Parrots, valued companion animals with a concerning conservation status, can act as reservoirs for zoonotic diseases. During various infections, systemic inflammation significantly impairs host health. However, the regulation of inflammatory responses in birds, particularly in cognitively advanced parrots, remains poorly understood. Here, we examine parrot systemic inflammation in response to virus-mimicking stimulation. In budgerigars (Melopsittacus undulatus), a novel model for neuroinflammation research, we induced sterile inflammation with synthetic poly(I:C) RNA and analysed dose-, time- and tissue-dependent gene expression patterns of key markers, including TLR3, NLRP3, CASP1, IL1B and IL6, during acute immune response. We report a significant relationship between cytokine expression (IL1B, IL6) in the intestine (local response) and brain (systemic response) that has not yet been described after viral stimulation in parrots. Peripheral IL6 expression was upregulated at 3-6 h after stimulation with poly(I:C). In the brain, multiple genes (TLR3, IL1B and IL6) showed activation early during the immune response. These findings highlight the susceptibility of parrots to neuroinflammation following viral infections, having specific relevance for basic research in neurobiology, immunology and behavioural science, and also veterinary research in psittacine birds. Our study provides a foundation for future comparative research on avian neuro-immune crosstalk and neuroinflammation-related behavioural disorders.

Department of Zoology Faculty of Science Charles University Praha Czech Republic

Faculty of Veterinary Medicine Ludwig Maximilian University München Bayern Germany

Institute of Vertebrate Biology Czech Academy of Sciences Brno Jihomoravský Czech Republic

Zobrazit více v PubMed

Forshaw JM, Knight F. 2024. Parrots of the world. Princeton, NJ: Princeton University Press. See http://www.jstor.org/stable/j.ctt7ssn3.

Mellor EL, McDonald Kinkaid HK, Mendl MT, Cuthill IC, van Zeeland YRA, Mason GJ. 2021. Nature calls: intelligence and natural foraging style predict poor welfare in captive parrots. Proc. R. Soc. B 288, 20211952. ( 10.1098/rspb.2021.1952) PubMed DOI PMC

Cleaveland S, Laurenson MK, Taylor LH. 2001. Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence. Phil. Trans. R. Soc. Lond. B 356, 991–999. ( 10.1098/rstb.2001.0889) PubMed DOI PMC

Rahman AU, Habib M, Shabbir MZ. 2018. Adaptation of Newcastle disease virus (NDV) in feral birds and their potential role in interspecies transmission. Open Virol. J. 12, 52–68. ( 10.2174/1874357901812010052) PubMed DOI PMC

Abdelwhab EM, Veits J, Mettenleiter TC. 2014. Prevalence and control of H7 avian influenza viruses in birds and humans. Epidemiol. Infect. 142, 896–920. ( 10.1017/s0950268813003324) PubMed DOI PMC

Greenacre CB. 2005. Viral diseases of companion birds. Vet. Clin. North Am. Exot. Anim. Pract. 8, 85–105. ( 10.1016/j.cvex.2004.09.005) PubMed DOI PMC

Jones JC, et al. 2014. Possible role of songbirds and parakeets in transmission of influenza A(H7N9) virus to humans. Emerg. Infect. Dis. 20, 380–385. ( 10.3201/eid2003.131271) PubMed DOI PMC

Smith KA, Campbell CT, Murphy J, Stobierski MG, Tengelsen LA. 2011. Compendium of measures to control Chlamydophila psittaci infection among humans (psittacosis) and pet birds (avian chlamydiosis), 2010 National Association of State Public Health Veterinarians (NASPHV). J. Exot. Pet Med. 20, 32–45. ( 10.1053/j.jepm.2010.11.007) DOI

Gaskins LA, Bergman L. 2011. Surveys of avian practitioners and pet owners regarding common behavior problems in psittacine birds. J. Avian Med. Surg. 25, 111–118. ( 10.1647/2010-027.1) PubMed DOI

Girling S. 2004. Diseases of the digestive tract of psittacine birds. In Pract. 26, 146–153. ( 10.1136/inpract.26.3.146) DOI

Divín D, et al. 2022. Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation. Proc. R. Soc. B 289, 20221941. ( 10.1098/rspb.2022.1941) PubMed DOI PMC

Rubbenstroth D. 2022. Avian bornavirus research—a comprehensive review. Viruses 14, 1513. ( 10.3390/v14071513) PubMed DOI PMC

Bode L, Ludwig H. 2003. Borna disease virus infection, a human mental-health risk. Clin. Microbiol. Rev. 16, 534–545. ( 10.1128/cmr.16.3.534-545.2003) PubMed DOI PMC

Kaspers B, Schat KA, Göbel TW, Vervelde L (eds). 2022. Avian immunology, p. 603, 3rd edn. London, UK: Elsevier Academic Press.

