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Clinical and diagnostic laboratory immunology2003; 10(2); 208-215; doi: 10.1128/cdli.10.2.208-215.2003

Clearance of virulent but not avirulent Rhodococcus equi from the lungs of adult horses is associated with intracytoplasmic gamma interferon production by CD4+ and CD8+ T lymphocytes.

Abstract: Rhodococcus equi is a gram-positive bacterium that infects alveolar macrophages and causes rhodococcal pneumonia in horses and humans. The virulence plasmid of R. equi appears to be required for both pathogenicity in the horse and the induction of protective immunity. An understanding of the mechanisms by which virulent R. equi circumvents protective host responses and by which bacteria are ultimately cleared is important for development of an effective vaccine. Six adult horses were challenged with either virulent R. equi or an avirulent, plasmid-cured derivative. By using a flow cytometric method for intracytoplasmic detection of gamma interferon (IFN-gamma) in equine bronchoalveolar lavage fluid (BALF) cells, clearance of the virulent strain was shown to be associated with increased numbers of pulmonary CD4(+) and CD8(+) T lymphocytes producing IFN-gamma. There was no change in IFN-gamma-positive cells in peripheral blood, suggesting that a type 1 recall response at the site of challenge was protective. The plasmid-cured strain of R. equi was cleared in horses without a significant increase in IFN-gamma-producing T lymphocytes in BALF. In contrast to these data, a previous report in foals suggested an immunomodulating role for R. equi virulence plasmid-encoded products in downregulating IFN-gamma expression by equine CD4(+) T lymphocytes. Intracytoplasmic detection of IFN-gamma provides a method to better determine whether modulation of macrophage-activating cytokines by virulent strains occurs uniquely in neonates and contributes to their susceptibility to rhodococcal pneumonia.
Publication Date: 2003-03-11 PubMed ID: 12626444PubMed Central: PMC150533DOI: 10.1128/cdli.10.2.208-215.2003Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

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.

The research presents a study about the effect of the virulent and avirulent strains of Rhodococcus equi, a bacteria causing pneumonia, on the immune response in adult horses. The study found that the clearance of the virulent strain is associated with an increase in certain immune cells producing gamma interferon.

Study Overview

The researchers’ primary aim was to understand how the virulent form of Rhodococcus equi, a bacterium causing rhodococcal pneumonia in horses and humans, evades the host’s immune responses and how the bacteria eventually gets cleared from the host’s system.

  • The researchers embarked on this study with the bigger goal of aiding the development of an effective vaccine.
  • Six adult horses were deliberately infected with either the virulent strain of R. equi or an avirulent form of the same bacterium, that had been cured of its virulence-conferring plasmid.

Methodology and Findings

Using a flow cytometric method, the researchers measured the intracytoplasmic production of a specific immune marker, gamma interferon (IFN-gamma), in the broncho-alveolar lavage fluid (BALF) cells of the horses.

  • They observed that the clearance of the virulent strain of R. equi was associated with an increase in the number of two types of immune cell, CD4(+) and CD8(+) T lymphocytes, producing IFN-gamma.
  • This significant increase was only seen in the lungs and not in the peripheral blood, suggesting that a targeted immune response was activated at the site of infection.
  • On the other hand, the avirulent strain of R. equi was cleared from the horses without a significant increase in T lymphocytes producing IFN-gamma in BALF.

Comparison to Previous Research

The researchers compared their findings to a previous study on foals, which suggested that the virulence factors encoded on R. equi’s plasmid could interfere with IFN-gamma expression in CD4(+) T lymphocytes, thus altering the immune response. The results of this current study suggest this phenomenon may be specifically applicable to neonates and could potentially explain their increased susceptibility to rhodococcal pneumonia.

Conclusion

The research concludes by endorsing further use of intracytoplasmic detection of IFN-gamma as a valuable method to better understand the effect of virulent strains of R. equi on the immune system’s response.

