Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent in Caseum.

Tuberculosis is the leading cause of mortality by infectious agents worldwide. The necrotic debris, known as caseum, which accumulates in the center of pulmonary lesions and cavities is home to nonreplicating drug-tolerant that presents a significant hurdle to achieving a fast and durable cure. Fluoroquinolones such as moxifloxacin are highly effective at killing this nonreplicating persistent bacterial population and boosting TB lesion sterilization.

IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.

Distributable, metabolic PET reporting of tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability.

Mucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques.

Immunization via the respiratory route is predicted to increase the effectiveness of a SARS-CoV-2 vaccine. Here, we evaluate the immunogenicity and protective efficacy of one or two doses of a live-attenuated murine pneumonia virus vector expressing SARS-CoV-2 prefusion-stabilized spike protein (MPV/S-2P), delivered intranasally/intratracheally to male rhesus macaques. A single dose of MPV/S-2P is highly immunogenic, and a second dose increases the magnitude and breadth of the mucosal and systemic anti-S antibody responses and increases levels of dimeric anti-S IgA in the airways.

Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified.

Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas.

Pathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation.

Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation.

A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach.

Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects.

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism.

Automated quantitative assay of fibrosis characteristics in tuberculosis granulomas.

Introduction: Granulomas, the pathological hallmark of () infection, are formed by different cell populations. Across various stages of tuberculosis conditions, most granulomas are classical caseous granulomas. They are composed of a necrotic center surrounded by multilayers of histocytes, with the outermost layer encircled by fibrosis.

High resolution imaging and five-year tuberculosis contact outcomes.

Background: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood.

Methods: 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy.

Distributable, Metabolic PET Reporting of Tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [F]FDG, yet lack specificity to the causative pathogen () and so do not directly correlate with pathogen viability.

A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum.

Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. An model that recapitulates the major features of Mycobacterium tuberculosis (Mtb) in caseum would accelerate the identification of compounds with treatment-shortening potential.

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition.

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against . To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer.

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys.

Pediatric SARS-CoV-2 vaccines are needed that elicit immunity directly in the airways as well as systemically. Building on pediatric parainfluenza virus vaccines in clinical development, we generated a live-attenuated parainfluenza-virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) and evaluated its immunogenicity and protective efficacy in rhesus macaques. A single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal immunoglobulin A (IgA) and IgG responses.

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine candidate is protective in macaques.

Pediatric SARS-CoV-2 vaccines are needed that elicit immunity directly in the airways, as well as systemically. Building on pediatric parainfluenza virus vaccines in clinical development, we generated a live-attenuated parainfluenza virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) and evaluated its immunogenicity and protective efficacy in rhesus macaques. A single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal IgA and IgG responses.

E3 Ligase FBXW7 Facilitates Immune Evasion by Modulating TNF-α Expression.

Tumor necrosis factor alpha (TNF-α) is a crucial factor in the control of () infection. Pathogenic mycobacteria can inhibit and/or regulate host cell TNF-α production in a variety of ways to evade antituberculosis (anti-TB) immunity as well as facilitate immune escape. However, the mechanisms by which TNF-α expression in host cells is modulated to the benefit of mycobacteria is still an interesting topic and needs further study.

Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts.

Background: Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a "real-time" measure of treatment efficacy could accelerate TB drug development.