Immune cell infiltration and modulation of the blood-brain barrier in a guinea pig model of tuberculosis: Observations without evidence of bacterial dissemination to the brain.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is a chronic inflammatory disease. Although typically associated with inflammation of the lungs and other peripheral tissues, increasing evidence has uncovered neurological consequences attributable to Mtb infection. These include deficits in memory and cognition, increased risk for neurodegenerative disease, and progressive neuropathology.

Establishment of CD1b-restricted immunity to lipid antigens in the pulmonary response to infection.

CD1 is an antigen-presenting glycoprotein homologous to MHC I; however, CD1 proteins present lipid rather than peptide antigens. CD1 proteins are well established to present lipid antigens of (Mtb) to T cells, but understanding the role of CD1-restricted immunity in response to Mtb infection has been limited by the availability of animal models naturally expressing the CD1 proteins implicated in human response: CD1a, CD1b, and CD1c. Guinea pigs, in contrast to other rodent models, express four CD1b orthologs, and here we utilize the guinea pig to establish the kinetics of gene and protein expression of CD1b orthologs, as well as the Mtb lipid-antigen and CD1b-restricted immune response at the tissue level over the course of Mtb infection.

Establishment of CD1b-restricted immunity to lipid antigens in the pulmonary response to infection.

CD1 is an antigen presenting glycoprotein homologous to MHC I; however, CD1 proteins present lipid rather than peptide antigen. CD1 proteins are well established to present lipid antigens of (Mtb) to T cells, but understanding the role of CD1-restricted immunity in response to Mtb infection has been limited by availability of animal models naturally expressing the CD1 proteins implicated in human response: CD1a, CD1b and CD1c. Guinea pigs, in contrast to other rodent models, express four CD1b orthologs, and here we utilize the guinea pig to establish the kinetics of gene and protein expression of CD1b orthologs, as well as the Mtb lipid-antigen and CD1b-restricted immune response at the tissue level over the course of Mtb infection.

Gliosis, misfolded protein aggregation, and neuronal loss in a guinea pig model of pulmonary tuberculosis.

Tuberculosis, caused by infection, is an ongoing epidemic with an estimated ten million active cases of the disease worldwide. Pulmonary tuberculosis is associated with cognitive and memory deficits, and patients with this disease are at an increased risk for Parkinson's disease and dementia. Although epidemiological data correlates neurological effects with peripheral disease, the pathology in the central nervous system is unknown.

The Impact of Vitamin A Deficiency on Tuberculosis Progression.

Background: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression.

Methods: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti.

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review.

Infection with (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs).

Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.

Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8CXCR3 T cells in naive mice, and in healthy individuals and patients with T2D.

Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis.

Tuberculosis (TB) is a chronic inflammatory disease that is often associated with alterations in systemic and cellular metabolism that resolves following successful antimicrobial drug treatment. We hypothesized that altered systemic glucose metabolism as a consequence of Mycobacterium tuberculosis (Mtb) infection, contributes to TB pathogenesis, and when normalized with anti-glycemic drugs would improve clinical outcomes. To test this hypothesis, guinea pigs were treated daily with the anti-diabetic drug metformin starting 4 weeks prior or concurrent with aerosol exposure to the H37Rv strain of Mtb.

Study of Real-Time Spatial and Temporal Behavior of Bacterial Biofilms Using 2-D Impedance Spectroscopy.

Objective: The purpose of this paper is to demonstrate the use of 2-D impedance spectroscopy to identify areas of biofilm growth on a CMOS biosensor microelectrode-array.

Methods: This paper presents the design and use of a novel multichannel impedance spectroscopy instrument to allow 2-D spatial and temporal evaluation of biofilm growth. The custom-designed circuits can provide a wide range of frequencies (1 Hz-100 kHz) to allow customization of impedance measurements, as the frequency of interest varies based on the type and state of biofilm under measurement.

Cyclin-Dependent Kinases 8 and 19 Regulate Host Cell Metabolism during Dengue Virus Serotype 2 Infection.

Dengue virus infection is associated with the upregulation of metabolic pathways within infected cells. This effect is common to infection by a broad array of viruses. These metabolic changes, including increased glucose metabolism, oxidative phosphorylation and autophagy, support the demands of viral genome replication and infectious particle formation.

A mouse model of pulmonary Mycobacteroides abscessus infection.

There is no preclinical mouse model to investigate pulmonary Mycobacteroides abscessus (formerly Mycobacterium abscessus) infection in an immunocompetent mouse strain, especially in the context of antibiotic testing and regimen development. We developed a mouse model of pulmonary M. abscessus infection using the aerosolized route of infection that leads to an increase in bacterial burden post- implantation and develops pathology as a result.

2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain.

There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment.