Cite This Article

APA
Hines SA, Stone DM, Hines MT, Alperin DC, Knowles DP, Norton LK, Hamilton MJ, Davis WC, McGuire TC. (2003). Clearance of virulent but not avirulent Rhodococcus equi from the lungs of adult horses is associated with intracytoplasmic gamma interferon production by CD4+ and CD8+ T lymphocytes. Clin Diagn Lab Immunol, 10(2), 208-215. https://doi.org/10.1128/cdli.10.2.208-215.2003

Publication

ISSN: 1071-412X
NlmUniqueID: 9421292
Country: United States
Language: English
Volume: 10
Issue: 2
Pages: 208-215

Researcher Affiliations

Hines, Stephen A
  • Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington 99164-7040, USA. shines@vetmed.wsu.edu
Stone, Diana M
    Hines, Melissa T
      Alperin, Debby C
        Knowles, Donald P
          Norton, Linda K
            Hamilton, Mary J
              Davis, William C
                McGuire, Travis C

                  MeSH Terms

                  • Actinomycetales Infections / immunology
                  • Actinomycetales Infections / veterinary
                  • Age Factors
                  • Animals
                  • Bronchoalveolar Lavage Fluid / cytology
                  • Bronchoalveolar Lavage Fluid / immunology
                  • CD2 Antigens / metabolism
                  • CD4-Positive T-Lymphocytes / immunology
                  • CD4-Positive T-Lymphocytes / metabolism
                  • CD4-Positive T-Lymphocytes / microbiology
                  • CD8-Positive T-Lymphocytes / immunology
                  • CD8-Positive T-Lymphocytes / metabolism
                  • CD8-Positive T-Lymphocytes / microbiology
                  • Cytoplasm / immunology
                  • Cytoplasm / microbiology
                  • Flow Cytometry / methods
                  • Horse Diseases / microbiology
                  • Horses
                  • Interferon-gamma / biosynthesis
                  • Plasmids
                  • Pneumonia / immunology
                  • Pneumonia / microbiology
                  • Pneumonia / veterinary
                  • Rhodococcus equi / genetics
                  • Rhodococcus equi / pathogenicity
                  • Virulence

