CD163, receptor for the haptoglobin-hemoglobin complex, is expressed on monocytes/macrophages and neutrophils. A soluble form of CD163 (sCD163) has been associated with the M2 macrophage phenotype, ...and M2 macrophages have been shown to down-modulate inflammatory responses. In particular, previous studies have shown that M2 is closely associated with the most severe clinical presentation of leprosy (i.e. lepromatous leprosy (LL)), as well as tuberculosis. We hypothesized that sCD163 correlates with severity of diseases caused by intracellular pathogens.
To assess this hypothesis, sCD163 levels were measured in the serum of leprosy and visceral leishmaniasis (VL) patients stratified by severity of the clinical presentation. sCD163 levels were significantly higher in patients with these diseases than those observed in healthy control individuals. Further analyses on infection and disease status of leprosy and VL patients revealed a clear association of sCD163 levels with clinical parameters of disease severity. In vitro culture assays revealed that Leishmania infection induced CD163 expression on the surface of both monocyte/macrophages and neutrophils, suggesting these cells as possible sources of sCD163. FACS analyses shows that the cells expressing CD163 produces both TNF-α and IL-4.
Taken together, our results reveal sCD163 as a potential biomarker of severity of diseases caused by intracellular pathogens M. leprae and Leishmania spp. and have a modulatory role, with a mix of an inflammatory property induced by TNF-α release, but that potentially induces an anti-inflammatory T cell response, related to IL-4 release.
Abstract
Congenital Zika syndrome (CZS) is a cluster of malformation, and the mechanisms that lead it are still unclear. Using hypothesis-driven candidate genes and their function in viral ...infections, single-nucleotide polymorphisms (SNPs) were genotyped by quantitative polymerase chain reaction in a sample population from Sergipe State, Brazil. This study shows that rs3775291 SNP at Toll-like receptor 3, which triggers type I interferon antiviral responses in mothers infected by Zika virus during pregnancy, is associated with CZS occurrence (odds ratio OR, 2.19; 95% confidence interval CI, 1.158–4.148). Moreover, rs1799964 SNP at tumor necrosis factor-α gene in CZS babies is associated with severe microcephaly (OR, 2.63; 95% CI, 1.13–6.21).
•stuA deletion impairs the growth of T. rubrum on keratin, and human skin and nail.•StuA is involved in the fungal mechanosensing and hydrophobicity.•StuA increases conidia tolerance to heat-shock ...and UV light exposure.•StuA is a potential target for antidermatophytic therapy.
The APSES family, comprising of the transcriptional regulators Asm1p, Phd1p, Sok2p, Efg1p, and StuA, is found exclusively in fungi and has been reported to control several cellular processes in these organisms. However, its function in dermatophytes has not yet been completely understood. Here, we generated two null mutant strains by deleting the stuA gene in the dermatophyte Trichophyton rubrum, the most common clinical isolate obtained from human skin and nail mycoses. The functional characterization of the knocked-out strains revealed the involvement of stuA in germination, morphogenesis of conidia and hyphae, pigmentation, stress responses, and virulence. Although the mutant strains could grow under several nutritional conditions, growth on the keratin medium, human nails, and skin was impaired. The co-culture of stuA mutants with human keratinocytes revealed enhanced development. Moreover, a stuA mutant grown on the keratin substrate showed a marked decrease in the transcript numbers of the hydrophobin encoding gene (hypA), suggesting the involvement of stuA in the molecular mechanisms underlying mechanosensing during the fungi-host interaction. In addition, bioinformatics analyses revealed the potential involvement of StuA in different biological processes such as oxidation-reduction, phosphorylation, proteolysis, transcription/translation regulation, and carbohydrate metabolism. Cumulatively, the present study suggested that StuA is a crosstalk mediator of many pathways and is an integral component of the infection process, implying that it could be a potential target for antifungal therapy.
Isolated growth hormone (GH) deficiency (IGHD) affects approximately 1 in 4,000 to 1 in 10,000 individuals worldwide. We have previously described a large cohort of subjects with IGHD due to a ...homozygous mutation in the GH releasing hormone (GHRH) receptor gene. These subjects exhibit throughout the life very low levels of GH and its principal mediator, the Insulin Growth Factor-I (IGF-I). The facilitating role of IGF-I in the infection of mouse macrophages by different
strains is well-known. Nevertheless, the role of IGF-I in
infection of human macrophages has not been studied. This study aimed to evaluate the behavior of
infection
in macrophages from untreated IGHD subjects. To this end, blood samples were collected from 14 IGHD individuals and 14 age and sex-matched healthy controls. Monocytes were isolated and derived into macrophages and infected with a strain of
. In addition, IGF-I was added to culture medium to evaluate its effect on the infection. Cytokines were measured in the culture supernatants. We found that macrophages from IGHD subjects were less prone to
infection compared to GH sufficient controls. Both inflammatory and anti-inflammatory cytokines increase only in the supernatants of the control macrophages. Addition of IGF-I to the culture medium increased infection rates. In conclusion, we demonstrated that IGF-I is crucial for
infection of human macrophages.
