821 research outputs found
Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients
Introduction: Systemic inflammation (e.g. following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum. Methods: 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)- and granulocyte macro-phage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day. Results: 13 patients were identified as TLR2 SNP carrier, 51 as TLR4 SNP carrier and 274 pa-tients as non-carrier. Basal levels of ACTH, cortisol and cytokines did not differ between groups. In all three groups a significant, transient perioperative rise of cortisol could be ob-served. However, only in the non-carrier group this was accompanied by a significant ACTH rise, TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers ((mean[95% confidence intervals]) non-carriers: 201.9[187.7 to 216.1]pg/ml; TLR4 SNP car-riers: 149.9[118.4 to 181.5]pg/ml; TLR2 SNP carriers: 176.4[110.5 to 242.3]pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks ((mean[95% confidence intervals]): IL-8: non-carriers: 42.6[36.7 to 48.5]pg/ml, TLR4 SNP carriers: 23.7[10.7 to 36.8]pg/ml; IL-10: non-carriers: 83.8[70.3 to 97.4]pg/ml, TLR4 SNP carriers: 54.2[24.1 to 84.2]pg/ml; GM-CSF: non-carriers: 33.0[27.8 to 38.3]pg/ml, TLR4 SNP carriers: 20.2[8.6 to 31.8]pg/ml). No significant changes over time or between the groups were found for the other cytokines. Conclusions: Regulation of the immunoendocrine stress response during systemic inflamma-tion is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this ge-notype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (e.g. adrenal insufficiency) during systemic inflammation and sepsis
TLR-6 SNP P249S is associated with healthy aging in nonsmoking Eastern European Caucasians - A cohort study
Background To investigate mechanisms that determine healthy aging is of major
interest in the modern world marked by longer life expectancies. In addition
to lifestyle and environmental factors genetic factors also play an important
role in aging phenotypes. The aged immune system is characterized by a chronic
micro-inflammation, known as inflamm-aging, that is suspected to trigger the
onset of age-related diseases such as cardiovascular disease, Alzheimer’s
disease, cancer, and Diabetes Mellitus Type 2 (DMT2). We have recently shown
that a Toll-like receptor 6 variant (P249S) is associated with susceptibility
to cardiovascular disease and speculated that this variant may also be
associated with healthy aging in general by decreasing the process of inflamm-
aging. Results Analyzing the PolSenior cohort we show here that nonsmoking S
allele carriers are significantly protected from age-related diseases (P =
0.008, OR: 0.654). This association depends not only on the association with
cardiovascular diseases (P = 0.018, OR: 0.483) for homozygous S allele
carriers, but is also driven by a protection from Diabetes Mellitus type 2 (P
= 0.010, OR: 0.486) for S allele carriers. In addition we detect a trend but
no significant association of this allele with inflamm-aging in terms of
baseline IL-6 levels. Conclusion We confirm our previous finding of the TLR-6
249S variant to be protective regarding cardiovascular diseases. Furthermore,
we present first evidence of TLR-6 249S being involved in DMT2 susceptibility
and may be in general associated with healthy aging possibly by reducing the
process of inflamm-aging
Denaturation transition of stretched DNA
We generalize the Poland-Scheraga model to consider DNA denaturation in the
presence of an external stretching force. We demonstrate the existence of a
force-induced DNA denaturation transition and obtain the temperature-force
phase diagram. The transition is determined by the loop exponent for which
we find the new value such that the transition is second order
with in . We show that a finite stretching force
destabilizes DNA, corresponding to a lower melting temperature , in
agreement with single-molecule DNA stretching experiments.Comment: 5 pages, 3 figure
a cross-sectional study on the association between urbanicity and the acquisition of immunity
Background Malaria incidence has declined considerably over the last decade.
This is partly due to a scale-up of control measures but is also attributed to
increasing urbanization. This study aimed to analyse the association between
malaria and urbanization and the effect of urbanicity on the acquisition of
semi-immunity. Methods In 2012, children with fever presenting to St Michael’s
Hospital Pramso/Ghana were recruited. The malaria-positive-fraction (MPF) of
fever cases was calculated on community-level to approximate the malaria risk.
The mean age of malaria cases was calculated for each community to estimate
the acquisition of semi-immunity. The level of urbanicity for the communities
was calculated and associations between MPF, urbanicity and immunity were
modelled using linear regression. Results Twenty-six villages were included
into the study with a mean MPF of 35 %. A linear decrease of 5 % (95 % CI: 4–6
%) in MPF with every ten-point increase in urbanicity was identified. The mean
age of malaria patients increased by 2.9 months (95 % CI: 1.0–4.8) with every
ten-point increase in urbanicity. Discussion The results confirm an
association between an increase in urbanicity and declining malaria risk and
demonstrate that the acquisition of semi-immunity is heterogeneous on a micro-
epidemiological scale and is associated with urbanicity
Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis
The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB
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
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
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 (β 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
The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans
Abstract The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for
innate immune sensing of various bacterial, viral and protozoal infections.
Recent studies identified the common HAQ and R232H alleles of TMEM173/STING,
but the functional consequences of these variants for primary infections are
unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages
as well as human cells of individuals carrying HAQ TMEM173/STING were severely
impaired in producing type I IFNs and pro-inflammatory cytokines in response
to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In
contrast, R232H attenuated cytokine production only following stimulation with
bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model
of Legionnaires’ disease, cGAS- and STING-deficient animals exhibited higher
bacterial loads as compared to wild-type mice. Moreover, the haplotype
frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased
in two independent cohorts of human Legionnaires’ disease patients as compared
to healthy controls. Our study reveals that the cGAS-STING cascade contributes
to antibacterial defense against L. pneumophila in mice and men, and provides
important insight into how the common HAQ TMEM173/STING variant affects
antimicrobial immune responses and susceptibility to infection. Trial
registration ClinicalTrials.gov DRKS00005274, German Clinical Trials Register
Author summary Interferons (IFNs) and pro-inflammatory cytokines are key
regulators of gene expression and antibacterial defense during Legionella
pneumophila infection. Here we demonstrate that production of these mediators
was largely or partly dependent on the cyclic GMP-AMP synthase (cGAS)-STING
pathway in human and murine cells. Cells of individuals carrying the common
HAQ allele of TMEM173/STING were strongly impaired in their ability to respond
to L. pneumophila, bacterial DNA or cyclic dinucleotides (CDNs), whereas the
R232H allele was only attenuated in sensing of exogenous CDNs. Importantly,
cGAS and STING contributed to antibacterial defense in mice during L.
pneumophila lung infection, and the allele frequency of HAQ TMEM173/STING, but
not of R232H TMEM173/STING, was increased in two independent cohorts of human
Legionnaires’ disease patients as compared to healthy controls. Hence, sensing
of bacterial DNA by the cGAS/STING pathway contributes to antibacterial
defense against L. pneumophila infection, and the hypomorphic variant HAQ
TMEM173/STING is associated with increased susceptibility to Legionnaires’
disease in humans
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