PE_PGRS3 of Mycobacterium tuberculosis is specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed in Mycobacterium smegmatis

Flavio De Maio, Basem Battah, Valentina Palmieri, Linda Petrone, Francesco Corrente, Alessandro Salustri, Ivana Palucci, Silvia Bellesi, Massimiliano Papi, Salvatore Rubino, Michela Sali, Delia Goletti, Maurizio Sanguinetti, Riccardo Manganelli, Marco De Spirito, Giovanni Delogu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

PE_PGRSs of Mycobacterium tuberculosis (Mtb) represent a family of complex and peculiar proteins whose role and function remain elusive. In this study, we investigated PE_PGRS3 and PE_PGRS4, two highly homologous PE_PGRSs encoded by two contiguous genes in the Mtb genome. Using a gene-reporter system in Mycobacterium smegmatis (Ms) and transcriptional analysis in Mtb, we show that PE_PGRS3, but not PE_PGRS4, is specifically expressed under low phosphate concentrations. Interestingly, PE_PGRS3, but not PE_PGRS4, has a unique, arginine-rich C-terminal domain of unknown function. Heterologous expression of PE_PGRS3 in Ms was used to demonstrate cellular localisation of the protein on the mycobacterial surface, where it significantly affects net surface charge. Moreover, expression of full-length PE_PGRS3 enhanced adhesion of Ms to murine macrophages and human epithelial cells and improved bacterial persistence in spleen tissue following infection in mice. Expression of the PE_PGRS3 functional deletion mutant lacking the C-terminal domain in Ms did not enhance adhesion to host cells, showing a phenotype similar to the Ms parental strain. Interestingly, enhanced persistence of Ms expressing PE_PGRS3 did not correlate with increased concentrations of inflammatory cytokines. These results point to a critical role for the ≈ 80 amino acids long, arginine-rich C-terminal domain of PE_PGRS3 in tuberculosis pathogenesis.

Original languageEnglish
Article numbere12952
JournalCellular Microbiology
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 2018

Fingerprint

Mycobacterium smegmatis
Mycobacterium tuberculosis
Arginine
Phosphates
Reporter Genes
Tuberculosis
Proteins
Spleen
Epithelial Cells
Macrophages
Genome
Cytokines
Phenotype
Amino Acids
Infection
Genes

Keywords

  • adhesion
  • Mycobacterium tuberculosis
  • PE_PGRS
  • phosphate

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

Cite this

PE_PGRS3 of Mycobacterium tuberculosis is specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed in Mycobacterium smegmatis. / De Maio, Flavio; Battah, Basem; Palmieri, Valentina; Petrone, Linda; Corrente, Francesco; Salustri, Alessandro; Palucci, Ivana; Bellesi, Silvia; Papi, Massimiliano; Rubino, Salvatore; Sali, Michela; Goletti, Delia; Sanguinetti, Maurizio; Manganelli, Riccardo; De Spirito, Marco; Delogu, Giovanni.

In: Cellular Microbiology, Vol. 20, No. 12, e12952, 12.2018.

Research output: Contribution to journalArticle

De Maio, F, Battah, B, Palmieri, V, Petrone, L, Corrente, F, Salustri, A, Palucci, I, Bellesi, S, Papi, M, Rubino, S, Sali, M, Goletti, D, Sanguinetti, M, Manganelli, R, De Spirito, M & Delogu, G 2018, 'PE_PGRS3 of Mycobacterium tuberculosis is specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed in Mycobacterium smegmatis', Cellular Microbiology, vol. 20, no. 12, e12952. https://doi.org/10.1111/cmi.12952
De Maio, Flavio ; Battah, Basem ; Palmieri, Valentina ; Petrone, Linda ; Corrente, Francesco ; Salustri, Alessandro ; Palucci, Ivana ; Bellesi, Silvia ; Papi, Massimiliano ; Rubino, Salvatore ; Sali, Michela ; Goletti, Delia ; Sanguinetti, Maurizio ; Manganelli, Riccardo ; De Spirito, Marco ; Delogu, Giovanni. / PE_PGRS3 of Mycobacterium tuberculosis is specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed in Mycobacterium smegmatis. In: Cellular Microbiology. 2018 ; Vol. 20, No. 12.
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abstract = "PE_PGRSs of Mycobacterium tuberculosis (Mtb) represent a family of complex and peculiar proteins whose role and function remain elusive. In this study, we investigated PE_PGRS3 and PE_PGRS4, two highly homologous PE_PGRSs encoded by two contiguous genes in the Mtb genome. Using a gene-reporter system in Mycobacterium smegmatis (Ms) and transcriptional analysis in Mtb, we show that PE_PGRS3, but not PE_PGRS4, is specifically expressed under low phosphate concentrations. Interestingly, PE_PGRS3, but not PE_PGRS4, has a unique, arginine-rich C-terminal domain of unknown function. Heterologous expression of PE_PGRS3 in Ms was used to demonstrate cellular localisation of the protein on the mycobacterial surface, where it significantly affects net surface charge. Moreover, expression of full-length PE_PGRS3 enhanced adhesion of Ms to murine macrophages and human epithelial cells and improved bacterial persistence in spleen tissue following infection in mice. Expression of the PE_PGRS3 functional deletion mutant lacking the C-terminal domain in Ms did not enhance adhesion to host cells, showing a phenotype similar to the Ms parental strain. Interestingly, enhanced persistence of Ms expressing PE_PGRS3 did not correlate with increased concentrations of inflammatory cytokines. These results point to a critical role for the ≈ 80 amino acids long, arginine-rich C-terminal domain of PE_PGRS3 in tuberculosis pathogenesis.",
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AU - De Maio, Flavio

AU - Battah, Basem

AU - Palmieri, Valentina

AU - Petrone, Linda

AU - Corrente, Francesco

AU - Salustri, Alessandro

AU - Palucci, Ivana

AU - Bellesi, Silvia

AU - Papi, Massimiliano

AU - Rubino, Salvatore

AU - Sali, Michela

AU - Goletti, Delia

AU - Sanguinetti, Maurizio

AU - Manganelli, Riccardo

AU - De Spirito, Marco

AU - Delogu, Giovanni

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AB - PE_PGRSs of Mycobacterium tuberculosis (Mtb) represent a family of complex and peculiar proteins whose role and function remain elusive. In this study, we investigated PE_PGRS3 and PE_PGRS4, two highly homologous PE_PGRSs encoded by two contiguous genes in the Mtb genome. Using a gene-reporter system in Mycobacterium smegmatis (Ms) and transcriptional analysis in Mtb, we show that PE_PGRS3, but not PE_PGRS4, is specifically expressed under low phosphate concentrations. Interestingly, PE_PGRS3, but not PE_PGRS4, has a unique, arginine-rich C-terminal domain of unknown function. Heterologous expression of PE_PGRS3 in Ms was used to demonstrate cellular localisation of the protein on the mycobacterial surface, where it significantly affects net surface charge. Moreover, expression of full-length PE_PGRS3 enhanced adhesion of Ms to murine macrophages and human epithelial cells and improved bacterial persistence in spleen tissue following infection in mice. Expression of the PE_PGRS3 functional deletion mutant lacking the C-terminal domain in Ms did not enhance adhesion to host cells, showing a phenotype similar to the Ms parental strain. Interestingly, enhanced persistence of Ms expressing PE_PGRS3 did not correlate with increased concentrations of inflammatory cytokines. These results point to a critical role for the ≈ 80 amino acids long, arginine-rich C-terminal domain of PE_PGRS3 in tuberculosis pathogenesis.

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