Leprosy reaction (LR) and physical disability (PD) are the most significant clinical complications of leprosy. Herein, we assessed the circulating serum-sTREM-1 and TNF-α levels and their genetic ...polymorphisms in leprosy. Serum-sTREM-1 and TNF-α levels were measured in leprosy patients (LP) before treatment (
= 51) and from their household contacts (HHCs;
= 25). DNA samples were genotyped using TREM-1 rs2234246 and TNF-α rs1800629-SNP in 210 LPs and 168 endemic controls. The circulating sTREM-1 and TNF-α levels are higher in the multibacillary form. The ROC curve of the serum-sTREM-1 levels was able to differentiate LR from non-LR and PD from non-PD. Similarly, LPs with serum-sTREM-1 levels >210 pg/ml have 3-fold and 6-fold higher chances of presenting with LR and PD, respectively. Genotypes CC+CT of the TREM-1 were associated with leprosy. Taken together, our analyses indicated that sTREM-1 and TNF-α play an important role in the pathogenesis of leprosy and provide promising biomarkers to assist in the diagnosis of leprosy complications.
Cutaneous mycoses are common human infections among healthy and immunocompromised hosts, and the anthropophilic fungus Trichophyton rubrum is the most prevalent microorganism isolated from such ...clinical cases worldwide. The aim of this study was to determine the transcriptional profile of T. rubrum exposed to various stimuli in order to obtain insights into the responses of this pathogen to different environmental challenges. Therefore, we generated an expressed sequence tag (EST) collection by constructing one cDNA library and nine suppression subtractive hybridization libraries.
The 1388 unigenes identified in this study were functionally classified based on the Munich Information Center for Protein Sequences (MIPS) categories. The identified proteins were involved in transcriptional regulation, cellular defense and stress, protein degradation, signaling, transport, and secretion, among other functions. Analysis of these unigenes revealed 575 T. rubrum sequences that had not been previously deposited in public databases.
In this study, we identified novel T. rubrum genes that will be useful for ORF prediction in genome sequencing and facilitating functional genome analysis. Annotation of these expressed genes revealed metabolic adaptations of T. rubrum to carbon sources, ambient pH shifts, and various antifungal drugs used in medical practice. Furthermore, challenging T. rubrum with cytotoxic drugs and ambient pH shifts extended our understanding of the molecular events possibly involved in the infectious process and resistance to antifungal drugs.
Trichophyton rubrum is a dermatophyte that infects human skin and nails. Its growth on keratin as its carbon source shifts the ambient pH from acidic to alkaline, which may be an efficient strategy ...for its successful infection and maintenance in the host. In this study, we used suppression subtractive hybridization to identify genes preferentially expressed in
T. rubrum incubated at either pH 5.0 or pH 8.0. The functional grouping of the 341 overexpressed unigenes indicated proteins putatively involved in diverse cellular processes, such as membrane remodeling, cellular transport, metabolism, cellular protection, fungal pathogenesis, gene regulation, interaction with the environment, and iron uptake. Although the basic metabolic machinery identified under both growth conditions seems to be functionally similar, distinct genes are upregulated at acidic or alkaline pHs. We also isolated a large number of genes of unknown function, probably unique to
T. rubrum or dermatophytes. Interestingly, the transcriptional profiling of several genes in a
pacC
-
mutant suggests that, in
T. rubrum, the transcription factor
PacC has a diversity of metabolic functions, in response to either acidic or alkaline ambient pH.
•The rs11030099 of brain-derived neurotrophic factor neurotrophin is associated with nerve damage in leprosy patients.•The rs11030099 is not associated with brain-derived neurotrophic factor serum ...level.•The rs11030099 is located in a miR-26a binding region.•The miR-26 and rs11030099 may be acting synergistically.•Other investigated single nucleotide polymorphisms of neurotrophins are not associated with leprosy phenotypes.
Mycobacterium leprae is able to infect Schwann cells leading to neural damage. Neurotrophins are involved in nervous system plasticity and impact neural integrity during diseases. Investigate the association between single nucleotide polymorphisms in neurotrophin genes and leprosy phenotypes, especially neural damage.
We selected single nucleotide polymorphisms in neurotrophins or their receptors genes associated with neural disorders: rs6265 and rs11030099 of brain-derived neurotrophic factor (BDNF), rs6330 of BDNF, rs6332 in NT3 and rs2072446 of P75NTR. The association of genetic frequencies with leprosy phenotypes was investigated in a case-control study.
An association of the BDNF single nucleotide polymorphism rs11030099 with the number of affected nerves was demonstrated. The “AA+AC” genotypes were demonstrated to be protective against nerve impairment. However, this variation does not affect BDNF serum levels. BDNF is an important factor for myelination of Schwann cells and polymorphisms in this gene can be associated with leprosy outcome. Moreover, rs11030099 is located in the binding region for micro-RNA (miRNA) 26a that could be involved in control of BDNF expression. We demonstrated different expression levels of this miRNA in polar forms of leprosy.
Our findings demonstrate for the first time an association between the polymorphism rs11030099 in the BDNF gene and neural commitment in leprosy and may indicate a possible role of miRNA-26a acting synergistically to these genetic variants in neural damage development.
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