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Mycobacterium tuberculosis employs various virulence strategies to subvert host immune responses in order to persist and cause disease. Interaction of M. tuberculosis with mannose receptor on macrophages via surface-exposed lipoarabinomannan (LAM) is believed to be critical for cell entry, inhibition of phagosome-lysosome fusion, and intracellular survival, but in vivo evidence is lacking. LprG, a cell envelope lipoprotein that is essential for virulence of M. tuberculosis, has been shown to bind to the acyl groups of lipoglycans but the role of LprG in LAM biosynthesis and localization remains unknown. Using an M. tuberculosis lprG mutant, we show that LprG is essential for normal surface expression of LAM and virulence of M. tuberculosis attributed to LAM. The lprG mutant had a normal quantity of LAM in the cell envelope, but its surface was altered and showed reduced expression of surface-exposed LAM. Functionally, the lprG mutant was defective for macrophage entry and inhibition of phagosome-lysosome fusion, was attenuated in macrophages, and was killed in the mouse lung with the onset of adaptive immunity. This study identifies the role of LprG in surface-exposed LAM expression and provides in vivo evidence for the essential role surface LAM plays in M. tuberculosis virulence. Findings have translational implications for therapy and vaccine development.

Titel:	LprG-mediated surface expression of lipoarabinomannan is essential for virulence of Mycobacterium tuberculosis.
Autor/in / Beteiligte Person:	Gaur, RL ; Ren, K ; Blumenthal, A ; Bhamidi, S ; González-Nilo, FD ; Jackson, M ; Zare, RN ; Ehrt, S ; Ernst, JD ; Banaei, N
Link:	Volltext (PDF)
Zeitschrift:	PLoS pathogens, Jg. 10 (2014-09-18), Heft 9, S. e1004376
Veröffentlichung:	San Francisco, CA : Public Library of Science, c2005-, 2014
Medientyp:	academicJournal
ISSN:	1553-7374 (electronic)
DOI:	10.1371/journal.ppat.1004376
Schlagwort:	Animals Bacterial Proteins genetics Bacterial Proteins immunology Cell Wall metabolism Immunoblotting Lipoproteins genetics Lipoproteins immunology Lung immunology Lung metabolism Lung microbiology Macrophages immunology Macrophages metabolism Macrophages microbiology Mice Mice, Inbred C57BL Mutation genetics Mycobacterium tuberculosis metabolism Phagocytosis physiology Tuberculosis metabolism Tuberculosis microbiology Bacterial Proteins metabolism Cell Wall immunology Lipopolysaccharides metabolism Lipoproteins metabolism Mycobacterium tuberculosis immunology Tuberculosis immunology Virulence immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural Language: English [PLoS Pathog] 2014 Sep 18; Vol. 10 (9), pp. e1004376. <i>Date of Electronic Publication: </i>2014 Sep 18 (<i>Print Publication: </i>2014). MeSH Terms: Bacterial Proteins / metabolism ; Cell Wall / immunology ; Lipopolysaccharides / metabolism ; Lipoproteins / metabolism ; Mycobacterium tuberculosis / immunology ; Tuberculosis / immunology ; Virulence / *immunology ; Animals ; Bacterial Proteins / genetics ; Bacterial Proteins / immunology ; Cell Wall / metabolism ; Immunoblotting ; Lipoproteins / genetics ; Lipoproteins / immunology ; Lung / immunology ; Lung / metabolism ; Lung / microbiology ; Macrophages / immunology ; Macrophages / metabolism ; Macrophages / microbiology ; Mice ; Mice, Inbred C57BL ; Mutation / genetics ; Mycobacterium tuberculosis / metabolism ; Phagocytosis / physiology ; Tuberculosis / metabolism ; Tuberculosis / microbiology Comments: Erratum in: PLoS Pathog. 