Frequency of Meningococcal Meningitis Susceptibility Associated TLR4 +896 A/G (rs4986790) Allele in the Saudi Population

Meningococcal meningitis (MM) is a severe central nervous system (CNS) infection that occurs primarily in children. MM can damage brain areas associated with hearing, learning, reasoning, focus, and memory. Genetic changes, including single nucleotide polymorphisms (SNPs), which compromise pathogen recognition increase the risk and severity of MM. There is little data on how the variation in the frequency of the rs4986790 polymorphism in the Toll-like receptor 4 (TLR4) gene may affect the population of Saudi Arabia. This study sought to determine the allelic frequency and distribution of the TLR4 rs4986790 A/G polymorphism in the Saudi population and compare the data to other global populations. Data from epidemiological studies conducted in various ethnic groups were extracted using PUBMED (Medline) and similar web databases. An estimated 5.88% of the Saudi population harbors the TLR4 rs4986790 G variant allele. This differed significantly from the frequencies in populations in China (p=0.0002), Japan (p=0.0001), Korea (p=0.0001), and Mexico (p=0.01). The TLR4 rs4986790 polymorphism variant allele has a unique pattern in the Saudi population, which may be the result of racial differences. These findings could assist in the risk assessment of people harboring the TLR4 +896 GG genotype susceptible to MM in the Saudi population

Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB

Understanding functional mechanisms of genetic susceptibility to mycobacterial infection

Tuberculosis remains a major public health problem and one of the leading causes of death worldwide. Human genetic factors determine susceptibility to M. tuberculosis (M. tb) infection and predispose to clinical TB. Genome-wide association studies (GWAS) aim to discover human genes associated with susceptibility to TB. Recently, a GWAS conducted by our lab identified a new TB-associated gene ASAP1 that encodes an Arf GTPase-activating protein (GAP). ASAP1 is known to be involved in regulation of actin and membrane remodeling. My Ph.D. included three projects. In my first project, I used RNAi and CRISPR-Cas9 technologies to study the role of ASAP1 in dendritic cells and macrophages, cells that play critical roles during mycobacterial infection. I demonstrated that in these cells ASAP1 is essential for migration and phagocytosis of mycobacteria. I characterized proteins that ASAP1 interacts with during mycobacterial infection. Finally, I found that the ASAP1-mediated pathway regulates expression of a large number of the immune response genes. These findings emphasize the important role of ASAP1 in mycobacterial infection and explain its involvement in TB pathogenesis. In my second project, I was involved in a large study conducted by our laboratory that characterized transcriptional responses to M. tb infection in macrophages from a cohort of 144 healthy subjects. We used RNA-Seq to study transcriptomes of the infected and non-infected macrophages and identified differentially expressed genes. We also genotyped DNA polymorphisms of these subjects and studied the association between genetic variants and levels of gene expression, which allows us to identify expression quantitative trait loci (eQTLs), i.e., DNA polymorphism that affect gene expression. In particular, we identified an eQTL located in the TLR10-TLR1-TLR6 gene cluster. In non-infected macrophages, a group of polymorphisms in this region was associated in cis with the level of expression of TLR1, but not of the other two TLR genes. In M. tb-infected macrophages the same polymorphisms were associated in trans with levels of expression of 37 genes. This network includes essential immune response proteins, including multiple cytokines and chemokines. The discovery of this TLR1-driven network will help to better understand mechanisms of macrophage responses to mycobacterial infection. Our study also identified a DNA polymorphism located upstream of the ARHGAP27 gene, regulating its expression in infected and non-infected macrophages. In our GWAS this polymorphism was associated with TB risk, which implicated ARHGAP27 in TB pathogenesis. The ARHGAP27 protein is a Rho-GAP involved in the endocytic pathway. In my third project, I used CRISPR technology to establish the ARHGAP27-knockout macrophage cell model and characterized the function of ARHGAP27, showing that it is involved in cell migration and phagocytosis of mycobacteria. Taken together, my studies highlighted functional mechanisms implicating TB-associated GAP proteins ASAP1 and ARHGAP27 in mycobacterial infection and TB pathogenesis.Al Baha University and Ministry of Education in Saudi Arabia

Comparison and Combination of Thermal, Fluorescence, and Hyperspectral Imaging for Monitoring Fusarium Head Blight of Wheat on Spikelet Scale

Optical sensors have shown high capabilities to improve the detection and monitoring of plant disease development. This study was designed to compare the feasibility of different sensors to characterize Fusarium head blight (FHB) caused by Fusarium graminearum and Fusarium culmorum. Under controlled conditions, time-series measurements were performed with infrared thermography (IRT), chlorophyll fluorescence imaging (CFI), and hyperspectral imaging (HSI) starting 3 days after inoculation (dai). IRT allowed the visualization of temperature differences within the infected spikelets beginning 5 dai. At the same time, a disorder of the photosynthetic activity was confirmed by CFI via maximal fluorescence yields of spikelets (Fm) 5 dai. Pigment-specific simple ratio PSSRa and PSSRb derived from HSI allowed discrimination between Fusarium-infected and non-inoculated spikelets 3 dai. This effect on assimilation started earlier and was more pronounced with F. graminearum. Except the maximum temperature difference (MTD), all parameters derived from different sensors were significantly correlated with each other and with disease severity (DS). A support vector machine (SVM) classification of parameters derived from IRT, CFI, or HSI allowed the differentiation between non-inoculated and infected spikelets 3 dai with an accuracy of 78, 56 and 78%, respectively. Combining the IRT-HSI or CFI-HSI parameters improved the accuracy to 89% 30 dai.peerReviewe

Topoisomerase 2β mutation impairs early B-cell development

Mutations impairing early B-cell development cause monogenic primary immunodeficiencies that manifest with markedly reduced or absent B cells, hypogammaglobulinemia, and recurrent bacterial infections from childhood. Approximately 85% of such patients have mutations in BTK, the gene responsible for X-linked agammaglobulinemia.1 Current research focuses on patients with unknown genetic defects, because the identification of the causative genes not only will facilitate diagnosis of primary immunodeficiencies but also can reveal new biological roles of the affected proteins in human B-cell development and point at novel drug targets