FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Clin Vaccine Immunol / Dexamethasone-induced cytokine changes associated with dimin...
Clinical and vaccine immunology : CVI2011; 18(11); 1962-1968; doi: 10.1128/CVI.05034-11

Dexamethasone-induced cytokine changes associated with diminished disease severity in horses infected with Anaplasma phagocytophilum.

Abstract: Anaplasma phagocytophilum is the zoonotic cause of granulocytic anaplasmosis. We hypothesized that immune response, specifically gamma interferon (IFN-γ), plays a role in disease severity. To test this, horses were infected and IFNG expression was pharmacologically downregulated using corticosteroids. Eight horses were infected with A. phagocytophilum; 4 received dexamethasone on days 4 to 8 of infection. Clinical signs, hematologic parameters, and transcription of cytokine/chemokine genes were compared among treated and untreated horses. Infection was quantitated by msp2 real-time PCR and microscopy. As anticipated, there was significantly greater leukopenia, thrombocytopenia, and anemia in infected versus uninfected horses. The A. phagocytophilum load was higher for dexamethasone-treated horses. Dexamethasone reduced IFNG transcription by day 12 and IL-8 and IL-18 by days 7 to 9 and increased IL-4 on day 7. The ratio of IL-10 to IFNG was increased by dexamethasone on day 9. There were no hematologic differences between the infected horses. Dexamethasone suppression of proinflammatory response resulted in delayed infection-induced limb edema and decreased icterus, anorexia, and reluctance to move between days 6 and 9 and lower fever on day 7. These results underscore the utility of the equine model of granulocytic anaplasmosis and suggest that Th1 proinflammatory response plays a role in worsening disease severity and that disease severity can be decreased by modulating proinflammatory response. A role for Th1 response and macrophage activation in hematologic derangements elicited by A. phagocytophilum is not supported by these data and remains unproven.
Get Full Text
Publication Date: 2011-08-31 PubMed ID: 21880854PubMed Central: PMC3209032DOI: 10.1128/CVI.05034-11Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the impact of dexamethasone, a corticosteroid, on the immune response and disease severity in horses infected with Anaplasma phagocytophilum, a bacterium that causes granulocytic anaplasmosis. The results suggest that reducing the proinflammatory response can lessen disease severity.

Research Purpose and Hypothesis

  • The study aimed to explore the role of the immune response, specifically gamma interferon (IFN-γ), in the severity of granulocytic anaplasmosis, caused by the Anaplasma phagocytophilum bacteria.
  • The researchers hypothesized that a pharmacological downregulation of IFNG expression using corticosteroids could impact disease severity.

Methodology

  • Eight horses were infected with A. phagocytophilum, with four of them receiving dexamethasone on days 4 to 8 of infection.
  • The researchers compared clinical signs, hematologic parameters, and transcription of cytokine/chemokine genes among treated and untreated horses.
  • Infection was quantified by msp2 real-time PCR and microscopy.

Findings

  • As expected, there were more significant incidences of leukopenia, thrombocytopenia, and anemia in infected versus uninfected horses.
  • The A. phagocytophilum load was higher in dexamethasone-treated horses.
  • Dexamethasone caused a reduction in IFNG transcription by day 12, and IL-8 and IL-18 by days 7 to 9. Meanwhile, IL-4 increased on day 7.
  • Dexamethasone resulted in a delay in infection-induced limb edema and decreased icterus, anorexia, and reluctance to move between days 6 and 9 and lower fever on day 7.
  • No significant hematologic differences were found between the infected horses.

Conclusion

  • The findings demonstrate the usefulness of the equine model of granulocytic anaplasmosis and suggest that Th1 proinflammatory response plays a role in worsening disease severity.
  • The study suggests that disease severity can be decreased by modulating the proinflammatory response, but the study does not support a role for Th1 response and macrophage activation in hematologic derangements elicited by A. phagocytophilum.

Cite This Article

APA
Davies RS, Madigan JE, Hodzic E, Borjesson DL, Dumler JS. (2011). Dexamethasone-induced cytokine changes associated with diminished disease severity in horses infected with Anaplasma phagocytophilum. Clin Vaccine Immunol, 18(11), 1962-1968. https://doi.org/10.1128/CVI.05034-11

Publication

Clinical and vaccine immunology : CVI
ISSN: 1556-679X
NlmUniqueID: 101252125
Country: United States
Language: English
Volume: 18
Issue: 11
Pages: 1962-1968

Researcher Affiliations

Davies, R S
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California, USA.
Madigan, J E
    Hodzic, E
      Borjesson, D L
        Dumler, J S

