E, Pflaum K, Liao X, Kutish G, Szczepanek S, et al. . Transcriptional profiling of the chicken tracheal response to virulent Mycoplasma gallisepticum strain Rlow. Infect Immun (2017) 85:e00343–17. doi: 10.1016/j.celrep.2022.111572 PubMed DOI PMC

Tian W, Zhao C, Hu Q, Sun J, Peng X. Roles of Toll-like receptors 2 and 6 in the inflammatory response to Mycoplasma gallisepticum infection in DF-1 cells and in chicken embryos. Dev Comp Immunol (2016) 59:39–47. doi: 10.1016/j.dci.2016.01.008 PubMed DOI

Stumptner-Cuvelette P, Benaroch P. Multiple roles of the invariant chain in MHC class II function. Biochim Biophys Acta BBA - Mol Cell Res (2002) 1542:1–13. doi: 10.1016/S0167-4889(01)00166-5 PubMed DOI

David K, Friedlander G, Pellegrino B, Radomir L, Lewinsky H, Leng L, et al. . CD74 as a regulator of transcription in normal B cells. Cell Rep (2022) 41:111572. doi: 10.1016/j.celrep.2022.111572 PubMed DOI

Fukuda Y, Bustos MA, Cho S-N, Roszik J, Ryu S, Lopez VM, et al. . Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient survival in melanoma. Cell Death Dis (2022) 13:117. doi: 10.1016/S0092-8674(00)80957-5 PubMed DOI PMC

Mohammed J, Frasca S, Cecchini K, Rood D, Nyaoke AC, Geary SJ, et al. . Chemokine and cytokine gene expression profiles in chickens inoculated with Mycoplasma gallisepticum strains Rlow or GT5. Vaccine (2007) 25:8611–21. doi: 10.1074/jbc.274.29.20127 PubMed DOI

Gehring T, Seeholzer T, Krappmann D. BCL10 – bridging CARDs to immune activation. Front Immunol (2018) 9:1539. doi: 10.3389/fimmu.2018.01539 PubMed DOI PMC

Willis TG, Jadayel DM, Du M-Q, Peng H, Perry AR, Abdul-Rauf M, et al. . Bcl10 is involved in t (1; 14)(p22; q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell (1999) 96:35–45. doi: 10.1016/s0092-8674(00)80957-5 PubMed DOI

Costanzo A, Guiet C, Vito P. c-E10 is a caspase-recruiting domain-containing protein that interacts with components of death receptors signaling pathway and activates nuclear factor-κB. J Biol Chem (1999) 274:20127–32. doi: 10.3389/fimmu.2021.786572 PubMed DOI

Koseki T, Inohara N, Chen S, Carrio R, Merino J, Hottiger MO, et al. . CIPER, a novel NF κB-activating protein containing a caspase recruitment domain with homology to herpesvirus-2 protein E10. J Biol Chem (1999) 274:9955–61. doi: 10.1152/physiolgenomics.00098.2006 PubMed DOI

Ruland J, Duncan GS, Elia A, del Barco Barrantes I, Nguyen L, Plyte S, et al. . Bcl10 is a positive regulator of antigen receptor–induced activation of NF-κ B and neural tube closure. Cell (2001) 104:33–42. doi: 10.1016/S0092-8674(01)00189-1 PubMed DOI

Garcia-Solis B, Van Den Rym A, Pérez-Caraballo JJ, Al–Ayoubi A, Alazami AM, Lorenzo L, et al. . Clinical and immunological features of human BCL10 deficiency. Front Immunol (2021) 4732. doi: 10.1073/pnas.0608388103 PubMed DOI PMC

Murphy JT, Sommer S, Kabara EA, Verman N, Kuelbs MA, Saama P, et al. . Gene expression profiling of monocyte-derived macrophages following infection with Mycobacterium avium subspecies avium and Mycobacterium avium subspecies paratuberculosis . Physiol Genomics (2006) 28:67–75. doi: 10.1111/j.1600-065X.2008.00699.x PubMed DOI

Wang Y, Miao X, Li H, Su P, Lin L, Liu L, et al. . The correlated expression of immune and energy metabolism related genes in the response to Salmonella enterica serovar Enteritidis inoculation in chicken. BMC Vet Res (2020) 16:1–9. doi: 10.1016/j.jdermsci.2011.11.007 PubMed DOI PMC

Klemm S, Zimmermann S, Peschel C, Mak TW, Ruland J. Bcl10 and Malt1 control lysophosphatidic acid-induced NF-κB activation and cytokine production. Proc Natl Acad Sci (2007) 104:134–8. doi: 10.1016/j.meegid.2013.12.004 PubMed DOI PMC

Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev (2008) 226:57–79. doi: 10.1038/s41385-022-00551-6 PubMed DOI

Mabuchi T, Chang TW, Quinter S, Hwang ST. Chemokine receptors in the pathogenesis and therapy of psoriasis. J Dermatol Sci (2012) 65:4–11. doi: 10.1007/BF02539415 PubMed DOI

Luo C, Qu H, Ma J, Wang J, Hu X, Li N, et al. . A genome-wide association study identifies major loci affecting the immune response against infectious bronchitis virus in chicken. Infect Genet Evol (2014) 21:351–8. doi: 10.1016/j.meegid.2013.12.004 PubMed DOI PMC

de Paiva CS, Leger AJS, Caspi RR. Mucosal immunology of the ocular surface. Mucosal Immunol (2022) 15:1143–57. doi: 10.1167/iovs.63.12.13 PubMed DOI PMC

