C-type lectin receptors in tuberculosis: what we know.

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), is recognized by a number of pathogen recognition receptors (PRRs), either soluble or predominantly expressed on the surface of various cells of innate and adaptive immunity. C-type lectin receptors (CTLRs) are a class of PRRs which can recognize a variety of endogenous and exogenous ligands, thereby playing a crucial role in immunity, as well as in maintaining homeostasis. Mtb surface ligands, including mannose-capped lipoarabinomannan and cord factor, are important immune modulators which recently have been found to be directly recognized by several CTLRs. Receptor ligation is followed by cellular activation, mainly via nuclear factor κB mediated by a series of adaptors with subsequent expression of pro-inflammatory cytokines. Mtb recognition by CTLRs and their cross talk with other PRRs on immune cells is of key importance for the better understanding of the Mtb-induced complexity of the host immune responses. Epidemiological studies have shown that single nucleotide polymorphisms (SNPs) in several PRRs, as well as the adaptors in their signaling cascades, are directly involved in the susceptibility for developing disease and the disease outcome. In addition, an increasing number of CTLRs have been studied for their functional effects in the pathogenesis of TB. This review summarizes current knowledge regarding the various roles played by different CTLRs in TB, as well as the role of their SNPs associated with disease susceptibility and outcome in different human populations.

The Interaction of Human Pathogenic Fungi With C-Type Lectin Receptors.

Fungi, usually present as commensals, are a major cause of opportunistic infections in immunocompromised patients. Such infections, if not diagnosed or treated properly, can prove fatal. However, in most cases healthy individuals are able to avert the fungal attacks by mounting proper antifungal immune responses. Among the pattern recognition receptors (PRRs), C-type lectin receptors (CLRs) are the major players in antifungal immunity. CLRs can recognize carbohydrate ligands, such as ß-glucans and mannans, which are mainly found on fungal cell surfaces. They induce proinflammatory immune reactions, including phagocytosis, oxidative burst, cytokine, and chemokine production from innate effector cells, as well as activation of adaptive immunity via Th17 responses. CLRs such as Dectin-1, Dectin-2, Mincle, mannose receptor (MR), and DC-SIGN can recognize many disease-causing fungi and also collaborate with each other as well as other PRRs in mounting a fungi-specific immune response. Mutations in these receptors affect the host response and have been linked to a higher risk in contracting fungal infections. This review focuses on how CLRs on various immune cells orchestrate the antifungal response and on the contribution of single nucleotide polymorphisms in these receptors toward the risk of developing such infections.

AmpliSeq Screening of Genes Encoding the C-Type Lectin Receptors and Their Signaling Components Reveals a Common Variant in MASP1 Associated with Pulmonary Tuberculosis in an Indian Population.

Tuberculosis (TB) is a multifactorial disease governed by bacterial, host and environmental factors. On the host side, growing evidence shows the crucial role that genetic variants play in the susceptibility to Mycobacterium tuberculosis (Mtb) infection. Such polymorphisms have been described in genes encoding for different cytokines and pattern recognition receptors (PRR), including numerous Toll-like receptors (TLRs). In recent years, several members of the C-type lectin receptors (CTLRs) have been identified as key PRRs in TB pathogenesis. Nevertheless, studies to date have only addressed particular genetic polymorphisms in these receptors or their related pathways in relation with TB. In the present study, we screened the main CTLR gene clusters as well as CTLR pathway-related genes for genetic variation associated with pulmonary tuberculosis (PTB). This case-control study comprised 144 newly diagnosed pulmonary TB patients and 181 healthy controls recruited at the Bhagwan Mahavir Medical Research Center (BMMRC), Hyderabad, India. A two-stage study was employed in which an explorative AmpliSeq-based screening was followed by a validation phase using iPLEX MassARRAY. Our results revealed one SNP (rs3774275) in MASP1 significantly associated with PTB in our population (joint analysis p = 0.0028). Furthermore, serum levels of MASP1 were significantly elevated in TB patients when compared to healthy controls. Moreover, in the present study we could observe an impact of increased MASP1 levels on the lectin pathway complement activity in vitro. In conclusion, our results demonstrate a significant association of MASP1 polymorphism rs3774275 and MASP1 serum levels with the development of pulmonary TB. The present work contributes to our understanding of host-Mtb interaction and reinforces the critical significance of mannose-binding lectin and the lectin-complement pathway in Mtb pathogenesis. Moreover, it proposes a MASP1 polymorphism as a potential genetic marker for TB resistance.

S100A12 is up-regulated in pulmonary tuberculosis and predicts the extent of alveolar infiltration on chest radiography: an observational study.