                  References

                  This article includes 43 references
                  1. Adkins B. Development of neonatal Th1/Th2 function.. Int Rev Immunol 2000;19(2-3):157-71.
                    pubmed: 10763707doi: 10.3109/08830180009088503google scholar: lookup
                  2. Anderson SJ, Coleclough C. Regulation of CD4 and CD8 expression on mouse T cells. Active removal from the cell surface by two mechanisms.. J Immunol 1993 Nov 15;151(10):5123-34.
                    pubmed: 8228214
                  3. Bot A. DNA vaccination and the immune responsiveness of neonates.. Int Rev Immunol 2000;19(2-3):221-45.
                    pubmed: 10763710doi: 10.3109/08830180009088506google scholar: lookup
                  4. Davis WC, Davis JE, Hamilton MJ. Use of monoclonal antibodies and flow cytometry to cluster and analyze leukocyte differentiation molecules.. Methods Mol Biol 1995;45:149-67.
                    pubmed: 7550677doi: 10.1385/0-89603-308-2:149google scholar: lookup
                  5. Ghanekar SA, Nomura LE, Suni MA, Picker LJ, Maecker HT, Maino VC. Gamma interferon expression in CD8(+) T cells is a marker for circulating cytotoxic T lymphocytes that recognize an HLA A2-restricted epitope of human cytomegalovirus phosphoprotein pp65.. Clin Diagn Lab Immunol 2001 May;8(3):628-31.
                    pmc: PMC96113pubmed: 11329470doi: 10.1128/CDLI.8.3.628-631.2001google scholar: lookup
                  6. Giguère S, Wilkie BN, Prescott JF. Modulation of cytokine response of pneumonic foals by virulent Rhodococcus equi.. Infect Immun 1999 Oct;67(10):5041-7.
                  7. Giguère S, Hondalus MK, Yager JA, Darrah P, Mosser DM, Prescott JF. Role of the 85-kilobase plasmid and plasmid-encoded virulence-associated protein A in intracellular survival and virulence of Rhodococcus equi.. Infect Immun 1999 Jul;67(7):3548-57.
                  8. Hietala SK, Ardans AA. Interaction of Rhodococcus equi with phagocytic cells from R. equi-exposed and non-exposed foals.. Vet Microbiol 1987 Aug;14(3):307-20.
                    pubmed: 3672873doi: 10.1016/0378-1135(87)90118-0google scholar: lookup
                  9. Hines MT, Paasch KM, Alperin DC, Palmer GH, Westhoff NC, Hines SA. Immunity to Rhodococcus equi: antigen-specific recall responses in the lungs of adult horses.. Vet Immunol Immunopathol 2001 May 10;79(1-2):101-14.
                    pubmed: 11356253doi: 10.1016/s0165-2427(01)00258-6google scholar: lookup
                  10. Hondalus MK, Mosser DM. Survival and replication of Rhodococcus equi in macrophages.. Infect Immun 1994 Oct;62(10):4167-75.
                  11. Jung T, Schauer U, Heusser C, Neumann C, Rieger C. Detection of intracellular cytokines by flow cytometry.. J Immunol Methods 1993 Feb 26;159(1-2):197-207.
                    pubmed: 8445253doi: 10.1016/0022-1759(93)90158-4google scholar: lookup
                  12. Kamath AT, Groat NL, Bean AG, Britton WJ. Protective effect of DNA immunization against mycobacterial infection is associated with the early emergence of interferon-gamma (IFN-gamma)-secreting lymphocytes.. Clin Exp Immunol 2000 Jun;120(3):476-82.
                  13. Kanaly ST, Hines SA, Palmer GH. Cytokine modulation alters pulmonary clearance of Rhodococcus equi and development of granulomatous pneumonia.. Infect Immun 1995 Aug;63(8):3037-41.
                  14. Kanaly ST, Hines SA, Palmer GH. Failure of pulmonary clearance of Rhodococcus equi infection in CD4+ T-lymphocyte-deficient transgenic mice.. Infect Immun 1993 Nov;61(11):4929-32.
                  15. Kanaly ST, Hines SA, Palmer GH. Transfer of a CD4+ Th1 cell line to nude mice effects clearance of Rhodococcus equi from the lung.. Infect Immun 1996 Apr;64(4):1126-32.