2014 Oct;10(10):e1004489. ; Erratum in: PLoS Pathog. 2014 Oct;10(10):e1004494. Gibbs, Sara [corrected to González-Nilo, Fernando D]. ; Erratum in: PLoS Pathog. 2015 Dec 9;11(12):e1005336. (PMID: 26650245) References: J Biol Chem. 2013 Jan 25;288(4):2388-402. (PMID: 23212917) ; Microbiology (Reading). 1995 Jul;141 ( Pt 7):1609-20. (PMID: 7551029) ; Immunity. 2009 Dec 18;31(6):974-85. (PMID: 20064452) ; Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12989-94. (PMID: 14569030) ; FEMS Microbiol Lett. 1994 Oct 15;123(1-2):11-8. (PMID: 7988876) ; PLoS Pathog. 2009 Aug;5(8):e1000545. (PMID: 19680450) ; Nat Struct Mol Biol. 2010 Sep;17(9):1088-95. (PMID: 20694006) ; Mol Microbiol. 2004 Jul;53(2):391-403. (PMID: 15228522) ; Methods Enzymol. 1989;179:215-42. (PMID: 2622349) ; J Exp Med. 2005 Oct 3;202(7):987-99. (PMID: 16203868) ; PLoS Pathog. 2010 Mar 05;6(3):e1000794. (PMID: 20221442) ; Clin Microbiol Rev. 2003 Jul;16(3):463-96. (PMID: 12857778) ; Tuberculosis (Edinb). 2008 Nov;88(6):560-5. (PMID: 18539533) ; Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13664-9. (PMID: 16945913) ; Curr Opin Microbiol. 2004 Feb;7(1):71-7. (PMID: 15036144) ; Microbiology (Reading). 2003 Jul;149(Pt 7):1837-1847. (PMID: 12855735) ; Infect Immun. 1991 May;59(5):1755-61. (PMID: 1850379) ; BMC Infect Dis. 2011 Jul 16;11:195. (PMID: 21762531) ; Microbiology (Reading). 2002 Oct;148(Pt 10):3007-3017. (PMID: 12368434) ; J Cell Sci. 2004 Apr 15;117(Pt 10):2131-40. (PMID: 15090599) ; J Lipid Res. 2007 Sep;48(9):1976-84. (PMID: 17565170) ; FEMS Microbiol Rev. 2011 Nov;35(6):1126-57. (PMID: 21521247) ; J Biol Chem. 2005 Dec 9;280(49):40699-706. (PMID: 16210318) ; J Lipid Res. 2005 Mar;46(3):475-83. (PMID: 15576843) ; Annu Rev Biochem. 1995;64:29-63. (PMID: 7574484) ; ACS Nano. 2012 May 22;6(5):4314-8. (PMID: 22468923) ; Cell. 2011 Apr 1;145(1):39-53. (PMID: 21376383) ; J Immunol. 1993 Apr 1;150(7):2920-30. (PMID: 8454864) ; J Bacteriol. 1995 Mar;177(5):1123-8. (PMID: 7868582) ; Am J Respir Crit Care Med. 2013 Sep 1;188(5):600-7. (PMID: 23805786) ; Antimicrob Agents Chemother. 2009 Sep;53(9):3675-82. (PMID: 19564371) ; J Immunol. 2006 Mar 1;176(5):3019-27. (PMID: 16493060) ; J Biol Chem. 1990 Jun 5;265(16):9272-9. (PMID: 2111816) ; Eur J Cell Biol. 2010 Jan;89(1):95-101. (PMID: 19892432) ; Microbes Infect. 2004 Feb;6(2):182-7. (PMID: 14998516) ; Microbes Infect. 1999 Jul;1(9):709-17. (PMID: 10611748) ; Analyst. 2012 Mar 21;137(6):1495-9. (PMID: 22324051) ; Nature. 1998 Jun 11;393(6685):537-44. (PMID: 9634230) ; Infect Immun. 2006 Nov;74(11):6449-57. (PMID: 16923787) ; J Bacteriol. 2008 Mar;190(5):1783-91. (PMID: 18156250) ; Antimicrob Agents Chemother. 2009 Sep;53(9):3799-802. (PMID: 19596883) ; Annu Rev Pathol. 2012;7:353-84. (PMID: 22054143) ; J Immunol. 1998 Nov 1;161(9):4983-91. (PMID: 9794435) ; Eur J Immunol. 2008 Feb;38(2):459-69. (PMID: 18203140) Grant Information: R01 AI064798 United States AI NIAID NIH HHS; AI064798 United States AI NIAID NIH HHS Substance Nomenclature: 0 (Bacterial Proteins) ; 0 (Lipopolysaccharides) ; 0 (Lipoproteins) ; 0 (lipoarabinomannan) Entry Date(s): Date Created: 20140919 Date Completed: 20151208 Latest Revision: 20211021 Update Code: 20231215 PubMed Central ID: PMC4169494

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LprG-mediated surface expression of lipoarabinomannan is essential for virulence of Mycobacterium tuberculosis.