Effects of maternal geohelminth infections on allergy in early childhood.

BACKGROUND: Maternal geohelminth infections during pregnancy may protect against allergy development in childhood. OBJECTIVE: We sought to investigate the effect of maternal geohelminths on the development of eczema, wheeze, and atopy during the first 3 years of life. METHODS: A cohort of 2404 neonates was followed to 3 years of age in a rural district in coastal Ecuador. Data on wheeze and eczema were collected by means of questionnaire and physical examination at 13, 24, and 36 months of age. Atopy was measured based on skin prick test (SPT) reactivity to 9 allergens at 36 months. Maternal stool samples were examined for geohelminths by microscopy. Data on potential confounders was collected after birth by questionnaire. RESULTS: Geohelminths were observed in 45.9% of mothers. Eczema and wheeze were reported for 17.7% and 25.9%, respectively, of 2069 (86.1%) children with complete follow-up to 3 years, and allergen SPT reactivity to any allergen was present in 17.2% and to house dust mite in 8.7%. Maternal geohelminth infections were not significantly associated with eczema (adjusted odds ratio [OR], 1.26; 95% CI, 0.98-1.61), wheeze (adjusted OR, 1.02; 95% CI, 0.82-1.27), and SPT reactivity to any allergen (adjusted OR, 0.79; 95% CI, 0.61-1.01). In subgroup analyses maternal geohelminths were associated with a significantly reduced risk of SPT reactivity to mite and other perennial allergens, and maternal ascariasis was associated with an increased risk of eczema and reduced risk of SPT reactivity to all allergens. CONCLUSION: Our data do not support a protective effect of maternal infections with geohelminth parasites during pregnancy against the development of eczema and wheeze in early childhood, although there was evidence in subgroup analyses for a reduction in SPT reactivity to house dust mites and perennial allergens

Targeting deficiencies in the TLR5 mediated vaginal response to treat female recurrent urinary tract infection

Abstract The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFκB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age-matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle

Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution

<p>Abstract</p> <p>Background</p> <p>The Toll-like receptors represent a large superfamily of type I transmembrane glycoproteins, some common to a wide range of species and others are more restricted in their distribution. Most members of the Toll-like receptor superfamily have few paralogues; the exception is the TLR1 gene family with four closely related genes in mammals TLR1, TLR2, TLR6 and TLR10, and four in birds TLR1A, TLR1B, TLR2A and TLR2B. These genes were previously thought to have arisen by a series of independent gene duplications. To understand the evolutionary pattern of the TLR1 gene family in vertebrates further, we cloned the sequences of TLR1A, TLR1B, TLR2A and TLR2B in duck and turkey, constructed phylogenetic trees, predicted codons under positive selection and identified co-evolutionary amino acid pairs within the TLR1 gene family using sequences from 4 birds, 28 mammals, an amphibian and a fish.</p> <p>Results</p> <p>This detailed phylogenetic analysis not only clarifies the gene gains and losses within the TLR1 gene family of birds and mammals, but also defines orthologues between these vertebrates. In mammals, we predict amino acid sites under positive selection in TLR1, TLR2 and TLR6 but not TLR10. We detect co-evolution between amino acid residues in TLR2 and the other members of this gene family predicted to maintain their ability to form functional heterodimers. In birds, we predict positive selection in the TLR2A and TLR2B genes at functionally significant amino acid residues. We demonstrate that the TLR1 gene family has mostly been subject to purifying selection but has also responded to directional selection at a few sites, possibly in response to pathogen challenge.</p> <p>Conclusions</p> <p>Our phylogenetic and structural analyses of the vertebrate TLR1 family have clarified their evolutionary origins and predict amino acid residues likely to be important in the host's defense against invading pathogens.</p

Dispersal and population structure at different spatial scales in the subterranean rodent Ctenomys australis

