2019 Spring.Includes bibliographical references.Cystic fibrosis (CF) is caused by mutation of the... more 2019 Spring.Includes bibliographical references.Cystic fibrosis (CF) is caused by mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which normally encodes an ABC transporter-class ion channel protein that allows chloride and thiocyanate ions transport across epithelial cell membranes. Thus, CFTR plays an important role in airway homeostasis. Mutations of CFTR in patients with CF leads to a defect in transport of chloride and thiocyanate ions by epithelial cells, resulting in a multi-system disorder that affects the respiratory tract, gastrointestinal tract, the endocrine system, among others. The epithelial cell dysfunction in the lungs of CF patients also leads to an impaired pulmonary defense mechanism, resulting in decreased bacterial clearance and chronic inflammation. In CF patients, lung disease due to non-tuberculous mycobacteria (NTM) — an environmental organisms found in soil, water, and biofilms — is one of the most feared complications. Amon...
Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood ... more Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tubercu...
2019 Spring.Includes bibliographical references.Cystic fibrosis (CF) is caused by mutation of the... more 2019 Spring.Includes bibliographical references.Cystic fibrosis (CF) is caused by mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which normally encodes an ABC transporter-class ion channel protein that allows chloride and thiocyanate ions transport across epithelial cell membranes. Thus, CFTR plays an important role in airway homeostasis. Mutations of CFTR in patients with CF leads to a defect in transport of chloride and thiocyanate ions by epithelial cells, resulting in a multi-system disorder that affects the respiratory tract, gastrointestinal tract, the endocrine system, among others. The epithelial cell dysfunction in the lungs of CF patients also leads to an impaired pulmonary defense mechanism, resulting in decreased bacterial clearance and chronic inflammation. In CF patients, lung disease due to non-tuberculous mycobacteria (NTM) — an environmental organisms found in soil, water, and biofilms — is one of the most feared complications. Amon...
Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood ... more Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tubercu...
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Papers by Kridakorn Vongtongsalee