Burt DW. 2007. Emergence of the chicken as a model organism: implications for agriculture and biology. Poult. Sci. 86, 1460–1471. ( 10.1093/ps/86.7.1460) PubMed DOI

Minias P, Pikus E, Whittingham LA, Dunn PO. 2019. Evolution of copy number at the MHC varies across the avian tree of life. Genome Biol. Evol. 11, 17–28. ( 10.1093/gbe/evy253) PubMed DOI PMC

Blount JD, Houston DC, Møller AP, Wright J. 2003. Do individual branches of immune defence correlate? A comparative case study of scavenging and non‐scavenging birds. Oikos 102, 340–350. ( 10.1034/j.1600-0706.2003.12413.x) DOI

Hasselquist D. 2007. Comparative immunoecology in birds: hypotheses and tests. J. Ornithol. 148, 571–582. ( 10.1007/s10336-007-0201-x) DOI

Tella JL, Scheuerlein A, Ricklefs RE. 2002. Is cell-mediated immunity related to the evolution of life-history strategies in birds? Proc. R. Soc. B 269, 1059–1066. ( 10.1098/rspb.2001.1951) PubMed DOI PMC

Ashley NT, Weil ZM, Nelson RJ. 2012. Inflammation: mechanisms, costs, and natural variation. Annu. Rev. Ecol. Evol. Syst. 43, 385–406. ( 10.1146/annurev-ecolsys-040212-092530) DOI

Illis LS. 2012. Central nervous system regeneration does not occur. Spinal Cord 50, 259–263. ( 10.1038/sc.2011.132) PubMed DOI

Kany S, Vollrath JT, Relja B. 2019. Cytokines in inflammatory disease. Int. J. Mol. Sci. 20, 6008. ( 10.3390/ijms20236008) PubMed DOI PMC

Kogut MH. 2000. Cytokines and prevention of infectious diseases in poultry: a review. Avian Pathol. 29, 395–404. ( 10.1080/030794500750047135) PubMed DOI

Konsman J. 2022. Cytokines in the brain and neuroinflammation: we didn’t starve the fire! Pharmaceuticals 15, 140. ( 10.3390/ph15020140) PubMed DOI PMC

Magor KE. 2022. Evolution of RNA sensing receptors in birds. Immunogenetics 74, 149–165. ( 10.1007/s00251-021-01238-1) PubMed DOI PMC

Mogensen TH. 2009. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273. ( 10.1128/cmr.00046-08) PubMed DOI PMC

Abo-Samaha MI, Sharaf MM, El Nahas AF, Odemuyiwa SO. 2024. Innate immune response to double-stranded RNA in American heritage chicken breeds. Poult. Sci. 103, 103318. ( 10.1016/j.psj.2023.103318) PubMed DOI PMC

Jacobs SR, Damania B. 2012. NLRs, inflammasomes, and viral infection. J. Leukoc. Biol. 92, 469–477. ( 10.1189/jlb.0312132) PubMed DOI PMC

Kalaiyarasu S, Kumar M, Senthil Kumar D, Bhatia S, Dash SK, Bhat S, Khetan RK, Nagarajan S. 2016. Highly pathogenic avian influenza H5N1 virus induces cytokine dysregulation with suppressed maturation of chicken monocyte‐derived dendritic cells. Microbiol. Immunol. 60, 687–693. ( 10.1111/1348-0421.12443) PubMed DOI

Kc M, Ngunjiri JM, Lee J, Ahn J, Elaish M, Ghorbani A, Abundo MEC, Lee K, Lee CW. 2020. Avian Toll-like receptor 3 isoforms and evaluation of Toll-like receptor 3–mediated immune responses using knockout quail fibroblast cells. Poult. Sci. 99, 6513–6524. ( 10.1016/j.psj.2020.09.029) PubMed DOI PMC

Yu M, Levine SJ. 2011. Toll-like receptor 3, RIG-I-like receptors and the NLRP3 inflammasome: key modulators of innate immune responses to double-stranded RNA viruses. Cytokine Growth Factor Rev. 22, 63–72. ( 10.1016/j.cytogfr.2011.02.001) PubMed DOI PMC

DiSabato DJ, Quan N, Godbout JP. 2016. Neuroinflammation: the devil is in the details. J. Neurochem. 139, 136–153. ( 10.1111/jnc.13607) PubMed DOI PMC

