Main conclusionProvides a first comprehensive review of integrated physiological and molecular aspects of desiccation toleranceXerophyta viscosa. A synopsis of biotechnological studies being undertaken to improve drought tolerance in maize is given.Xerophyta viscosa (Baker) is a monocotyledonous resurrection plant from the family Vellociacea that occurs in summer-rainfall areas of South Africa, Lesotho and Swaziland. It inhabits rocky terrain in exposed grasslands and frequently experiences periods of water deficit. Being a resurrection plant it tolerates the loss of 95 % of total cellular water, regaining full metabolic competency within 3 days of rehydration. In this paper, we review some of the molecular and physiological adaptations that occur during various stages of dehydration of X. viscosa, these being functionally grouped into early and late responses, which might be relevant to the attainment of desiccation tolerance. During early drying (to 55 % RWC) photosynthesis is shut down, there is increased presence and activity of housekeeping antioxidants and a redirection of metabolism to the increased formation of sucrose and raffinose family oligosaccharides. Other metabolic shifts suggest water replacement in vacuoles proposed to facilitate mechanical stabilization. Some regulatory processes observed include increased presence of a linker histone H1 variant, a Type 2C protein phosphatase, a calmodulin- and an ERD15-like protein. During the late stages of drying (to 10 % RWC) there was increased expression of several proteins involved in signal transduction, and retroelements speculated to be instrumental in gene silencing. There was induction of antioxidants not typically found in desiccation-sensitive systems, classical stress-associated proteins (HSP and LEAs), proteins involved in structural stabilization and those associated with changes in various metabolite pools during drying. Metabolites accumulated in this stage are proposed, inter alia, to facilitate subcellular stabilization by vitrification process which can include glass- and ionic liquid formation.
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against
Mycobacterium tuberculosis
through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg
2+
-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones.
Tuberculosis is the leading infectious cause of death worldwide, and HIV-1 the best recognized risk factor for active TB. This review focuses on immune complex formation; the interplay of type I and II interferon signaling; and T cell activation in HIV-TB pathogenesis. Recent findings Circulating immune complexes and complement, and Fc signaling in whole blood act as early markers of TB disease in HIV-1 infected persons. HIV-1 is associated with a type I interferon response in whole blood, reducing the specificity of TB biomarkers dependent on type I and II interferon genes. Type I and type II interferons are implicated in both protection and TB pathology, a protective outcome may depend on modulating these pathways. Whilst Mtb-specific CD4 T cells are preferentially depleted during HIV-1 infection, activation markers on Mtb-specific CD4 T cells, in particular HLA-DR, reflect immune activation and have promise as biomarkers of Mtb disease activity in individuals with HIV-1. Summary TB pathogenesis in HIV-1 involves a complex interaction of underlying activation of both the innate and adaptive immune systems. Further research is required to understand whether biomarkers of activation could be used to predict or quantify TB disease in the context of HIV-1 infection.
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores the importance of a continuous pipeline of new anti-TB agents. From recent studies, it is evident that the increase in drug efficacy is being achieved through re-engineering old TB-drug families and repurposing known drugs. This approach has led to producing a newer class of compounds which not only saves time and investment in developing newer drugs but is also effective in identifying drug candidates with novel mechanisms to treat multi-drug resistant strains. The repurposed drugs moxifloxacin, linezolid, and clofazimine are used to treat extensively drug-resistant TB when first- and/or second-line drugs fail. The chapter covers a detailed background on the current status of the repurposed drugs in the TB drug-discovery pipeline and discusses a potential way forward.
Macrophages provide a first line of defense against invading pathogens, including the leading cause of bacterial mortality, Mycobacterium tuberculosis (Mtb). Phagocytosing extracellular organisms mediate pathogen clearance via a multitude of antimicrobial mechanisms, uniquely designed against an array of pathogens. Macrophages are able to execute different programs of activation in response to pathogenic challenge with host mediators, polarizing them to a variety of differentiation states, including the pro-inflammatory M1 and anti-inflammatory M2 states. The functional polarization of a macrophage prior to infection, thus impacts the outcome of host-pathogen interaction. One of the limitations when using in vitro differentiated human primary monocyte-derived macrophages (MDMs) is the heterogeneous nature of the mature population, which presents a challenge for quantitative characterization of various host-pathogen processes. Here, we describe an approach to minimize this heterogeneity, based on micropatterning of cells to reintroduce aspects of cellular homogeneity lost in a 2D tissue culture. Micropatterning consists of growing cells at the single cell level on microfabricated patterns, to constrain the size and shape of the cell, reducing cell-to-cell variation and mimicking the physiological spatial confinement that cells experience in tissues. We infected micropatterned GM-CSF- (M1) and M-CSF- (M2) derived human MDMs with Mtb, which allowed us to study host-pathogen interactions at a single cell level, at high resolution and in a quantitative manner, across tens to hundreds of cells in parallel. Using our approach, we were able to quantify phagocytosis of Mtb in MDMs, finding phagocytic contraction is increased by interferon-gamma stimulation, whilst contraction and bacterial uptake is decreased following silencing of phagocytosis regulator NHLRC2 or Tween80 removal of bacterial surface lipids. We also identify alterations in host organelle position within Mtb infected MDMs, as well as identifying differences in Mtb subcellular localization in relation to the microtubule organizing center (MTOC) and in line with the cellular polarity in M1 and M2 MDMs. Our approach described here can be adapted to study other host-pathogen interactions and co-infections in MDMs and can be coupled with downstream automated analytical approaches.
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