Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

Velez, Digna R.; Wejse, Christian; Stryjewski, Martín E.; Abbate, Eduardo; Hulme, William; Myers, Jamie L.; Estevan, Rosa; Patillo, Sara G.; Olesen, Rikke; Tacconelli, Alessandra; Sirugo, Giorgio; Gilbert, John R.; Hamilton, Carol; Scott, William K.

doi:10.1007/s00439-009-0741-7

Cited by 151 publications

(133 citation statements)

References 29 publications

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“…It is also worth noting that the common rs4586 SNP, flanking the promoter of CCL2 gene, which appeared significant for genotype frequencies between our cases and controls (p = 0.0079, OR = 8.5, Table II), was recently found to be significantly correlated with anti-tumour immune reaction in Korean patients with colorectal cancer [26] and associated with the clinical outcome in Japanese individuals with locoregional gastric cancer [27]. Moreover, the TLR2 intergenic polymorphism rs4585282 (previous rs numbers: rs6535939, rs61329579), which was found in our study as significant for genotype frequencies (at p = 0.0000033 or p = 0.0083, depending on the model of association, Table II), was recently indicated as displaying modest associations with some vitiligo subgroups [28], while the T allele of this SNP was previously reported to be associated with pulmonary tuberculosis in a West African but not a European population sample [29].…”

Section: Resultssupporting

confidence: 56%

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

Skonieczna¹,

Styczyński²,

Krenska³

et al. 2017

pjp

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This study aimed to find novel genetic variants of susceptibility to aspergillosis in paediatric patients with haematological malignancies. Complete sequences of fifteen genes of human innate immunity (CCL2, CCR2, CD209, CLEC6A, CLEC7A and ten TLR genes) were studied in 40 patients diagnosed with haematological disorders (20 unaffected and 20 affected by aspergillosis). All samples were sequenced with MiSeq (Illumina) and 454 (Roche Diagnostics) technologies. Statistical significance of the differences between studied groups was determined using the twotailed Fisher's exact test. Sixty variants of potential importance were identified, the vast majority of which are located in non-coding parts of the targeted genes. At the threshold of p < 0.000005, one intergenic (TLR2 rs4585282) and one intronic variant (CLEC6A rs12099687) were found significant between the case and control groups for genotype and allele frequencies, respectively. Rs12099687 in CLE-C6A was predicted to constitute an alternative isoform or cryptic splice site, which potentially changes activity of the Dectin-2 protein. Overall, we assume that the two strongest associations reported in this study are expected to be reproducible even in the absence of other evidence, while another twelve associations may be strong enough to justify additional research in larger cohorts.

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Section: Resultssupporting

confidence: 56%

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

Skonieczna¹,

Styczyński²,

Krenska³

et al. 2017

pjp

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“…neutralizing antibodies and an association of human Toll-like receptor polymorphisms with an increased disease risk (4,41,42). FURIN can process target molecules that are important in innate immunity in vitro (e.g., TNF converting enzyme and Toll-like receptor 7) (43, 44), but whether it also regulates innate immune responses in infections in vivo has not been addressed.…”

Section: Resultsmentioning

confidence: 99%

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

et al. 2015

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Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinA td204e/؉ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinuminfected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinA td204e/؉ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinA td204e/؉ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.T uberculosis (TB) is an epidemic infectious disease caused by the mycobacterial species Mycobacterium tuberculosis (1, 2). Circa 13% of the individuals with active TB were simultaneous carriers of the human immunodeficiency virus (HIV), and almost one-third of TB-associated deaths occurred among HIV ϩ patients, demonstrating the critical role of cluster of differentiation 4 (CD4 ϩ ) T lymphocyte-mediated immunity in the control of M. tuberculosis infection (3, 4). More specifically, the adaptive immunity against TB is primarily mediated by T helper (Th) type 1 cells, as is suggested by the gene expression profile upon infection (5), as well as the infection-induced mortality of gamma interferon-deficient (6, 7) and interleukin-12 (IL-12)-deficient (8) mice.The proprotein convertase subtilisin/kexin (PCSK) enzymes are a family of serine endoproteases with nine members in humans: PCSK1 and -2, FURIN, PCSK4 to -7, membrane-bound transcription factor peptidase site 1 (MBTPS1), and PCSK9 (9). Typically, PCSKs convert precursor proteins (proproteins) into their biologically active forms by cleaving them at specific target motifs made up of the basic amino acids lysine and arginine (9, 10). FURIN was the first identified mammalian PCSK and is present in vertebrates and many invertebrates (11,12). A series of in vitro experiments have suggested a central role for FURIN in host defense because it proteolytically activates several immunoregulatory proproteins, such as membrane-inserted matrix metallo...