Pulmonary tuberculosis (PTB) results in lung functional impairment and there are no surrogate markers to monitor the extent of lung involvement. We investigated the clinical significance of S100A12 and soluble receptor for advanced glycation end-products (sRAGE) for predicting the extent of lung involvement. We performed an observational study in India with 119 newly diagnosed, treatment naïve, sputum smear positive, HIV-negative PTB patients and 163 healthy controls. All patients were followed-up for six months. Sociodemographic variables and the serum levels of S100A12, sRAGE, esRAGE, HMGB-1, TNF-α, IFN-γ and CRP were measured. Lung involvement in PTB patients was assessed by chest radiography. Compared with healthy controls, PTB patients had increased serum concentrations of S100A12 while sRAGE was decreased. S100A12 was an independent predictor of disease occurrence (OR 1.873, 95%CI 1.212-2.891, p = 0.004). Under DOTS therapy, S100A12 decreased significantly after 4 months whereas CRP significantly decreased after 2 months (p < 0.0001). Importantly, although CRP was also an independent predictor of disease occurrence, only S100A12 was a significant predictor of lung alveolar infiltration (OR 2.60, 95%CI 1.35-5.00, p = 0.004). These results suggest that S100A12 has the potential to assess the extent of alveolar infiltration in PTB.

Toll-like receptor 1 variations influence susceptibility and immune response to Mycobacterium tuberculosis.

BACKGROUND: Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (MTB) infection, is still a global public health problem. TB susceptibility varies greatly in infected individuals, and mycobacterial recognition by the innate immune system likely affects disease course and outcome. This research describes a single nucleotide polymorphism in the Toll-like receptor (TLR) 1 gene that functionally alters the innate immune response to MTB and is associated with TB susceptibility in India. METHODS: 206 TB patients and 239 healthy controls from Hyderabad, India were analyzed for SNPs in the TLR1 and TLR2 genes, which were subsequently correlated to TB susceptibility. To test individual responses to MTB lysates, we stimulated PBMCs from genotyped healthy German individuals, as well as HEK cells transfected with TLR1/2 variants. TNF production and NF-kB activation were assessed respectively. RESULTS: Cohort analysis associated the TLR1-248N SNP (RS4833095) with TB protection. TLR1-248N expressing PBMCs from healthy controls exhibited an increased TNF response to MTB lysates. In addition to this, functional studies using HEK cell lines transfected with TLR1-248N and stimulated with MTB showed an increased NF-kB activation. CONCLUSION: SNP TLR1-248N is associated with TB protection in an Indian population and exhibits an increased immune response to MTB lysate in vitro.

A Novel Reading Scheme for Assessing the Extent of Radiographic Abnormalities and Its Association with Disease Severity in Sputum Smear-Positive Tuberculosis: An Observational Study in Hyderabad/India.

BACKGROUND: Existing reading schemes for chest X-ray (CXR) used to grade the extent of disease severity at diagnosis in patients with pulmonary tuberculosis (PTB) are often based on numerical scores that summate specific radiographic features. However, since PTB is known to exhibit a wide heterogeneity in pathology, certain features might be differentially associated with clinical parameters of disease severity. OBJECTIVE: We aimed to grade disease severity in PTB patients at diagnosis and after completion of DOTS treatment by developing a reading scheme based on five different radiographic manifestations and analyze their association with the clinical parameters of systemic involvement and infectivity. METHODS: 141 HIV-negative adults with newly diagnosed sputum smear-positive PTB were enrolled in a prospective observational study in Hyderabad, India. The presence and extent on CXRs of five radiographic manifestations, i.e., lung involvement, alveolar infiltration, cavitation, lymphadenopathy and pleural effusion, were classified using the new reading scheme by using a four-quadrant approach. We evaluated the inter-reader reliability of each manifestation, and its association with BMI and sputum smear positivity at diagnosis. The presence and extent of these radiographic manifestations were further compared with CXRs on completion of DOTS treatment. RESULTS: At diagnosis, an average lung area of 51.7% +/- 23.3% was affected by radiographic abnormalities. 94% of the patients had alveolar infiltrates, with 89.4% located in the upper quadrants, suggesting post primary PTB and in 34.8% of patients cavities were found. We further showed that the extent of affected lung area was a negative predictor of BMI (ß value -0.035, p 0.019). No significant association of BMI with any of the other CXR features was found. The extent of alveolar infiltrates, along with the presence of cavitation, were strongly associated with sputum smear positivity. The microbiological cure rate in our cohort after 6 months of DOTS treatment was 95%. The extent of the affected lung area in these patients decreased from 56.0% +/- 21.5% to 31.0 +/- 20% and a decrease was also observed in the extent of alveolar infiltrates from 98.4% to 25.8% in at least one quadrant, presence of cavities from 34.8% to 1.6%, lymphadenopathy from 46.8% to 16.1%, and pleural effusion from 19.4% to 6.5%. CONCLUSIONS: We established a new assessment scheme for grading disease severity in PTB by specifically considering five radiographic manifestations which were differently associated with the BMI and sputum smear positivity, changed to a different extent after 6 months of treatment and exhibited an excellent agreement between radiologists. Our results suggest that this reading scheme might contribute to the estimation of disease severity with respect to differences in disease pathology. Further studies are needed to determine a correlation with short and long-term pulmonary function impairment and whether there would be any benefit in lengthening or modulating therapy based on this CXR severity assessment.