                  16. Kasuga-Aoki H, Takai S, Sasaki Y, Tsubaki S, Madarame H, Nakane A. Tumour necrosis factor and interferon-gamma are required in host resistance against virulent Rhodococcus equi infection in mice: cytokine production depends on the virulence levels of R. equi.. Immunology 1999 Jan;96(1):122-7.
                  17. Krouwels FH, Hol BE, Bruinier B, Lutter R, Jansen HM, Out TA. Cytokine production by T-cell clones from bronchoalveolar lavage fluid of patients with asthma and healthy subjects.. Eur Respir J Suppl 1996 Aug;22:95s-103s.
                    pubmed: 8871052
                  18. Krouwels FH, Nocker RE, Snoek M, Lutter R, van der Zee JS, Weller FR, Jansen HM, Out TA. Immunocytochemical and flow cytofluorimetric detection of intracellular IL-4, IL-5 and IFN-gamma: applications using blood- and airway-derived cells.. J Immunol Methods 1997 Apr 11;203(1):89-101.
                    pubmed: 9134033doi: 10.1016/s0022-1759(97)00016-1google scholar: lookup
                  19. Krug N, Madden J, Redington AE, Lackie P, Djukanovic R, Schauer U, Holgate ST, Frew AJ, Howarth PH. T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma.. Am J Respir Cell Mol Biol 1996 Apr;14(4):319-26.
                    pubmed: 8600935doi: 10.1165/ajrcmb.14.4.8600935google scholar: lookup
                  20. Lopez AM, Hines MT, Palmer GH, Alperin DC, Hines SA. Identification of pulmonary T-lymphocyte and serum antibody isotype responses associated with protection against Rhodococcus equi.. Clin Diagn Lab Immunol 2002 Nov;9(6):1270-6.
                  21. Madarame H, Takai S, Matsumoto C, Minamiyama K, Sasaki Y, Tsubaki S, Hasegawa Y, Nakane A. Virulent and avirulent Rhodococcus equi infection in T-cell deficient athymic nude mice: pathologic, bacteriologic and immunologic responses.. FEMS Immunol Med Microbiol 1997 Apr;17(4):251-62.
                  22. Madigan JE, Hietala S, Muller N. Protection against naturally acquired Rhodococcus equi pneumonia in foals by administration of hyperimmune plasma.. J Reprod Fertil Suppl 1991;44:571-8.
                    pubmed: 1795301
                  23. Martens RJ, Martens JG, Fiske RA, Hietala SK. Rhodococcus equi foal pneumonia: protective effects of immune plasma in experimentally infected foals.. Equine Vet J 1989 Jul;21(4):249-55.
                  24. Möllers M, Aries SP, Drömann D, Mascher B, Braun J, Dalhoff K. Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis.. Thorax 2001 Jun;56(6):487-93.
                    pmc: PMC1746073pubmed: 11359967doi: 10.1136/thorax.56.6.487google scholar: lookup
                  25. Mosser DM, Hondalus MK. Rhodococcus equi: an emerging opportunistic pathogen.. Trends Microbiol 1996 Jan;4(1):29-33.
                    pubmed: 8824792doi: 10.1016/0966-842x(96)81502-2google scholar: lookup
                  26. Nordmann P, Ronco E, Nauciel C. Role of T-lymphocyte subsets in Rhodococcus equi infection.. Infect Immun 1992 Jul;60(7):2748-52.
                  27. Ostler T, Hussell T, Surh CD, Openshaw P, Ehl S. Long-term persistence and reactivation of T cell memory in the lung of mice infected with respiratory syncytial virus.. Eur J Immunol 2001 Sep;31(9):2574-82.
                  28. Picker LJ, Singh MK, Zdraveski Z, Treer JR, Waldrop SL, Bergstresser PR, Maino VC. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry.. Blood 1995 Aug 15;86(4):1408-19.
                    pubmed: 7632949
                  29. Prescott JF. Rhodococcus equi: an animal and human pathogen.. Clin Microbiol Rev 1991 Jan;4(1):20-34.
                    pmc: PMC358176pubmed: 2004346doi: 10.1128/CMR.4.1.20google scholar: lookup
