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PLoS pathogens2011; 7(8); e1002181; doi: 10.1371/journal.ppat.1002181

The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development.

Abstract: Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551), ipdB (rv3552), fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD) and 3aα-H-4α(3'-propionic acid)-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP). Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections.
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Publication Date: 2011-08-25 PubMed ID: 21901092PubMed Central: PMC3161971DOI: 10.1371/journal.ppat.1002181Google Scholar: Lookup
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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 article investigates the role of the steroid catabolic pathway in the pathogenesis of an infection caused by the bacterium Rhodococcus equi. The research findings suggest that genes involved in steroid catabolism are potential targets for developing a live-attenuated vaccine against R. equi infections, effective in foals and potentially relevant to other susceptible animals or humans.

Understanding the Study and Its Context

  • The bacteria Rhodococcus equi is responsible for causing fatal pneumonia in foals (young horses), immunocompromised animals, and humans. Despite the critical impact of this disease, no effective vaccine exists currently.
  • The researchers compare R. equi bacteria with the human pathogen Mycobacterium tuberculosis due to their similar effects; both cause pulmonary diseases. They have previously established that essential steps in the cholesterol catabolic pathway contribute to the pathogenicity of Mycobacterium tuberculosis and have found similar clusters in R. equi.

The Study’s Approach and Findings

  • The research team identified orthologs (genes in different species that evolved from a common ancestral gene by speciation, typically have similar functions) of predicted M. tuberculosis virulence genes i.e. ipdA, ipdB, fadA6 and fadE30 in R. equi.
  • Inactivation of these genes resulted in different scenarios. Mutant strains with deactivated ipdA and ipdB genes, and fadE30, were unable to grow on steroid catabolic pathway intermediates, namely 4-androstene-3,17-dione (AD) and 3aα-H-4α(3′-propionic acid)-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5OH-HIP).
  • Interestingly, the same mutant strains showed an attenuated (reduced severity) infection phenotype in a macrophage infection assay, suggesting a diminished ability to cause infection. In contrast, deactivating fadA6 did not result in such effects.

Implications of the Study

  • These results indicate that genes crucial for growth on 5OH-HIP, a component of the steroid catabolic pathway, may play a significant role in the pathogenicity of R. equi. In other words, these genes seem to be involved in enabling the bacteria to cause infection.
  • The researchers also showed that the mutant strain with deactivated ipdA and ipdB genes could be safely administered to young foals, indicating that this strain may serve as a basis for a live-attenuated vaccine. Furthermore, oral immunization of foals led to substantial protection against a virulent R. equi strain.
  • The research team concludes that the genes involved in steroid catabolism are promising targets for creating a live-attenuated vaccine against R. equi infections.

Cite This Article

APA
van der Geize R, Grommen AW, Hessels GI, Jacobs AA, Dijkhuizen L. (2011). The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development. PLoS Pathog, 7(8), e1002181. https://doi.org/10.1371/journal.ppat.1002181

Publication

PLoS pathogens
ISSN: 1553-7374
NlmUniqueID: 101238921
Country: United States
Language: English
Volume: 7
Issue: 8
Pages: e1002181
PII: e1002181

Researcher Affiliations

van der Geize, R
  • Groningen Biomolecular Sciences and Biotechnology Institute (GBB), Department of Microbiology, University of Groningen, Groningen, The Netherlands. r.van.der.geize@rug.nl
Grommen, A W F
    Hessels, G I
      Jacobs, A A C
        Dijkhuizen, L

          MeSH Terms

          • Actinomycetales Infections / immunology
          • Actinomycetales Infections / microbiology
          • Actinomycetales Infections / prevention & control
          • Actinomycetales Infections / veterinary
          • Administration, Oral
          • Animals
          • Bacterial Vaccines / administration & dosage
          • Bacterial Vaccines / genetics
          • Bacterial Vaccines / immunology
          • Cell Line
          • Cholesterol / biosynthesis
          • Cloning, Molecular
          • Computational Biology
          • Genes, Bacterial
          • Horse Diseases / immunology
          • Horse Diseases / microbiology
          • Horse Diseases / prevention & control
          • Horses / immunology
          • Horses / microbiology
          • Humans
          • Macrophages / immunology
          • Macrophages / microbiology
          • Multigene Family
          • Pneumonia, Bacterial / immunology
          • Pneumonia, Bacterial / microbiology
          • Pneumonia, Bacterial / prevention & control
          • Pneumonia, Bacterial / veterinary
          • Rhodococcus equi / genetics
          • Rhodococcus equi / immunology
          • Rhodococcus equi / pathogenicity
          • Vaccines, Attenuated / administration & dosage
          • Vaccines, Attenuated / genetics
          • Vaccines, Attenuated / immunology
          • Virulence

          Conflict of Interest Statement

          AWFG and AACJ are employed by Intervet International BV, which is developing a rhodococcal vaccine.

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