Bialasiewicz AA, Schaudig U, Ma J-X, Vieth S, Richard G. α/β-and γ/δ-T cell-receptor-positive lymphocytes in healthy and inflamed human conjunctiva. Graefes Arch Clin Exp Ophthalmol (1996) 234:467–71. doi: 10.1136/gut.2010.233304 PubMed DOI

Arnous R, Arshad S, Sandgren K, Cunningham AL, Carnt N, White A. Tissue resident memory T cells inhabit the deep human conjunctiva. Sci Rep (2022) 12:6077. doi: 10.4049/jimmunol.0803978 PubMed DOI PMC

Li L, Li Y, Zhu X, Wu B, Tang Z, Wen H, et al. . Conjunctiva resident γδ T cells expressed high level of IL-17A and promoted the severity of dry eye. Invest Ophthalmol Vis Sci (2022) 63:13–3. doi: 10.2741/A845 PubMed DOI PMC

Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief Bioinform (2011) 12:449–62. doi: 10.12688/f1000research.7010.1 PubMed DOI PMC

Wildenberg ME, van den Brink GR. FXR activation inhibits inflammation and preserves the intestinal barrier in IBD. Gut (2011) 60:432–3. doi: 10.1016/S1074-7613(00)00070-4 PubMed DOI

Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol (2009) 183:6251–61. doi: 10.1038/nm.3895 PubMed DOI

Hickman-Davis JM. Role of innate immunity in respiratory mycoplasma infection. Front Biosci-Landmark (2002) 7:1347–55. doi: 10.4049/jimmunol.173.3.1779 PubMed DOI

Ma X, Yan W, Zheng H, Du Q, Zhang L, Ban Y, et al. . Regulation of IL-10 and IL-12 production and function in macrophages and dendritic cells. F1000Research (2015) 4:1465. doi: 10.12688/f1000research.7010.1 PubMed DOI PMC

Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. . Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity (2000) 13:715–25. doi: 10.1128/IAI.67.9.4435-4442.1999 PubMed DOI

Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova J-L, Cooper AM, et al. . IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med (2015) 21:719–29. doi: 10.1002/eji.200636012 PubMed DOI

Wassink L, Vieira PL, Smits HH, Kingsbury GA, Coyle AJ, Kapsenberg ML, et al. . ICOS expression by activated human th cells is enhanced by IL-12 and IL-23: increased ICOS expression enhances the effector function of both th1 and th2 cells. J Immunol (2004) 173:1779–86. doi: 10.4049/jimmunol.173.3.1779 PubMed DOI

Chen D, Tang T-X, Deng H, Yang X-P, Tang Z-H. Interleukin-7 biology and its effects on immune cells: mediator of generation, differentiation, survival, and homeostasis. Front Immunol (2021) 12:747324. doi: 10.3389/fimmu.2021.747324 PubMed DOI PMC

Li C, Corraliza I, Langhorne J. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect Immun (1999) 67:4435–42. doi: 10.1186/1471-2180-14-156 PubMed DOI PMC

Siewe L, Bollati–Fogolin M, Wickenhauser C, Krieg T, Müller W, Roers A. Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA. Eur J Immunol (2006) 36:3248–55. doi: 10.3389/fimmu.2022.919973 PubMed DOI

Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med (2009) 15:277–84. doi: 10.1186/s13567-020-00777-x PubMed DOI PMC

Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, et al. . Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med (2006) 203:2461–72. doi: 10.3389/fimmu.2020.02148 PubMed DOI PMC

Kurata S, Osaki T, Yonezawa H, Arae K, Taguchi H, Kamiya S. Role of IL-17A and IL-10 in the antigen induced inflammation model by Mycoplasma pneumoniae. BMC Microbiol (2014) 14:1–11. doi: 10.1371/journal.pone.0278853 PubMed DOI PMC

Ihim SA, Abubakar SD, Zian Z, Sasaki T, Saffarioun M, Maleknia S, et al. . Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front Immunol (2022) 4470. doi: 10.1038/nrg2484 PubMed DOI PMC

Chen C, Li J, Zhang W, Shah SWA, Ishfaq M. Mycoplasma gallisepticum triggers immune damage in the chicken thymus by activating the TLR-2/MyD88/NF-κB signaling pathway and NLRP3 inflammasome. Vet Res (2020) 51(1):52. doi: 10.1186/s13567-020-00777-x PubMed DOI PMC

Arshad T, Mansur F, Palek R, Manzoor S, Liska V. A double edged sword role of interleukin-22 in wound healing and tissue regeneration. Front Immunol (2020) 11:2148. doi: 10.1098/rsbl.2010.0020 PubMed DOI PMC

Gupta SK, Parlane N, Bridgeman B, Lynch AT, Dangerfield EM, Timmer MS, et al. . The trehalose glycolipid C18Brar promotes antibody and T-cell immune responses to Mannheimia haemolytica and Mycoplasma ovipneumoniae whole cell antigens in sheep. PloS One (2023) 18:e0278853. doi: 10.1371/journal.pone.0278853 PubMed DOI PMC

Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet (2009) 10:57–63. doi: 10.1038/nrg2484 PubMed DOI PMC

Vo TTM, Nguyen TV, Amoroso G, Ventura T, Elizur A. Deploying new generation sequencing for the study of flesh color depletion in Atlantic Salmon (Salmo salar). BMC Genomics (2021) 22:545. doi: 10.1186/s12864-021-07884-9 PubMed DOI PMC

Bouwman KM, Hawley DM. Sickness behaviour acting as an evolutionary trap? Male house finches preferentially feed near diseased conspecifics. Biol Lett (2010) 6:462–5. doi: 10.1093/bib/bbr042 PubMed DOI PMC