                  30. Ross TL, Balson GA, Miners JS, Smith GD, Shewen PE, Prescott JF, Yager JA. Role of CD4+, CD8+ and double negative T-cells in the protection of SCID/beige mice against respiratory challenge with Rhodococcus equi.. Can J Vet Res 1996 Jul;60(3):186-92.
                    pmc: PMC1263831pubmed: 8809381
                  31. Serbina NV, Flynn JL. CD8(+) T cells participate in the memory immune response to Mycobacterium tuberculosis.. Infect Immun 2001 Jul;69(7):4320-8.
                  32. Siegrist CA. Neonatal and early life vaccinology.. Vaccine 2001 May 14;19(25-26):3331-46.
                    pubmed: 11348697doi: 10.1016/s0264-410x(01)00028-7google scholar: lookup
                  33. Stenger S. Cytolytic T cells in the immune response to mycobacterium tuberculosis.. Scand J Infect Dis 2001;33(7):483-7.
                    pubmed: 11515755doi: 10.1080/00365540110026584google scholar: lookup
                  34. Takai S. Epidemiology of Rhodococcus equi infections: a review.. Vet Microbiol 1997 Jun 16;56(3-4):167-76.
                    pubmed: 9226831doi: 10.1016/s0378-1135(97)00085-0google scholar: lookup
                  35. Takai S, Kobayashi C, Murakami K, Sasaki Y, Tsubaki S. Live virulent Rhodococcus equi, rather than killed or avirulent, elicits protective immunity to R. equi infection in mice.. FEMS Immunol Med Microbiol 1999 May;24(1):1-9.
                  36. Takai S, Imai Y, Fukunaga N, Uchida Y, Kamisawa K, Sasaki Y, Tsubaki S, Sekizaki T. Identification of virulence-associated antigens and plasmids in Rhodococcus equi from patients with AIDS.. J Infect Dis 1995 Nov;172(5):1306-11.
                    pubmed: 7594668doi: 10.1093/infdis/172.5.1306google scholar: lookup
                  37. Takai S, Watanabe Y, Ikeda T, Ozawa T, Matsukura S, Tamada Y, Tsubaki S, Sekizaki T. Virulence-associated plasmids in Rhodococcus equi.. J Clin Microbiol 1993 Jul;31(7):1726-9.
                  38. Tascon RE, Stavropoulos E, Lukacs KV, Colston MJ. Protection against Mycobacterium tuberculosis infection by CD8+ T cells requires the production of gamma interferon.. Infect Immun 1998 Feb;66(2):830-4.
                    pmc: PMC107978pubmed: 9453650doi: 10.1128/IAI.66.2.830-834.1998google scholar: lookup
                  39. Tumas DB, Brassfield AL, Travenor AS, Hines MT, Davis WC, McGuire TC. Monoclonal antibodies to the equine CD2 T lymphocyte marker, to a pan-granulocyte/monocyte marker and to a unique pan-B lymphocyte marker.. Immunobiology 1994 Dec;192(1-2):48-64.
                    pubmed: 7750989doi: 10.1016/S0171-2985(11)80407-9google scholar: lookup
                  40. Wada R, Kamada M, Anzai T, Nakanishi A, Kanemaru T, Takai S, Tsubaki S. Pathogenicity and virulence of Rhodococcus equi in foals following intratracheal challenge.. Vet Microbiol 1997 Jun 16;56(3-4):301-12.
                    pubmed: 9226844doi: 10.1016/s0378-1135(97)00098-9google scholar: lookup
                  41. Wahlström J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J. Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T cells in sarcoidosis.. Am J Respir Crit Care Med 2001 Jan;163(1):115-21.
                    pubmed: 11208635doi: 10.1164/ajrccm.163.1.9906071google scholar: lookup
                  42. Weinstock DM, Brown AE. Rhodococcus equi: an emerging pathogen.. Clin Infect Dis 2002 May 15;34(10):1379-85.
                    pubmed: 11981734doi: 10.1086/340259google scholar: lookup
                  43. Zhang CH, Grünig G, Davis W, Antczak DF. Down-regulation followed by re-expression of equine CD4 molecules in response to phorbol myristate acetate.. Vet Immunol Immunopathol 1994 Jul;42(1):71-82.
                    pubmed: 7975181doi: 10.1016/0165-2427(94)90090-6google scholar: lookup

