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Administration of a nitric oxide donor inhibits mglA expression by intracellular Francisella tularensis and counteracts phagosomal escape and subversion of TNF-α secretion.

Abstract：

:Francisella tularensis is a highly virulent intracellular bacterium capable of rapid multiplication in phagocytic cells. Previous studies have revealed that activation of F. tularensis-infected macrophages leads to control of infection and reactive nitrogen and oxygen species make important contributions to the bacterial killing. We investigated the effects of adding S-nitroso-acetyl-penicillamine (SNAP), which generates nitric oxide, or 3-morpholinosydnonimine hydrochloride, which indirectly leads to formation of peroxynitrite, to J774 murine macrophage-like cell cultures infected with F. tularensis LVS. Addition of SNAP led to significantly increased colocalization between LAMP-1 and bacteria, indicating containment of F. tularensis in the phagosome within 2 h, although no killing occurred within 4 h. A specific inhibitory effect on bacterial transcription was observed since the gene encoding the global regulator MglA was inhibited 50-100-fold. F. tularensis-infected J774 cells were incapable of secreting TNF-α in response to Escherichia coli LPS but addition of SNAP almost completely reversed the suppression. Similarly, infection with an MglA mutant did not inhibit LPS-induced TNF-α secretion of J774 cells. Strong staining of nitrotyrosine was observed in SNAP-treated bacteria, and MS identified nitration of two ribosomal 50S proteins, a CBS domain pair protein and bacterioferritin. The results demonstrated that addition of SNAP initially did not affect the viability of intracellular F. tularensis LVS but led to containment of the bacteria in the phagosome. Moreover, the treatment resulted in modification by nitration of several F. tularensis proteins.

journal_name

J Med Microbiol

journal_title

Journal of medical microbiology

authors

Tancred L,Telepnev MV,Golovliov I,Andersson B,Andersson H,Lindgren H,Sjöstedt A

doi

10.1099/jmm.0.032870-0

subject

Has Abstract

pub_date

2011-11-01 00:00:00

pages

1570-1583

issue

Pt 11

eissn

0022-2615

issn

1473-5644

journal_volume

pub_type

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Administration of a nitric oxide donor inhibits mglA expression by intracellular Francisella tularensis and counteracts phagosomal escape and subversion of TNF-α secretion.