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“…The risk of developing TB has been shown to be associated with polymorphisms within the TLR2 gene (25,39), and shorter guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene were more common in TB patients and correlated with lower expression of TLR2 (42). The mechanisms through which these TLR2 polymorphisms affect host defense remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Development of a Secondary Immune Response toMycobacterium tuberculosisIs Independent of Toll-Like Receptor 2

2011

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Published work indicates that the contribution of Toll-like receptor 2 (TLR2) to host resistance during acuteMycobacterium tuberculosis expresses a large repertoire of lipoproteins that can trigger signaling from Toll-like receptor 2 (TLR2) (13), including the 19-kDa lipoprotein (LpqH) (5), LprA (Rv1270) (29), and LprG (Rv1411c) (11). In addition to lipoproteins, lipomannan (31) and phosphatidyl-myo-inositol mannoside (PIM) (12, 16) also interact with TLR2 to initiate cellular activation (16). Despite this collection of TLR2 agonists on the tuberculosis (TB) bacillus, murine studies indicate that TLR2 is not essential for host resistance against acute M. tuberculosis infection (34, 37).It is well appreciated that memory immunity in tuberculosis does not provide long-term protective immunity, as evidenced in humans and experimental infections of mice. In a study performed in Cape Town, South Africa, it was determined that the incidence rate of TB attributable to reinfection after successful chemotherapy was four times that of new TB (40). In mouse models, immunological memory induced by M. tuberculosis infection can provide short-term protection, as evidenced by early reduction in the bacterial burden in the lungs following reexposure (6, 36). The memory immune mice exhibit a transient early induction of Th1 cells compared to naïve mice and concomitant early control of bacterial replication. However, despite the skewed kinetics, the memory mice do not achieve bacterial sterility in the lung, and bacteria continue to be maintained in a stable state. Clearly, this major gap in our understanding of how to induce sterilizing memory immunity in TB is an impediment to vaccine development.In vitro studies have documented opposing outcomes from antigen-presenting cells (APC) following interaction of their surface TLR2 with M. tuberculosis. For example, TLR2 signals upregulate B7 expression, induce interleukin 12 (IL-12) secretion (15), and initiate antimicrobial responses within M. tuberculosis-infected macrophages (22). TLR2 also initiates signaling that inhibits major histocompatibility complex (MHC) class II-dependent antigen presentation (24, 26) by macrophages and responsiveness to gamma interferon (IFN-␥) (2,8,18,27). How these opposing changes to APC by TLR2 signals affect naïve T cell differentiation into effector and memory T cells following M. tuberculosis infection remains unclear. Furthermore, recent studies indicate that high expression levels of IL-12 in the environment promote effector T cell development while low expression levels (17) or even the absence (28, 41) of the cytokine is favorable for central memory T cell development. Together with the report that TLR2 regulates IL-10 production from macrophages and dendritic cells (DC) following M. tuberculosis infection (15, 30), these findings suggest that TLR2 signals may modulate the inflammatory milieu during T cell priming to influence effector versus memory T cell development.The literature on inhibition of APC function by TLR2 predicts that removal o...

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Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

Cited by 151 publications

References 29 publications

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

Development of a Secondary Immune Response toMycobacterium tuberculosisIs Independent of Toll-Like Receptor 2

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