Dual-action compounds unleash a one-two punch against tuberculosis.

In this issue of Cell Chemical Biology, Gries et al. employ an innovative screening approach to identify anti-tuberculosis compounds with dual modes of action: anti-virulence against the type VII secretion system ESX-1 and enhanced ethionamide efficacy. These compounds hold promise for developing multi-target tuberculosis drugs with potential clinical applications.

ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection.

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces, and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis (Mtb) infection alters the phenotype and function of lung IL-18Rα ILC toward a protective interferon-γ-producing ILC1-like population.

To Treat or Not to Treat Bees? Handy VarLoad: A Predictive Model for Load.

The parasitic is considered a major pathogenic threat to honey bees and to beekeeping. Without regular treatment against this mite, honey bee colonies can collapse within a 2-3-year period in temperate climates. Beyond this dramatic scenario, Varroa induces reductions in colony performance, which can have significant economic impacts for beekeepers.

Preclinical assessment of a new live attenuated Mycobacterium tuberculosis Beijing-based vaccine for tuberculosis.

Tuberculosis still claims more lives than any other pathogen, and a vaccine better than BCG is urgently needed. One of the challenges for novel TB vaccines is to protect against all Mycobacterium tuberculosis lineages, including the most virulent ones, such as the Beijing lineage. Here we developed a live attenuated M.

The Host Microbiota Contributes to Early Protection Against Lung Colonization by .

Tuberculosis (TB), caused by the airborne bacterial pathogen , remains a major source of morbidity and mortality worldwide. So far, the study of host-pathogen interactions in TB has mostly focused on the physiology and virulence of the pathogen, as well as, on the various innate and adaptive immune compartments of the host. Microbial organisms endogenous to our body, the so-called microbiota, interact not only with invading pathogens, but also with our immune system.

The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases.

The pulmonary microbial community, described only a few years ago, forms a discreet part of the human host microbiota. The airway microbiota has been found to be substantially altered in the context of numerous respiratory disorders; nonetheless, its role in health and disease is as yet only poorly understood. Another important parameter to consider is the gut-lung axis, where distal (gut) immune modulation during respiratory disease is mediated by the gut microbiota.

Horizontal acquisition of a hypoxia-responsive molybdenum cofactor biosynthesis pathway contributed to Mycobacterium tuberculosis pathoadaptation.

The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species.

Assessment of the toxic effect of pesticides on honey bee drone fertility using laboratory and semifield approaches: A case study of fipronil.

Concern about the reproductive toxicity of plant protection products in honey bee reproducers is increasing. Because the reproductive capacity of honey bees is not currently considered during the risk assessment procedure performed during plant protection product registration, it is important to provide methods to assess such potential impairments. To achieve this aim, we used 2 different approaches that involved semifield and laboratory conditions to study the impact of fipronil on drone fertility.

Wings as a new route of exposure to pesticides in the honey bee.

In pesticide risk assessment, estimating the routes and levels of exposure is critical. For honey bees subjected to pesticide spray, toxicity is assessed by thorax contact to account for all possible contact exposures. In the present study, the authors tested 6 active substances with different hydrophobicity.

A pragmatic approach to assess the exposure of the honey bee (Apis mellifera) when subjected to pesticide spray.

Plant protection spray treatments may expose non-target organisms to pesticides. In the pesticide registration procedure, the honey bee represents one of the non-target model species for which the risk posed by pesticides must be assessed on the basis of the hazard quotient (HQ). The HQ is defined as the ratio between environmental exposure and toxicity.

Nitrogen metabolism in Mycobacterium tuberculosis physiology and virulence.

Several major pathogens, including Mycobacterium tuberculosis, parasitize host cells and exploit host-derived nutrients to sustain their own metabolism. Although the carbon sources that are used by M. tuberculosis have been extensively studied, the mechanisms by which mycobacteria capture and metabolize nitrogen, which is another essential constituent of biomolecules, have only recently been revisited.

Amino acid capture and utilization within the Mycobacterium tuberculosis phagosome.