Kuttiyarthu Veetil N, et al. 2024. Peripheral inflammation-induced changes in songbird brain gene expression: 3’ mRNA transcriptomic approach. Dev. Comp. Immunol. 151, 105106. ( 10.1016/j.dci.2023.105106) PubMed DOI

Salinas S, Schiavo G, Kremer EJ. 2010. A hitchhiker’s guide to the nervous system: the complex journey of viruses and toxins. Nat. Rev. Microbiol. 8, 645–655. ( 10.1038/nrmicro2395) PubMed DOI

Fortier ME, Kent S, Ashdown H, Poole S, Boksa P, Luheshi GN. 2004. The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R759–66. ( 10.1152/ajpregu.00293.2004) PubMed DOI

Hart BL. 1988. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12, 123–137. ( 10.1016/s0149-7634(88)80004-6) PubMed DOI

Tamura Y, Yamato M, Kataoka Y. 2022. Animal models for neuroinflammation and potential treatment methods. Front. Neurol. 13, 890217. ( 10.3389/fneur.2022.890217) PubMed DOI PMC

Kent S, Dedda K, Hale MW, Crowe SF. 2007. Polyinosinic:polycytidylic acid induces memory processing deficits in the day-old chick. Behav. Pharmacol. 18, 19–27. ( 10.1097/FBP.0b013e328014261d) PubMed DOI

McGarry N, et al. 2021. Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age. Brain Behav. Immun. 95, 413–428. ( 10.1016/j.bbi.2021.04.016) PubMed DOI PMC

Rymut HE, Bolt CR, Corbett MP, Rund LA, Johnson RW, Rodriguez-Zas SL. 2020. PSV-18 Program chair poster pick: poly(I:C) dose response and its effects on piglet sickness behaviors. J. Anim. Sci. 98, 218–218. ( 10.1093/jas/skaa278.402) DOI

Tachibana T, Ishimaru Y, Makino R, Khan SI, Cline MA. 2018. Effect of central injection of tumor-necrosis factor-like cytokine 1A and interferons on food intake in chicks. Physiol. Behav. 194, 199–204. ( 10.1016/j.physbeh.2018.05.015) PubMed DOI

Uysal AK, Martin LB, Burkett-Cadena ND, Barron DG, Shimizu T. 2018. Simulated viral infection in early-life alters brain morphology, activity and behavior in Zebra finches (Taeniopygia guttata). Physiol. Behav. 196, 36–46. ( 10.1016/j.physbeh.2018.08.004) PubMed DOI

Yu MC, Young PA, Yu WH. 1971. Ultrastructural changes in chick cerebellum induced by polyinosinic polycytidylic acid. Am. J. Pathol. 64, 305–320. PubMed PMC

Coon CAC, Warne RW, Martin LB. 2011. Acute-phase responses vary with pathogen identity in house sparrows (Passer domesticus). Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1418–R1425. ( 10.1152/ajpregu.00187.2010) PubMed DOI

Tella JL, Blanco G, Carrete M. 2022. Recent advances in parrot research and conservation. Diversity 14, 419. ( 10.3390/d14060419) DOI

Gómez Samblás M, Melepat B, Divín D, Li T, Voukali E, Marková K. In preparation. Dynamics of cytokine expression profile changes during inflammation induced by bacterial lipopolysaccharide in a model parrot.

Voukali E, et al. 2024. Subclinical peripheral inflammation has systemic effects impacting central nervous system proteome in budgerigars. Dev. Comp. Immunol. 159, 105213. ( 10.1016/j.dci.2024.105213) PubMed DOI

Cunningham C, Campion S, Teeling J, Felton L, Perry VH. 2007. The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav. Immun. 21, 490–502. ( 10.1016/j.bbi.2006.12.007) PubMed DOI

Vinkler M, Schnitzer J, Munclinger P, Votýpka J, Albrecht T. 2010. Haematological health assessment in a passerine with extremely high proportion of basophils in peripheral blood. J. Ornithol. 151, 841–849. ( 10.1007/s10336-010-0521-0) DOI

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

R Core Team . 2021. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. See https://www.r-project.org/.

RStudio Team . 2021. RStudio: integrated development environment for R. Boston, MA: RStudio, PBC. See https://www.rstudio.com/.