<p>Abstract</p> <p><b>Background</b></p> <p>The population genetic structure of subterranean rodent species is strongly affected by demographic (e.g. rates of dispersal and social structure) and stochastic factors (e.g. random genetic drift among subpopulations and habitat fragmentation). In particular, gene flow estimates at different spatial scales are essential to understand genetic differentiation among populations of a species living in a highly fragmented landscape. <it>Ctenomys australis </it>(the sand dune tuco-tuco) is a territorial subterranean rodent that inhabits a relatively secure, permanently sealed burrow system, occurring in sand dune habitats on the coastal landscape in the south-east of Buenos Aires province, Argentina. Currently, this habitat is threatened by urban development and forestry and, therefore, the survival of this endemic species is at risk. Here, we assess population genetic structure and patterns of dispersal among individuals of this species at different spatial scales using 8 polymorphic microsatellite loci. Furthermore, we evaluate the relative importance of sex and habitat configuration in modulating the dispersal patterns at these geographical scales.</p> <p>Results</p> <p>Our results show that dispersal in <it>C. australis </it>is not restricted at regional spatial scales (~ 4 km). Assignment tests revealed significant population substructure within the study area, providing support for the presence of two subpopulations from three original sampling sites. Finally, male-biased dispersal was found in the Western side of our study area, but in the Eastern side no apparent philopatric pattern was found, suggesting that in a more continuous habitat males might move longer distances than females.</p> <p>Conclusions</p> <p>Overall, the assignment-based approaches were able to detect population substructure at fine geographical scales. Additionally, the maintenance of a significant genetic structure at regional (~ 4 km) and small (less than 1 km) spatial scales despite apparently moderate to high levels of gene flow between local sampling sites could not be explained simply by the linear distance among them. On the whole, our results support the hypothesis that males disperse more frequently than females; however they do not provide support for strict philopatry within females.</p

Melanism in Peromyscus Is Caused by Independent Mutations in Agouti

Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity. Melanic (darkly pigmented) phenotypes in mammals provide a potent system in which to study the genetic basis of naturally occurring mutant phenotypes because melanism occurs in many mammals, and the mammalian pigmentation pathway is well understood. Spontaneous alleles of a few key pigmentation loci are known to cause melanism in domestic or laboratory populations of mammals, but in natural populations, mutations at one gene, the melanocortin-1 receptor (Mc1r), have been implicated in the vast majority of cases, possibly due to its minimal pleiotropic effects. To investigate whether mutations in this or other genes cause melanism in the wild, we investigated the genetic basis of melanism in the rodent genus Peromyscus, in which melanic mice have been reported in several populations. We focused on two genes known to cause melanism in other taxa, Mc1r and its antagonist, the agouti signaling protein (Agouti). While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color. In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype. These results show that melanism has evolved independently in these populations through mutations in the same gene, and suggest that melanism produced by mutations in genes other than Mc1r may be more common than previously thought

Is Promiscuity Associated with Enhanced Selection on MHC-DQα in Mice (genus Peromyscus)?

Reproductive behavior may play an important role in shaping selection on Major Histocompatibility Complex (MHC) genes. For example, the number of sexual partners that an individual has may affect exposure to sexually transmitted pathogens, with more partners leading to greater exposure and, hence, potentially greater selection for variation at MHC loci. To explore this hypothesis, we examined the strength of selection on exon 2 of the MHC-DQα locus in two species of Peromyscus. While the California mouse (P. californicus) is characterized by lifetime social and genetic monogamy, the deer mouse (P. maniculatus) is socially and genetically promiscuous; consistent with these differences in mating behavior, the diversity of bacteria present within the reproductive tracts of females is significantly greater for P. maniculatus. To test the prediction that more reproductive partners and exposure to a greater range of sexually transmitted pathogens are associated with enhanced diversifying selection on genes responsible for immune function, we compared patterns and levels of diversity at the Class II MHC-DQα locus in sympatric populations of P. maniculatus and P. californicus. Using likelihood based analyses, we show that selection is enhanced in the promiscuous P. maniculatus. This study is the first to compare the strength of selection in wild sympatric rodents with known differences in pathogen milieu

Toll-like receptors (TLRs) and mannan-binding lectin (MBL): On constant alert in a hostile environment

In the beginning were neither B cells nor T cells nor antibodies, but innate immune defense alone. The primary functional theme of innate immunity is the distinction between self and non-self, which is maintained by a vast number of cellular and subcellular components. In this context, the immense importance of the Toll-like receptors (TLRs) is well established. Positive (Darwinian) selection seems to be acting on the ligand-binding domains of these molecules, suggesting a selection pattern similar to that previously observed in the MHC proteins. In sharp contrast to TLRs, the biological significance of mannan-binding lectin (MBL) is controversial, and, concerning humans, it has been suggested that low concentration of MBL in serum represents a selective advantage. In this mini-review, based on a doctoral thesis, evolutionary aspects of TLRs and MBL are discussed

Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease

Role of deficits in pathogen recognition receptors in infection susceptibility

This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to A.C. and SFRH/BPD/96176/2013 to C.C.