Mycobacterium tuberculosis, the agent of TB, is a facultative intracellular bacterial pathogen that replicates inside host macrophages and other phagocytes within a membrane-bound vacuole or phagosome. How M. tuberculosis captures and exploits vital nutrients inside host cells is an intensive research area that might lead to novel therapeutics for tuberculosis.

Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress during infection.

Mycobacterium tuberculosis is an intracellular pathogen. Within macrophages, M. tuberculosis thrives in a specialized membrane-bound vacuole, the phagosome, whose pH is slightly acidic, and where access to nutrients is limited.

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection.

Foamy macrophages from tuberculous patients' granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence.

Tuberculosis (TB) is characterized by a tight interplay between Mycobacterium tuberculosis and host cells within granulomas. These cellular aggregates restrict bacterial spreading, but do not kill all the bacilli, which can persist for years. In-depth investigation of M.

Langhans giant cells from M. tuberculosis-induced human granulomas cannot mediate mycobacterial uptake.

Tuberculosis is characterized by a tight interplay between Mycobacterium tuberculosis (M. tb) and host cells within granulomas. These cellular aggregates restrain M.

Functional reconstitution of the HIV receptors CCR5 and CD4 in liposomes.

Reconstitution of membrane proteins allows their study in a membrane environment that can be manipulated at will. Because membrane proteins have diverse biophysical properties, reconstitution methods have so far been developed for individual proteins on an ad hoc basis. We developed a postinsertion reconstitution method for CCR5, a G protein coupled receptor, with seven transmembrane alpha helices and small ecto- and endodomains.

3-Formyl-1-butyl pyrophosphate A novel mycobacterial metabolite-activating human gammadelta T cells.

Most human blood gammadelta T cells react without major histocompatibility complex restriction to small phosphorylated nonpeptide antigens (phosphoantigens) that are abundantly produced by mycobacteria and several other microbial pathogens. Although isopentenyl pyrophosphate has been identified as a mycobacterial antigen for gammadelta T cells, the structure of several other stimulating compounds with bioactivities around 1000-fold higher than isopentenyl pyrophosphate remains to be elucidated. This paper describes the structural identification of 3-formyl-1-butyl-pyrophosphate as the core of several non-prenyl mycobacterial phosphoantigens bioactive at the nM range.

Regulation by cytokines (IL-12, IL-15, IL-4 and IL-10) of the Vgamma9Vdelta2 T cell response to mycobacterial phosphoantigens in responder and anergic HIV-infected persons.

Human Vgamma9Vdelta2 T cells contribute to immunity against intracellular pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decrease of peripheral Vgamma9Vdelta2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobacterium tuberculosis in 60% of patients. Because of alterations in the Th1/Th2 cytokine balance reported in HIV infection, we analyzed, at the single-cell level, the influence of exogenous IL-4, IL-10, IL-12 and IL-15 on the response to mycobacterial phosphoantigens of gammadelta T cells from HIV-infected patients and healthy donors.

Phosphoantigen activation induces surface translocation of intracellular CD94/NKG2A class I receptor on CD94- peripheral Vgamma9 Vdelta2 T cells but not on CD94- thymic or mature gammadelta T cell clones.

Most adult peripheral blood gammadelta T cells express Vgamma9/Vdelta2-encoded TCR that recognize a restricted set of nonpeptidic phosphorylated compounds, referred to as phosphoantigens. They also express various MHC class I-specific inhibitory receptors (IR), in particular CD94/ NKG2-A heterodimers, which participate in the fine tuning of their TCR-mediated activation threshold. Most mature Vgamma9/Vdelta2 T cells express surface CD94 receptors, unlike cord blood or thymus-derived Vgamma9/Vdelta2 clones, thus suggesting a role for the microenvironment in IR expression.

Expansion of Vgamma9 Vdelta2 T cells is triggered by Francisella tularensis-derived phosphoantigens in tularemia but not after tularemia vaccination.

Tularemia is a disease caused by the facultative intracellular bacterium Francisella tularensis. Here we demonstrate that during the first weeks of infection, a significant increase in levels of Vgamma9 Vdelta2 cells occurred in peripheral blood: in 13 patients analyzed 7 to 18 days after the onset of disease, these lymphocytes represented, on average, 30.5% of CD3+ cells and nearly 100% of gammadelta+ T cells.