Vinkler M, et al. 2023. Understanding the evolution of immune genes in jawed vertebrates. J. Evol. Biol. 36, 847–873. ( 10.1111/jeb.14181) PubMed DOI PMC

Yirmiya R, Goshen I. 2011. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 25, 181–213. ( 10.1016/j.bbi.2010.10.015) PubMed DOI

Bsibsi M, Persoon-Deen C, Verwer RWH, Meeuwsen S, Ravid R, Van Noort JM. 2006. Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53, 688–695. ( 10.1002/glia.20328) PubMed DOI

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. 2005. Preferential expression and function of Toll-like receptor 3 in human astrocytes. J. Neuroimmunol. 159, 12–19. ( 10.1016/j.jneuroim.2004.09.009) PubMed DOI

Scumpia PO, Kelly KM, Reeves WH, Stevens BR. 2005. Double-stranded RNA signals antiviral and inflammatory programs and dysfunctional glutamate transport in TLR3-expressing astrocytes. Glia 52, 153–162. ( 10.1002/glia.20234) PubMed DOI

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. 2006. Microglia recognize double-stranded RNA via TLR3. J. Immunol. 176, 3804–3812. ( 10.4049/jimmunol.176.6.3804) PubMed DOI

Field R, Campion S, Warren C, Murray C, Cunningham C. 2010. Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav. Immun. 24, 996–1007. ( 10.1016/j.bbi.2010.04.004) PubMed DOI PMC

Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. 2004. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10, 1366–1373. ( 10.1038/nm1140) PubMed DOI

Pan L na, Zhu W, Li C, Xu X lin, Guo L jun, Lu Q. 2012. Toll-like receptor 3 agonist poly I:C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol. Sin. 33, 1246–1253. ( 10.1038/aps.2012.122) PubMed DOI PMC

St. Paul M, Mallick AI, Read LR, Villanueva AI, Parvizi P, Abdul-Careem MF, Nagy É, Sharif S. 2012. Prophylactic treatment with Toll-like receptor ligands enhances host immunity to avian influenza virus in chickens. Vaccine 30, 4524–4531. ( 10.1016/j.vaccine.2012.04.033) PubMed DOI

Kanneganti TD, et al. 2006. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568. ( 10.1074/jbc.M607594200) PubMed DOI

Rajan JV, Warren SE, Miao EA, Aderem A. 2010. Activation of the NLRP3 inflammasome by intracellular poly I:C. FEBS Lett. 584, 4627–4632. ( 10.1016/j.febslet.2010.10.036) PubMed DOI PMC

Billman ZP, Hancks DC, Miao EA. 2024. Unanticipated loss of inflammasomes in birds. Genome Biol. Evol. 16, e138. ( 10.1093/gbe/evae138) PubMed DOI PMC

Ogaili A, Hameed S, Noori N. 2022. LPS-induced NLRP3 gene-expression in chicken. Open Vet. J. 12, 197. ( 10.5455/ovj.2022.v12.i2.7) PubMed DOI PMC

Gurung P, Li B, Subbarao Malireddi RK, Lamkanfi M, Geiger TL, Kanneganti TD. 2015. Chronic TLR stimulation controls NLRP3 inflammasome activation through IL-10 mediated regulation of NLRP3 expression and caspase-8 activation. Sci. Rep. 5, 14488. ( 10.1038/srep14488) PubMed DOI PMC

Koller BH, Nguyen M, Snouwaert JN, Gabel CA, Ting JPY. 2024. Species-specific NLRP3 regulation and its role in CNS autoinflammatory diseases. Cell Rep. 43, 113852. ( 10.1016/j.celrep.2024.113852) PubMed DOI PMC

He T, et al. 2022. Duck plague virus UL41 protein inhibits RIG-I/MDA5-mediated duck IFN-β production via mRNA degradation activity. Vet. Res. 53, 22. ( 10.1186/s13567-022-01043-y) PubMed DOI PMC

Morahan PS, Munson AE, Regelson W, Commerford SL, Hamilton LD. 1972. Antiviral activity and side effects of polyriboinosinic-cytidylic acid complexes as affected by molecular size. Proc. Natl Acad. Sci. USA 69, 842–846. ( 10.1073/pnas.69.4.842) PubMed DOI PMC

Alexander DJ. 2000. A review of avian influenza in different bird species. Vet. Microbiol. 74, 3–13. ( 10.1016/s0378-1135(00)00160-7) PubMed DOI

Melepat B, et al. 2025. Supplementary material from: The neuro-immune crosstalk between periphery and CNS during acute immune response to virus-mimicking RNA in parrots. Figshare. ( 10.6084/m9.figshare.c.8039807) DOI

Zobrazit více v PubMed

figshare
10.6084/m9.figshare.c.8039807