Analogue synthesis reveals decoupling of antibiofilm and β-lactam potentiation activities of a lead 2-aminoimidazole adjuvant against Mycobacterium smegmatis.

Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M.

Topical therapy for refractory rhinosinusitis caused by methicillin-resistant Staphylococcus aureus: First report in a prospective series.

Objective: The incidence of refractory chronic rhinosinusitis (CRS) associated with methicillin-resistant Staphylococcus aureus (MRSA) is rising and remains a therapeutic challenge. The goal of this study is to demonstrate the efficacy of a non-invasive topical therapy against MRSA in these patients.

Methods: Seventeen patients with refractory CRS caused by MRSA were treated with a topical therapy protocol.

2-aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability.

There is an urgent need to develop new drug treatment strategies to control the global spread of drug-sensitive and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). The ß-lactam class of antibiotics is among the safest and most widely prescribed antibiotics, but they are not effective against M.

Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models.

Tuberculosis (TB) is a chronic inflammatory disease caused by the pathogenic bacterium . A wide variety of host- and pathogen-associated variables influence the clinical manifestation of TB in different individuals within the human population. As a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition.

Mycobacterial Biofilms: Revisiting Tuberculosis Bacilli in Extracellular Necrotizing Lesions.

Under detergent-free conditions, , the etiological agent of tuberculosis in humans, spontaneously forms organized multicellular structures called biofilms. Moreover, biofilms of are more persistent against antibiotics than their single-cell planktonic counterparts, thereby raising questions about the occurrence of biofilms in the host tissues and their significance in persistence during chemotherapy of tuberculosis. In this article, we present arguments that extracellular in necrotizing lesions likely grows as biofilms.

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 2: Underlying Biologic Mechanisms.

There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and TB, but the underlying biologic mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiologic, public health, basic science, and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-occurrence of TB and DM. We identified gaps in current knowledge of altered immunity in patients with DM during TB, where most studies suggest an underperforming innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis.

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 1: Epidemiology and Clinical Management.

There is growing interest in the interaction between type 2 diabetes mellitus (DM) and TB, but many research questions remain unanswered. Epidemiologists, basic scientists, and clinical experts recently convened and identified priorities. This is the first of two reviews on this topic, summarizing priority areas of research regarding epidemiology, clinical management, and public health.

The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β-Lactam Antibiotics in a Pattern Distinct from β-Lactamase Inhibitors.

A library of 2-aminobenzimidazole derivatives was screened for the ability to suppress β-lactam resistance in Mycobacterium smegmatis. Several non-bactericidal compounds were identified that reversed intrinsic resistance to β-lactam antibiotics in a manner distinct from β-lactamase inhibitors. Activity also translates to M.

A model of type 2 diabetes in the guinea pig using sequential diet-induced glucose intolerance and streptozotocin treatment.

Type 2 diabetes is a leading cause of morbidity and mortality among noncommunicable diseases, and additional animal models that more closely replicate the pathogenesis of human type 2 diabetes are needed. The goal of this study was to develop a model of type 2 diabetes in guinea pigs, in which diet-induced glucose intolerance precedes β-cell cytotoxicity, two processes that are crucial to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after 8 weeks of feeding on a high-fat, high-carbohydrate diet, as determined by oral glucose challenge.

Host-directed therapy targeting the Mycobacterium tuberculosis granuloma: a review.

Infection by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb) is a major cause of morbidity and mortality worldwide. Slow progress has been made in lessening the impact of tuberculosis (TB) on human health, especially in parts of the world where Mtb is endemic. Due to the complexity of TB disease, there is still an urgent need to improve diagnosis, prevention, and treatment strategies to control global spread of disease.

Second generation 2-aminoimidazole based advanced glycation end product inhibitors and breakers.

The formation of advanced glycation end-products (AGE) as a result of the action of reducing sugars on host macromolecules plays a role in increased morbidity of diabetic patients. There are currently no clinically available therapeutics for the prevention or eradication of AGEs. Following our previous identification of 2-aminoimidazole (2-AI) based AGE inhibitors and breakers, we now report the use of a rapid, scalable, two-step procedure to access a second generation of 2-AI based anti-AGE compounds from commercially available amino acids.

Inhibition and breaking of advanced glycation end-products (AGEs) with bis-2-aminoimidazole derivatives.

Advanced glycation end-products (AGEs), unregulated modifications to host macromolecules that occur as a result of metabolic dysregulation, play a role in many diabetes related complications, inflammation and aging, and may lead to increased cardiovascular risk. Small molecules that have the ability to inhibit AGE formation, and even break preformed AGEs have enormous therapeutic potential in the treatment of these disease states. We report the screening of a series of 2-aminoimidazloles for anti-AGE activity, and the identification of a bis-2-aminoimidazole lead compound that possesses superior AGE inhibition and breaking activity compared to the known AGE inhibitor aminoguanidine.