Botrytis cinerea is a necrotrophic fungal pathogen causing disease in many plant species, leading to economically important crop losses. So far, fungicides have been widely used to control this ...pathogen. However, in addition to their detrimental effects on the environment and potential risks for human health, increasing fungicide resistance has been observed in the B. cinerea population. Biological control, that is the application of microbial organisms to reduce disease, has gained importance as an alternative or complementary approach to fungicides. In this respect, the genus Trichoderma constitutes a promising pool of organisms with potential for B. cinerea control. In the first part of this article, we review the specific mechanisms involved in the direct interaction between the two fungi, including mycoparasitism, the production of antimicrobial compounds and enzymes (collectively called antagonism), and competition for nutrients and space. In addition, biocontrol has also been observed when Trichoderma is physically separated from the pathogen, thus implying an indirect systemic plant defence response. Therefore, in the second part, we describe the consecutive steps leading to induced systemic resistance (ISR), starting with the initial Trichoderma–plant interaction and followed by the activation of downstream signal transduction pathways and, ultimately, the defence response resulting in ISR (ISR‐prime phase). Finally, we discuss the ISR‐boost phase, representing the effect of ISR priming by Trichoderma spp. on plant responses after additional challenge with B. cinerea.
We investigated the cellular mechanisms responsible for the occurrence of miconazole-tolerant persisters in Candida albicans biofilms. Miconazole induced about 30% killing of sessile C. albicans ...cells at 75 µM. The fraction of miconazole-tolerant persisters, i.e., cells that can survive high doses of miconazole (0.6 to 2.4 mM), in these biofilms was 1 to 2%. Since miconazole induces reactive oxygen species (ROS) in sessile C. albicans cells, we focused on a role for superoxide dismutases (Sods) in persistence and found the expression of Sod-encoding genes in sessile C. albicans cells induced by miconazole compared to the expression levels in untreated sessile C. albicans cells. Moreover, addition of the superoxide dismutase inhibitor N,N'-diethyldithiocarbamate (DDC) to C. albicans biofilms resulted in an 18-fold reduction of the miconazole-tolerant persister fraction and in increased endogenous ROS levels in these cells. Treatment of biofilms of C. albicans clinical isolates with DDC resulted in an 18-fold to more than 200-fold reduction of their miconazole-tolerant persister fraction. To further confirm the important role for Sods in C. albicans biofilm persistence, we used a Δsod4 Δsod5 mutant lacking Sods 4 and 5. Biofilms of the Δsod4 Δsod5 mutant contained at least 3-fold less of the miconazole-tolerant persisters and had increased ROS levels compared to biofilms of the isogenic wild type (WT). In conclusion, the occurrence of miconazole-tolerant persisters in C. albicans biofilms is linked to the ROS-detoxifying activity of Sods. Moreover, Sod inhibitors can be used to potentiate the activity of miconazole against C. albicans biofilms.
This manuscript presents the quantification and correlation of three aspects of Alzheimer's Disease evolution, including structural, biochemical, and cognitive assessments. We aimed to test a novel ...structural biomarker for neurodegeneration based on a cortical folding model for mammals. Our central hypothesis is that the cortical folding variable, representative of axonal tension in white matter, is an optimal discriminator of pathological aging and correlates with altered loadings in Cerebrospinal Fluid samples and a decline in cognition and memory. We extracted morphological features from T1w 3T MRI acquisitions using FreeSurfer from 77 Healthy Controls (age = 66 ± 8.4, 69% females), 31 Mild Cognitive Impairment (age = 72 ± 4.8, 61% females), and 13 Alzheimer's Disease patients (age = 77 ± 6.1, 62% females) of recruited volunteers in Brazil to test its discriminative power using optimal cut-point analysis. Cortical folding distinguishes the groups with reasonable accuracy (Healthy Control-Alzheimer's Disease, accuracy = 0.82; Healthy Control-Mild Cognitive Impairment, accuracy = 0.56). Moreover, Cerebrospinal Fluid biomarkers (total Tau, AFormula: see text1-40, AFormula: see text1-42, and Lipoxin) and cognitive scores (Cognitive Index, Rey's Auditory Verbal Learning Test, Trail Making Test, Digit Span Backward) were correlated with the global neurodegeneration in MRI aiming to describe health, disease, and the transition between the two states using morphology.
