Impact of pe_pgrs33 gene polymorphisms on mycobacterium tuberculosis infection and pathogenesis

Serena Camassa, Ivana Palucci, Raffaella Iantomasi, Tiziana Cubeddu, Mariachiara Minerva, Flavio De Maio, Samuel Jouny, Elisa Petruccioli, Delia Goletti, Francesco Ria, Michela Sali, Maurizio Sanguinetti, Riccardo Manganelli, Stefano Rocca, Priscille Brodin, Giovanni Delogu

Research output: Contribution to journalArticle

Abstract

PE_PGRS33 is a surface-exposed protein of Mycobacterium tuberculosis (Mtb) which exerts its role in macrophages entry and immunomodulation. In this study, we aimed to investigate the polymorphisms in the pe_pgrs33 gene of Mtb clinical isolates and evaluate their impact on protein functions. We sequenced pe_pgrs33 in a collection of 135 clinical strains, genotyped by 15-loci MIRU-VNTR and spoligotyping and belonging to the Mtb complex (MTBC). Overall, an association between pe_pgrs33 alleles and MTBC genotypes was observed and a dN/dS ratio of 0.64 was obtained, suggesting that a purifying selective pressure is acting on pe_pgrs33 against deleterious SNPs. Among a total of 19 pe_pgrs33 alleles identified in this study, 5 were cloned and used to complement the pe_pgrs33 knock-out mutant strain of Mtb H37Rv (MtbΔ33) to assess the functional impact of the respective polymorphisms in in vitro infections of primary macrophages. In human monocyte-derived macrophages (MDMs) infection, large in-frame and frameshift mutations were unable to restore the phenotype of Mtb H37Rv, impairing the cell entry capacity of Mtb, but neither its intracellular replication rate nor its immunomodulatory properties. In vivo studies performed in the murine model of tuberculosis (TB) demonstrated that the MtbΔ33 mutant strain was not impaired in the ability to infect and replicate in the lung tissue compared to the parental strain. Interestingly, MtbΔ33 showed an enhanced virulence during the chronic steps of infection compared to Mtb H37Rv. Similarly, the complementation of MtbΔ33 with a frameshift allele also resulted in a Mtb strain capable of causing a surprisingly enhanced tissue damage in murine lungs, during the chronic steps of infection. Together, these results further support the role of PE_PGRS33 in the pathogenesis and virulence of Mtb.

Original languageEnglish
Article number137
JournalFrontiers in cellular and infection microbiology
Volume7
Issue numberAPR
DOIs
Publication statusPublished - Apr 21 2017

Keywords

  • Bacterial pathogenesis
  • Genetic variability
  • Host-pathogen Interactions
  • Mycobacterium tuberculosis
  • PE_PGRS
  • Polymorphisms

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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  • Cite this

    Camassa, S., Palucci, I., Iantomasi, R., Cubeddu, T., Minerva, M., De Maio, F., Jouny, S., Petruccioli, E., Goletti, D., Ria, F., Sali, M., Sanguinetti, M., Manganelli, R., Rocca, S., Brodin, P., & Delogu, G. (2017). Impact of pe_pgrs33 gene polymorphisms on mycobacterium tuberculosis infection and pathogenesis. Frontiers in cellular and infection microbiology, 7(APR), [137]. https://doi.org/10.3389/fcimb.2017.00137