EGFR Regulation of Epidermal Barrier Function

Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammals to survive in the ex utero environment. This process is tightly controlled by the expression of many well-characterized genes. Although a few of these genes are known to be regulated by the epidermal growth factor receptor (EGFR), an important regulator of multiple epidermal functions, neither the genome-wide scale of EGFR-mediated regulation nor the mechanisms by which EGFR signaling controls keratinocyte differentiation are well understood. Using microarray analysis we identified 2,676 genes that are regulated by EGF, a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all essential metabolic processes of keratinocyte differentiation by (1) decreasing the expression of lipid matrix biosynthetic enzymes, (2) regulating numerous genes forming the cornified envelope, and (3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, the collective effect of EGF impaired epidermal barrier integrity, evidenced by increased transepidermal water loss. As defective epidermal differentiation and disruption of the epidermal barrier are primary features of many human skin diseases, we used bioinformatics analysis to identify genes that are known to be associated with human skin diseases. In comparison to non-EGF-regulated genes, the EGF-regulated gene list was significantly enriched for disease genes. Further validation of the expression profiles of many of the 114 identified skin disease genes included the transcription factors GATA binding protein 3 (GATA3) and Kruppel-like factor 4 (KLF4), both required for establishing the barrier function of the skin in developing mice. These results provide a new systems level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation. As the overall effect of this inhibition is to impair epidermal barrier integrity, this study clarifies how dysregulation of the EGFR and its ligands may contribute to diseases of the skin

Comparison of two dengue NS1 rapid tests for sensitivity, specificity and relationship to viraemia and antibody responses

<p>Abstract</p> <p>Background</p> <p>Dengue is a major public health problem in tropical and subtropical countries. Rapid and easy diagnosis of dengue can assist patient triage and care-management. The detection of DENV NS1 on rapid lateral flow tests offers a fast route to a presumptive dengue diagnosis but careful evaluations are urgently needed as more and more people use them.</p> <p>Methods</p> <p>The sensitivity and specificity of the Bio-Rad NS1 Ag Strip and SD Dengue Duo (NS1/IgM/IgG) lateral flow rapid tests were evaluated in a panel of plasma samples from 245 Vietnamese patients with RT-PCR confirmed dengue and 47 with other febrile illnesses.</p> <p>Results</p> <p>The NS1 rapid tests had similar diagnostic sensitivities (respectively 61.6% and 62.4%) in confirmed dengue cases but were 100% specific. When IgM/IgG results from the SD Dengue Duo were included in the test interpretation, the sensitivity improved significantly from 62.4% with NS1 alone to 75.5% when NS1 and/or IgM was positive and 83.7% when NS1 and/or IgM and/or IgG was positive. Both NS1 assays were significantly more sensitive for primary than secondary dengue. NS1 positivity was associated with the underlying viraemia as NS1-positive samples had a significantly higher viraemia than NS1-negative samples.</p> <p>Conclusions</p> <p>These data suggest that the NS1 test component of these assays are highly specific and have similar levels of sensitivity. The IgM parameter in the SD Duo test improved overall test sensitivity without compromising specificity. The SD Dengue Duo lateral flow rapid test deserves further prospective evaluation in dengue endemic settings.</p

Social Contact Patterns in Vietnam and Implications for the Control of Infectious Diseases

BACKGROUND: The spread of infectious diseases from person to person is determined by the frequency and nature of contacts between infected and susceptible members of the population. Although there is a long history of using mathematical models to understand these transmission dynamics, there are still remarkably little empirical data on contact behaviors with which to parameterize these models. Even starker is the almost complete absence of data from developing countries. We sought to address this knowledge gap by conducting a household based social contact diary in rural Vietnam. METHODS AND FINDINGS: A diary based survey of social contact patterns was conducted in a household-structured community cohort in North Vietnam in 2007. We used generalized estimating equations to model the number of contacts while taking into account the household sampling design, and used weighting to balance the household size and age distribution towards the Vietnamese population. We recorded 6675 contacts from 865 participants in 264 different households and found that mixing patterns were assortative by age but were more homogenous than observed in a recent European study. We also observed that physical contacts were more concentrated in the home setting in Vietnam than in Europe but the overall level of physical contact was lower. A model of individual versus household vaccination strategies revealed no difference between strategies in the impact on R(0). CONCLUSIONS AND SIGNIFICANCE: This work is the first to estimate contact patterns relevant to the spread of infections transmitted from person to person by non-sexual routes in a developing country setting. The results show interesting similarities and differences from European data and demonstrate the importance of context specific data

The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis

The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193–0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15–2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis

Demographic data for cases of TBM and pulmonary tuberculosis recruited to the study.

a<p>Defined as the main place of residence on entry to the study. Urban addresses were those within the central districts of Ho Chi Minh City (HCMC); sub-urban addresses were those within the outer districts of HCMC; rural (HCMC surrounds) addresses were in the immediate surrounding rural districts of HCMC; the other rural addresses were defined by whether they were south east or south west of HCMC.</p

<i>TLR</i>2 T597C SNP allele and bacterial genotype frequencies: comparison with host genotype distribution in the cord blood control group.

a<p>OR was calculated comparing each group to the genotype/allele distribution in the cord blood controls.</p

<i>Mycobacterium tuberculosis</i> lineages defined by large sequence polymorphism (LSP) analysis.

<p>The circles represent Region of difference (RD region) deleted in each lineage. Only East Asian, Indo-Oceanic and Euro-American lineages were identified in Vietnam.</p

LSP lineages of <i>M. tuberculosis</i> isolates causing pulmonary and meningeal tuberculosis.

a<p>Undefined isolates failed to generate a product on repeated PCR for one of the two RD regions despite generating product for other PCRs; it is likely these isolates carried additional deletions or mutations in the primer region.</p>b<p>Odds ratio was calculated comparing the meningeal and pulmonary proportions for each lineage.</p

Spoligotype, IS6110 RFLP and MIRU typing for all <i>M. tuberculosis</i> isolates in the study.

a<p> where <i>N</i> = the total number of strains in the sample population, <i>s</i> = the total number of types described and <i>n_j</i> = the total number of strains belonging to the <i>j</i>^th type <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Hunter1" target="_blank">[52]</a>.</p>b<p>ST319, also known as the Vietnam genotype <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Anh1" target="_blank">[39]</a>.</p>c<p>The Ha Noi genotype has a single IS6110 copy and is prevalent throughout Vietnam <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Le1" target="_blank">[53]</a>.</p>d<p><i>M. tuberculosis</i> isolates with no IS6110 insertion elements are relatively common in South-East Asia and have been reported in several studies of Vietnamese strains <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Le1" target="_blank">[53]</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Yuen1" target="_blank">[54]</a>.</p>*<p>Isolates of East-Asian Genotype in the LSP typing system of Gagneux et al. <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Gagneux1" target="_blank">[24]</a>.</p>†<p>Isolates of the Indo-Oceanic genotype in the LSP typing scheme of Gagneux et al. <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000034#ppat.1000034-Gagneux1" target="_blank">[24]</a>.</p