                  Citations

                  This article has been cited 23 times.
                  1. Rivolta AA, Bujold AR, Wilmarth PA, Phinney BS, Navelski JP, Horohov DW, Sanz MG. Comparison of the broncoalveolar lavage fluid proteomics between foals and adult horses. PLoS One 2023;18(9):e0290778.
                    doi: 10.1371/journal.pone.0290778pubmed: 37669266google scholar: lookup
                  2. Lohmann KL, Lopez AM, Manning ST, Marques FJ, Brownlie R, Allen AL, Sangster AE, Mutwiri G, Gerdts V, Potter A, Townsend HG. Failure of a VapA/CpG oligodeoxynucleotide vaccine to protect foals against experimental Rhocococcus equi pneumonia despite induction of VapA-specific antibody and interferon-γ response. Can J Vet Res 2013 Jul;77(3):161-9.
                    pubmed: 24101791
                  3. Gurel V, Lambert K, Page AE, Loynachan AT, Huges K, Timoney JF, Fettinger M, Horohov DW, McMichael J. Streptolysin-O/antibiotics adjunct therapy modulates site-specific expression of extracellular matrix and inflammatory genes in lungs of Rhodococcus equi infected foals. Vet Res Commun 2013 Jun;37(2):145-54.
                    doi: 10.1007/s11259-013-9557-ypubmed: 23475766google scholar: lookup
                  4. Harris SP, Hines MT, Mealey RH, Alperin DC, Hines SA. Early development of cytotoxic T lymphocytes in neonatal foals following oral inoculation with Rhodococcus equi. Vet Immunol Immunopathol 2011 Jun 15;141(3-4):312-6.
                    doi: 10.1016/j.vetimm.2011.03.015pubmed: 21481947google scholar: lookup
                  5. Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleukin-4 and interleukin-10 production by T helper cells reveals intact Th1 and regulatory TR1 cell activation and a delay of the Th2 cell response in equine neonates and foals. Vet Res 2010 Jul-Aug;41(4):47.
                    doi: 10.1051/vetres/2010019pubmed: 20374696google scholar: lookup
                  6. Harris SP, Fujiwara N, Mealey RH, Alperin DC, Naka T, Goda R, Hines SA. Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes. Microbiology (Reading) 2010 Jun;156(Pt 6):1836-1847.
                    doi: 10.1099/mic.0.035915-0pubmed: 20299405google scholar: lookup
                  7. Paillot R, Robinson C, Steward K, Wright N, Jourdan T, Butcher N, Heather Z, Waller AS. Contribution of each of four Superantigens to Streptococcus equi-induced mitogenicity, gamma interferon synthesis, and immunity. Infect Immun 2010 Apr;78(4):1728-39.
                    doi: 10.1128/IAI.01079-09pubmed: 20123710google scholar: lookup
                  8. Oliveira AF, Ruas LP, Cardoso SA, Soares SG, Roque-Barreira MC. Vaccination of mice with salmonella expressing VapA: mucosal and systemic Th1 responses provide protection against Rhodococcus equi infection. PLoS One 2010 Jan 13;5(1):e8644.
                    doi: 10.1371/journal.pone.0008644pubmed: 20072623google scholar: lookup
                  9. Flaminio MJ, Nydam DV, Marquis H, Matychak MB, Giguère S. Foal monocyte-derived dendritic cells become activated upon Rhodococcus equi infection. Clin Vaccine Immunol 2009 Feb;16(2):176-83.
                    doi: 10.1128/CVI.00336-08pubmed: 19109450google scholar: lookup
                  10. Mealey RH, Stone DM, Hines MT, Alperin DC, Littke MH, Leib SR, Leach SE, Hines SA. Experimental Rhodococcus equi and equine infectious anemia virus DNA vaccination in adult and neonatal horses: effect of IL-12, dose, and route. Vaccine 2007 Oct 23;25(43):7582-97.
                    doi: 10.1016/j.vaccine.2007.07.055pubmed: 17889970google scholar: lookup
                  11. Jacks S, Giguère S, Crawford PC, Castleman WL. Experimental infection of neonatal foals with Rhodococcus equi triggers adult-like gamma interferon induction. Clin Vaccine Immunol 2007 Jun;14(6):669-77.
                    doi: 10.1128/CVI.00042-07pubmed: 17409222google scholar: lookup
