Plasticity of NADH dehydrogenases and their role in virulence.

Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant () strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued.

Enhanced respiration prevents drug tolerance and drug resistance in .

Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially growing () cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in cultures.

Synthesis and biological activity of alkynoic acids derivatives against mycobacteria.

2-Alkynoic acids have bactericidal activity against Mycobacterium smegmatis but their activity fall sharply as the length of the carbon chain increased. In this study, derivatives of 2-alkynoic acids were synthesized and tested against fast- and slow-growing mycobacteria. Their activity was first evaluated in M.

Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency.

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs).

A mutation in the Ebola virus envelope glycoprotein restricts viral entry in a host species- and cell-type-specific manner.

Zaire Ebola virus (EBOV) is a zoonotic pathogen that causes severe hemorrhagic fever in humans. A single viral glycoprotein (GP) mediates viral attachment and entry. Here, virus-like particle (VLP)-based entry assays demonstrate that a GP mutant, GP-F88A, which is defective for entry into a variety of human cell types, including antigen-presenting cells (APCs), such as macrophages and dendritic cells, can mediate viral entry into mouse CD11b(+) APCs.

The role of antigen-presenting cells in filoviral hemorrhagic fever: gaps in current knowledge.

The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are highly lethal zoonotic agents of concern as emerging pathogens and potential bioweapons. Antigen-presenting cells (APCs), particularly macrophages and dendritic cells, are targets of filovirus infection in vivo. Infection of these cell types has been proposed to contribute to the inflammation, activation of coagulation cascades and ineffective immune responses characteristic of filovirus hemorrhagic fever.

Ebola virus failure to stimulate plasmacytoid dendritic cell interferon responses correlates with impaired cellular entry.

We examined the ability of the Ebola virus to elicit an antiviral response from plasmacytoid dendritic cells (pDCs). Exposure of pDCs to Ebola virus did not result in significantly higher levels of interferon-α production than the levels in mock-infected cells. After inoculation with Ebola virus under the same conditions, conventional dendritic cells expressed viral proteins whereas pDCs did not, suggesting that the latter cells were not infected.

Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions.

Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drug-resistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]).

Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells.

Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-α/β (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways.

Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling.

The Ebolavirus VP24 protein counteracts alpha/beta interferon (IFN-alpha/beta) and IFN-gamma signaling by blocking the nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1). According to the proposed model, VP24 binding to members of the NPI-1 subfamily of karyopherin alpha (KPNalpha) nuclear localization signal receptors prevents their binding to PY-STAT1, thereby preventing PY-STAT1 nuclear accumulation. This study now identifies two domains of VP24 required for inhibition of IFN-beta-induced gene expression and PY-STAT1 nuclear accumulation.

A five-amino-acid deletion of the eastern equine encephalitis virus capsid protein attenuates replication in mammalian systems but not in mosquito cells.

Eastern equine encephalitis virus (EEEV) is a human and veterinary pathogen that causes sporadic cases of fatal neurological disease. We previously demonstrated that the capsid protein of EEEV is a potent inhibitor of host cell gene expression and that this function maps to the amino terminus of the protein. We now identify amino acids 55 to 75, within the N terminus of the capsid, as critical for the inhibition of host cell gene expression.

Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation.

Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-alpha/beta) and the ability of cells to respond to IFN-alpha/beta or IFN-gamma. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-alpha/beta production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined.

Inhibitors of glycosphingolipid biosynthesis reduce transepithelial electrical resistance in MDCK I and FRT cells.

Madin-Darby canine kidney (MDCK) I and Fisher rat thyroid (FRT) cells exhibit transepithelial electrical resistance (TER) values in excess of 5,000 Omega. cm(2). When these cells were incubated in the presence of various inhibitors of sphingolipid biosynthesis, a >5-fold reduction of TER was observed without changes in the gate function for uncharged solutes or the fence function for apically applied fluorescent lipids.

The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium.

Daily phagocytosis of spent photoreceptor outer segments is a critical maintenance function performed by the retinal pigment epithelium (RPE) to preserve vision. Aging RPE accumulates lipofuscin, which includes N-retinylidene-N-retinylethanolamine (A2E) as the major autofluorescent component. We studied the effect of physiological levels of A2E in RPE cultures on their ability to phagocytose outer segments.

Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis.

Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, beta-amyloid (Abeta) burden in animal models of Alzheimer's disease, and secretion of Abeta from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17beta-estradiol (17beta-E2) stimulates formation of vesicles containing the beta-amyloid precursor protein (betaAPP) from the trans-Golgi network (TGN).