          MeSH Terms

          • Anaplasma phagocytophilum / immunology
          • Anaplasma phagocytophilum / pathogenicity
          • Anemia / prevention & control
          • Animals
          • Cytokines / biosynthesis
          • Dexamethasone / administration & dosage
          • Edema / prevention & control
          • Ehrlichiosis / complications
          • Ehrlichiosis / drug therapy
          • Ehrlichiosis / pathology
          • Gene Expression Profiling
          • Horse Diseases / drug therapy
          • Horse Diseases / pathology
          • Horses
          • Immunologic Factors / administration & dosage
          • Jaundice / prevention & control
          • Real-Time Polymerase Chain Reaction
          • Severity of Illness Index

          Grant Funding

          • R01 AI041213 / NIAID NIH HHS
          • R56 AI041213 / NIAID NIH HHS
          • R01 AI41213 / NIAID NIH HHS
          • R56 AI41213 / NIAID NIH HHS

          References

          This article includes 38 references
          1. Akkoyunlu M, Fikrig E. Gamma interferon dominates the murine cytokine response to the agent of human granulocytic ehrlichiosis and helps to control the degree of early rickettsemia. Infect. Immun. 2000;68:1827–1833.
            pmc: PMC97354pubmed: 10722570
          2. Arceci RJ. When T cells and macrophages do not talk: the hemophagocytic syndromes. Curr. Opin. Hematol. 2008;15:359–367.
            pubmed: 18536575
          3. Bakken JS. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging?. JAMA 1994;272:212–218.
            pubmed: 8022040
          4. Barlough JE, Madigan JE, DeRock E, Dumler JS, Bakken JS. Protection against Ehrlichia equi is conferred by prior infection with the human granulocytotropic Ehrlichia (HGE agent). J. Clin. Microbiol. 1995;33:3333–3334.
            pmc: PMC228702pubmed: 8586731
          5. Browning MD, Garyu JW, Dumler JS, Scorpio DG. Role of reactive nitrogen species in development of hepatic injury in a C57bl/6 mouse model of human granulocytic anaplasmosis. Comp. Med. 2006;56:55–62.
            pubmed: 16521860
          6. Chen SM, Dumler JS, Bakken JS, Walker DH. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J. Clin. Microbiol. 1994;32:589–595.
            pmc: PMC263091pubmed: 8195363
          7. Choi KS, Dumler JS. Mitogenic component in polar lipid-enriched A. phagocytophilum membranes. Clin. Vaccine Immunol. 2007;14:1260–1265.
            pmc: PMC2168108pubmed: 17687112
          8. Choi KS, Scorpio DG, Barat NC, Dumler JS. Msp2 variation in Anaplasma phagocytophilum in vivo does not stimulate T cell immune responses or interferon-gamma production. FEMS Immunol. Med. Microbiol. 2007;49:374–386.
            pubmed: 17286796
          9. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J. Immunol. 2008;180:5771–5777.
            pubmed: 18424693
          10. Dumler JS, Barat NC, Barat CE, Bakken JS. Human granulocytic anaplasmosis and macrophage activation. Clin. Infect. Dis. 2007;45:199–204.
            pubmed: 17578779
          11. Dumler JS. Human granulocytic anaplasmosis and Anaplasma phagocytophilum. Emerg. Infect. Dis. 2005;11:1828–1834.
            pmc: PMC3367650pubmed: 16485466
          12. Dumler JS, Trigiani ER, Bakken JS, Aguero-Rosenfeld ME, Wormser GP. Serum cytokine responses during acute human granulocytic ehrlichiosis. Clin. Diagn. Lab. Immunol. 2000;7:6–8.
            pmc: PMC95813pubmed: 10618268
          13. Foley JE, Lerche NW, Dumler JS, Madigan JE. A simian model of human granulocytic ehrlichiosis. Am. J. Trop. Med. Hyg. 1999;60:987–993.
            pubmed: 10403332
          14. Foley JE, Leutenegger CM, Dumler JS, Pedersen NC, Madigan JE. Evidence for modulated immune response to Anaplasma phagocytophila sensu lato in cats with FIV-induced immunosuppression. Comp. Immunol. Microbiol. Infect. Dis. 2003;26:103–113.
            pubmed: 12493491
          15. Hodzic E. Infection of mice with the agent of human granulocytic ehrlichiosis after different routes of inoculation. J. Infect. Dis. 2001;183:1781–1786.
            pubmed: 11372031
          16. Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 2006;6:644–658.
            pubmed: 16932750
          17. Hu X, Chakravarty SD, Ivashkiv LB. Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol. Rev. 2008;226:41–56.
            pmc: PMC2630590pubmed: 19161415
          18. Klein MB, Hu S, Chao CC, Goodman JL. The agent of human granulocytic ehrlichiosis induces the production of myelosuppressing chemokines without induction of proinflammatory cytokines. J. Infect. Dis. 2000;182:200–205.
