Number of genetic variants identified.

<p>Number of genetic variants identified.</p

<i>TLR1</i> Variant H305L Associated with Protection from Pulmonary Tuberculosis

<div><p>Toll like receptors (TLR) are key elements of the innate immune response and involved in the recognition of pathogens. To test common and rare <i>TLR</i> variants involved in susceptibility or resistance to infection with <i>Mycobacterium tuberculosis</i> we screened the exons of the genes encoding TLR 1, 2, 4, and the adaptor molecule TIRAP in more than 4500 tuberculosis (TB) cases and controls from Ghana. The analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variants, three stop-variants, and five indels. Association analyses yielded a significant result for the <i>TLR1</i> variant rs3923647, conferring strong protection against TB (Odds ratio [OR] 0.21, CI confidence interval [CI] 0.05–0.6, P_{<i>nominal</i>} 1 x 10⁻³) when applying a recessive model of inheritance. Replication analyses with an additional 3370 Ghanaian cases and control samples, and with data from a recent TB study of 533 African-Americans confirmed the protective effect and resulted in a combined OR of 0.19, with a nominal P value of 2.2 x 10⁻⁵, and a corrected P value of 4.1 x 10⁻⁴. The SNP is located near the binding pocket of TLR1 and causes an amino acid exchange from histidine to leucine at position 305. The observed effect may, therefore, be attributable to structural changes in the recognition site of the TLR1 molecule, allowing to bind those mycobacterial ligands which preferentially may induce a protective immune response. This is supported by the analysis of BCG-stimulated peripheral blood mononuclear cells, showing increased induction of the proinflammatory cytokine IFN-γ in carriers of the mutant TLR1 rs3923647 TT genotype, compared to the IFN-γ levels of individuals with the AT and AA genotypes.</p></div

IFN-y expression in <i>M</i>. <i>bovis</i> BCG stimulated cultured PBMCs.

<p>Comparison of IFN-y mRNA expression in <i>M</i>. <i>bovis</i> BCG stimulated cultured PBMCs of Ghanaian individuals carrying either the TT genotype or the AT/AA genotype of TLR1 SNP rs3923647. Comparison of IFN-y levels yields a significant difference between TT and AT/AA carriers (* P = 0.05, T-test).</p

Gene-set associations tests.

<p>Gene-set associations tests.</p

Association results of TLR1 variant rs3923647.

<p>Association results of TLR1 variant rs3923647.</p

Distribution of dengue samples per region from 2017–2019.

Distribution of dengue samples per region from 2017–2019.</p

List of DENV-1 Tanzania sequences names, 2017–2019.

List of DENV-1 Tanzania sequences names, 2017–2019.</p

Socio-demographic characteristics of patients with dengue infection in Tanzania from 2017 to 2019.

Socio-demographic characteristics of patients with dengue infection in Tanzania from 2017 to 2019.</p

List of DENV-3 Tanzania sequences names, 2017–2019.

List of DENV-3 Tanzania sequences names, 2017–2019.</p

Distribution of dengue fever cases in Tanzania from 2017 to 2019.

The map shows 26 Tanzania mainland administrative regions. The five color-coded regions show dengue fever cases distribution between 2017–2019. Map created with QGIS 3.24.1 All shape files are openly available sources (https://www.nbs.go.tz/index.php/en/census-surveys/gis/385-2012-phc-shapefiles-level-one-and-two). The shapefiles were made based on the 2012 population and housing census, but in this study, the shapefile has been modified to capture all the regions and district information.</p