Indoleamine 2,3-Dioxygenase 1 Is a Lung-Specific Innate Immune Defense Mechanism That Inhibits Growth ofFrancisella tularensisTryptophan Auxotrophs

Abstract

Upon microbial challenge, organs at various anatomic sites of the body employ different innate immune mechanisms to defend against potential infections. Accordingly, microbial pathogens evolved to subvert these organ-specific host immune mechanisms to survive and grow in infected organs. Francisella tularensis is a bacterium capable of infecting multiple organs and thus encounters a myriad of organ-specific defense mechanisms. This suggests that F. tularensis may possess specific factors that aid in evasion of these innate immune defenses. We carried out a microarray-based, negative-selection screen in an intranasal model of Francisella novicida infection to identify Francisella genes that contribute to bacterial growth specifically in the lungs of mice. Genes in the bacterial tryptophan biosynthetic pathway were identified as being important for F. novicida growth specifically in the lungs. In addition, a host tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase 1 (IDO1), is induced specifically in the lungs of mice infected with F. novicida or Streptococcus pneumoniae. Furthermore, the attenuation of F. novicida tryptophan mutant bacteria was rescued in the lungs of IDO1 ؊/؊ mice. IDO1 is a lung-specific innate immune mechanism that controls pulmonary Francisella infections.

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

“…Francisella tularensis is a facultative intracellular pathogen whose presence has been shown to induce host IDO within infected mouse lungs (102). Even though the genes for Trp biosynthesis are present in F. tularensis and were indeed shown to be important for survival, unlike the case for chlamydiae, this biosynthetic potential is not completely able to offset the antimicrobial action of host IDO.…”

“…The growth of extracellular bacteria can also be vulnerable to IDO-mediated Trp depletion, as has been shown with group B streptococci (Streptococcus agalactiae) in human cord blood macrophages (77), Streptococcus pneumoniae in mouse lungs (102), and Enterococcus faecalis (and close relatives) in human uroepi-thelial cells (78). It is suggestive that E. faecalis, Streptococcus mutans, Streptococcus pyogenes, Streptococcus equi, Streptococcus gordonii, and S. pneumoniae comprise a phylogenetic clade in which the Trp biosynthetic pathway appears to have been lost independently in some of its members, i.e., E. faecalis, S. pyogenes, and S. equi (141).…”

Subversion of Host Recognition and Defense Systems by Francisella spp

“…Upon intranasal infection with Francisella, IDO is significantly upregulated in the lung (172). Francisella is capable of overcoming this host defense by maintaining the ability to synthesize tryptophan de novo, although this process is very energy intensive (241).…”

“…Francisella is capable of overcoming this host defense by maintaining the ability to synthesize tryptophan de novo, although this process is very energy intensive (241). The importance of tryptophan prototrophy is exemplified by the fact that strains with mutations in trpB, which is necessary for the final step of tryptophan biosynthesis, are significantly attenuated during intranasal infection (50,172) and that this attenuation can be overcome in IDO Ϫ/Ϫ mice (172). trpB mutants are capable of limited intracellular replication in macrophages and show decreased survival in IFN-␥-stimulated macrophages compared to wild-type Francisella (50).…”

“…IDO is expressed in nearly every cell type, excluding hepatic cells, and is particularly highly expressed in the lungs and placenta (218). Infection by Chlamydia (26) or Streptococcus (172), as well as stimulation with IFN-␥ (238) or LPS (237), induces IDO expression and results in decreased tryptophan levels. This is an important defensive mechanism, as it creates an innate nutritional barrier that limits the ability of microbes to replicate.…”