                  12. Jacks S, Giguère S, Prescott JF. In vivo expression of and cell-mediated immune responses to the plasmid-encoded virulence-associated proteins of Rhodococcus equi in foals. Clin Vaccine Immunol 2007 Apr;14(4):369-74.
                    doi: 10.1128/CVI.00448-06pubmed: 17301216google scholar: lookup
                  13. Flaminio MJ, Borges AS, Nydam DV, Horohov DW, Hecker R, Matychak MB. The effect of CpG-ODN on antigen presenting cells of the foal. J Immune Based Ther Vaccines 2007 Jan 25;5:1.
                    doi: 10.1186/1476-8518-5-1pubmed: 17254326google scholar: lookup
                  14. Mealey RH, Sharif A, Ellis SA, Littke MH, Leib SR, McGuire TC. Early detection of dominant Env-specific and subdominant Gag-specific CD8+ lymphocytes in equine infectious anemia virus-infected horses using major histocompatibility complex class I/peptide tetrameric complexes. Virology 2005 Aug 15;339(1):110-26.
                    doi: 10.1016/j.virol.2005.05.025pubmed: 15979679google scholar: lookup
                  15. Patton KM, McGuire TC, Hines MT, Mealey RH, Hines SA. Rhodococcus equi-specific cytotoxic T lymphocytes in immune horses and development in asymptomatic foals. Infect Immun 2005 Apr;73(4):2083-93.
                  16. Patton KM, McGuire TC, Fraser DG, Hines SA. Rhodococcus equi-infected macrophages are recognized and killed by CD8+ T lymphocytes in a major histocompatibility complex class I-unrestricted fashion. Infect Immun 2004 Dec;72(12):7073-83.
                  17. Horín P, Smola J, Matiasovic J, Vyskocil M, Lukeszová L, Tomanová K, Králík P, Glasnák V, Schröffelová D, Knoll A, Sedlinská M, Krenková L, Jahn P. Polymorphisms in equine immune response genes and their associations with infections. Mamm Genome 2004 Oct;15(10):843-50.
                    doi: 10.1007/s00335-004-2356-6pubmed: 15520887google scholar: lookup
                  18. Lührmann A, Mauder N, Sydor T, Fernandez-Mora E, Schulze-Luehrmann J, Takai S, Haas A. Necrotic death of Rhodococcus equi-infected macrophages is regulated by virulence-associated plasmids. Infect Immun 2004 Feb;72(2):853-62.
                    doi: 10.1128/IAI.72.2.853-862.2004pubmed: 14742529google scholar: lookup
                  19. Kohler AK, Stone DM, Hines MT, Byrne BA, Alperin DC, Norton LK, Hines SA. Rhodococcus equi secreted antigens are immunogenic and stimulate a type 1 recall response in the lungs of horses immune to R. equi infection. Infect Immun 2003 Nov;71(11):6329-37.
                  20. Berghaus LJ, Venner M, Helbig H, Hildebrandt D, Hart K. The potential value of cytokine, cortisol and vitamin D profiles in foals from birth to weaning for respiratory disease prediction on a farm endemic for Rhodococcus equi pneumonia. Equine Vet J 2026 Mar;58(2):359-371.
                    doi: 10.1111/evj.70093pubmed: 40923138google scholar: lookup
                  21. Mizuguchi Y, Tsuzuki N, Ebana MD, Suzuki Y, Kakuda T. IgG Subtype Response against Virulence-Associated Protein A in Foals Naturally Infected with Rhodococcus equi. Vet Sci 2024 Sep 9;11(9).
                    doi: 10.3390/vetsci11090422pubmed: 39330801google scholar: lookup
                  22. da Silveira BP, Cohen ND, Lawhon SD, Watson RO, Bordin AI. Protective immune response against Rhodococcus equi: An innate immunity-focused review. Equine Vet J 2025 May;57(3):563-586.
                    doi: 10.1111/evj.14214pubmed: 39258739google scholar: lookup
                  23. Liu L, Cai P, Gu W, Duan X, Gao S, Ma X, Ma Y, Ma S, Li G, Wang X, Cai K, Wang Y, Cai T, Zhao H. Evaluation of vaccine candidates against Rhodococcus equi in BALB/c mice infection model: cellular and humoral immune responses. BMC Microbiol 2024 Jul 8;24(1):249.
                    doi: 10.1186/s12866-024-03408-zpubmed: 38977999google scholar: lookup