            pubmed: 10882598
          19. Kracht M, Saklatvala J. Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine 2002;20:91–106.
            pubmed: 12453467
          20. Lepidi H. Comparative pathology and immunohistology associated with clinical illness after Ehrlichia phagocytophila-group infections. Am. J. Trop. Med. Hyg. 2000;62:29–37.
            pubmed: 10761721
          21. Lepidi H. Cardiac valves in patients with Whipple endocarditis: microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. J. Infect. Dis. 2004;190:935–945.
            pubmed: 15295699
          22. Leutenegger CM. Quantitative real-time PCR for the measurement of feline cytokine mRNA. Vet. Immunol. Immunopathol. 1999;71:291–305.
            pmc: PMC7119904pubmed: 10587308
          23. Madigan JE, Gribble D. Equine ehrlichiosis in northern California: 49 cases (1968-1981). J. Am. Vet. Med. Assoc. 1987;190:445–448.
            pubmed: 3558086
          24. Madigan JE. Transmission and passage in horses of the agent of human granulocytic ehrlichiosis. J. Infect. Dis. 1995;172:1141–1144.
            pubmed: 7561199
          25. Martin ME, Bunnell JE, Dumler JS. Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model. J. Infect. Dis. 2000;181:374–378.
            pubmed: 10608792
          26. Martin ME, Caspersen K, Dumler JS. Immunopathology and ehrlichial propagation are regulated by interferon-gamma and interleukin-10 in a murine model of human granulocytic ehrlichiosis. Am. J. Pathol. 2001;158:1881–1888.
            pmc: PMC1891945pubmed: 11337387
          27. Miller JC, Ma Y, Crandall H, Wang X, Weis JJ. Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: murine model of Lyme disease. Exp. Mol. Pathol. 2008;85:20–27.
            pmc: PMC2565650pubmed: 18462718
          28. Newton R, Holden NS. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?. Mol. Pharmacol. 2007;72:799–809.
            pubmed: 17622575
          29. Pusterla N. Transmission of Anaplasma phagocytophila (human granulocytic ehrlichiosis agent) in horses using experimentally infected ticks (Ixodes scapularis). J. Vet. Med. B Infect. Dis. Vet. Public Health 2002;49:484–488.
            pubmed: 12485358
          30. Pusterla N. Quantitative real-time PCR for detection of members of the Ehrlichia phagocytophila genogroup in host animals and Ixodes ricinus ticks. J. Clin. Microbiol. 1999;37:1329–1331.
            pmc: PMC84766pubmed: 10203480
          31. Pusterla N. Quantitative evaluation of ehrlichial burden in horses after experimental transmission of human granulocytic Ehrlichia agent by intravenous inoculation with infected leukocytes and by infected ticks. J. Clin. Microbiol. 1999;37:4042–4044.
            pmc: PMC85876pubmed: 10565928
          32. Pusterla N. Cytokine gene signatures in neural tissue of horses with equine protozoal myeloencephalitis or equine herpes type 1 myeloencephalopathy. Vet. Rec. 2006;159:341–345.
            pubmed: 16963713
          33. Pusterla N, Wilson WD, Conrad PA, Mapes S, Leutenegger CM. Comparative analysis of cytokine gene expression in cerebrospinal fluid of horses without neurologic signs or with selected neurologic disorders. Am. J. Vet. Res. 2006;67:1433–1437.
            pubmed: 16881858
          34. Rogatsky I, Ivashkiv LB. Glucocorticoid modulation of cytokine signaling. Tissue Antigens 2006;68:1–12.
            pubmed: 16774534
          35. Scorpio DG, Akkoyunlu M, Fikrig E, Dumler JS. CXCR2 blockade influences Anaplasma phagocytophilum propagation but not histopathology in the mouse model of human granulocytic anaplasmosis. Clin. Diagn. Lab. Immunol. 2004;11:963–968.
            pmc: PMC515272pubmed: 15358660
          36. Scorpio DG, Von Loewenich FD, Bogdan C, Dumler JS. Innate immune tissue injury and murine HGA: tissue injury in the murine model of granulocytic anaplasmosis relates to host innate immune response and not pathogen load. Ann. N. Y. Acad. Sci. 2005;1063:425–428.
            pubmed: 16481553
          37. Scorpio DG. Sequential analysis of Anaplasma phagocytophilum msp2 transcription in murine and equine models of human granulocytic anaplasmosis. Clin. Vaccine Immunol. 2008;15:418–424.
            pmc: PMC2268257pubmed: 18094110
          38. Scorpio DG, von Loewenich FD, Gobel H, Bogdan C, Dumler JS. Innate immune response to Anaplasma phagocytophilum contributes to hepatic injury. Clin. Vaccine Immunol. 2006;13:806–809.
            pmc: PMC1489578pubmed: 16829620
          Subscribe to our newsletter
          Join 99,344 horse owners like you who receive our email updates on horse health and nutrition.