Innate immunity in tuberculosis: myths and truth

Korbel, Daniel S.; Schneider, Bianca E.; Schaible, Ulrich E.

doi:10.1016/j.micinf.2008.07.039

Cited by 213 publications

(216 citation statements)

References 97 publications

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“…IL-17 and CXCL-1/-2 were down-regulated in MyD88 KO mice. Accordingly, we did not observe a PMN-dominated pathology in their lungs.The mycobactericidal functions of PMN remain controversial [33] but PMN depletion studies in mice deficient for T, B and NK cells revealed a residual function of PMN in anti-mycobacterial host responses [34]. As shown herein, depletion of PMN during the course of M. tuberculosis infection led to a significant increase in mycobacterial numbers in lungs of immune competent WT mice suggesting a role of PMN in anti-TB defence.…”

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confidence: 60%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

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A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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“…It is well established that macrophages (Mϕ) also play a central role in TB pathogenesis (25)(26). They are one of the primary cell targets of MTB, which have developed different strategies to survive and to multiply inside the Mϕ phagosome such as prevention of phagosome acidification (41) and inhibition of phagolysosomal fusion (42).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins are probably the two most important cytokines known to be involved in immune protection against TB. These genes participate in the formation and maintenance of the granulomes (25) and activate the bactericidal activity of phagocytes (26).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

Barreiro

Tailleux²,

Pai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

245

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Tuberculosis (TB) is a major public health problem. One-third of the world's population is estimated to be infected with Mycobacterium tuberculosis (MTB), the etiological agent causing TB, and active disease kills nearly 2 million individuals worldwide every year. Several lines of evidence indicate that interindividual variation in susceptibility to TB has a heritable component, yet we still know little about the underlying genetic architecture. To address this, we performed a genome-wide mapping study of loci that are associated with functional variation in immune response to MTB. Specifically, we characterized transcript and protein expression levels and mapped expression quantitative trait loci (eQTL) in primary dendritic cells (DCs) from 65 individuals, before and after infection with MTB. We found 198 response eQTL, namely loci that were associated with variation in gene expression levels in either untreated or MTB-infected DCs, but not both. These response eQTL are associated with natural regulatory variation that likely affects (directly or indirectly) host interaction with MTB. Indeed, when we integrated our data with results from a genome-wide association study (GWAS) for pulmonary TB, we found that the response eQTL were more likely to be genetically associated with the disease. We thus identified a number of candidate loci, including the MAPK phosphatase DUSP14 in particular, that are promising susceptibility genes to pulmonary TB.

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“…The precise mechanisms by which these innate processes contribute to the control of latent infection remain elusive. 10,11 In part of the infected population, latent infection progresses to active disease. Once immune control of infection wanes, granulomas liquefy and containment breaks down.…”

Section: Introductionmentioning

confidence: 99%

“…13 However, the exact role of Toll-like receptor and other pattern recognition receptors in immunity against M. tuberculosis remains controversial. 11,14 Bacterial killing is a key function of macrophages, which are activated by cytokines, notably tumour necrosis factor alpha and interferon gamma, which are mainly produced by T cells and natural killer (NK) cells. NK cells are wellknown key players in innate immunity, which actively induce death of M. tuberculosis-infected monocytes.…”

Section: Introductionmentioning

confidence: 99%

Human gene expression profiles of susceptibility and resistance in tuberculosis

et al. 2010

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Tuberculosis (TB) still poses a profound burden on global health, owing to significant morbidity and mortality worldwide. Although a fully functional immune system is essential for the control of Mycobacterium tuberculosis infection, the underlying mechanisms and reasons for failure in part of the infected population remain enigmatic. Here, whole-blood microarray gene expression analyses were performed in TB patients and in latently as well as uninfected healthy controls to define biomarkers predictive of susceptibility and resistance. Fc gamma receptor 1B (FCGRIB)was identified as the most differentially expressed gene, and, in combination with four other markers, produced a high degree of accuracy in discriminating TB patients and latently infected donors. We determined differentially expressed genes unique for active disease and identified profiles that correlated with susceptibility and resistance to TB. Elevated expression of innate immune-related genes in active TB and higher expression of particular gene clusters involved in apoptosis and natural killer cell activity in latently infected donors are likely to be the major distinctive factors determining failure or success in controlling M. tuberculosis infection. The gene expression profiles defined in this study provide valuable clues for better understanding of progression from latent infection to active disease and pave the way for defining predictive correlates of protection in TB.

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Innate immunity in tuberculosis: myths and truth

Cited by 213 publications

References 97 publications

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

Human gene expression profiles of susceptibility and resistance in tuberculosis

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