•Root defense responses are less well studied than those in leaves.•Root and leaf defense responses share many similarities as well as differences.•Roots possess specialized structures as part of ...their defense response.•The availability of plant and fungal genomes makes it an exciting era to study root responses.
Diseases caused by soil-borne pathogens result worldwide in significant yield losses in economically important crops. In contrast to foliar diseases, relatively little is known about the nature of root defenses against these pathogens. This review summarizes the current knowledge on root infection strategies, root-specific preformed barriers, pathogen recognition, and defense signaling. Studies reviewed here suggest that many commonalities as well as differences exist in defense strategies employed by roots and foliar tissues during pathogen attack. Importantly, in addition to pathogens, plant roots interact with a plethora of non-pathogenic and symbiotic microorganisms. Therefore, a good understanding of how plant roots interact with the microbiome would be particularly important to engineer resistance to root pathogens without negatively altering root-beneficial microbe interactions.
Defensins are small basic amphiphilic peptides (up to 5 kDa) that have been shown to be important effector molecules of the innate immune system of animals, plants and fungi. In addition to immune ...modulatory functions, they have potent direct antimicrobial activity against a broad spectrum of bacteria, fungi and/or viruses, which makes them promising lead compounds for the development of next-generation antiinfectives. The mode of antibiotic action of defensins was long thought to result from electrostatic interaction between the positively charged defensins and negatively charged microbial membranes, followed by unspecific membrane permeabilization or pore-formation. Microbial membranes are more negatively charged than human membranes, which may explain to some extent the specificity of defensin action against microbes and associated low toxicity for the host. However, research during the past decade has demonstrated that defensin activities can be much more targeted and that microbe-specific lipid receptors are involved in the killing activity of various defensins. In this respect, human, fungal and invertebrate defensins have been shown to bind to and sequester the bacterial cell wall building block lipid II, thereby specifically inhibiting cell wall biosynthesis. Moreover, plant and insect defensins were found to interact with fungal sphingolipid receptors, resulting in fungal cell death. This review summarizes the current knowledge on the mode of action and structure of defensins from different kingdoms, with specific emphasis on their interaction with microbial lipid receptors.
Coronavirus disease 2019 (COVID-19) is a major public health challenge, and the current antiviral arsenal for treatment is limited, with questionable efficacy. Major efforts are under way for ...discovery of new effective agents, but the validation of new potential treatments for COVID-19 may take a long time. Therefore, the repurposing of existing drugs for new indications is needed. In this article, we argue for the potential benefits of using doxycycline with either hydroxycholoroquine or other putative agents for COVID-19 treatment, as doxycycline has antiviral and anti-inflammatory activities by dampening the cytokine storm and to prevent lung damage.
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide ...association studies point out several genetic variants-
, and
-potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish
and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
Transcription regulation by steroid hormones and other metabolites is mediated by nuclear receptors (NRs) such as the vitamin D and retinoid X receptors (VDR and RXR). Here, we present the cryo ...electron microscopy (cryo‐EM) structure of the heterodimeric complex of the liganded human RXR and VDR bound to a consensus DNA response element forming a direct repeat (DR3). The cryo‐EM map of the 100‐kDa complex allows positioning the individual crystal structures of ligand‐ and DNA‐binding domains (LBDs and DBDs). The LBDs are arranged perpendicular to the DNA and are located asymmetrically at the DNA 5′‐end of the response element. The structure reveals that the VDR N‐terminal A/B domain is located close to the DNA. The hinges of both VDR and RXR are fully visible and hold the complex in an open conformation in which co‐regulators can bind. The asymmetric topology of the complex provides the structural basis for RXR being an adaptive partner within NR heterodimers, while the specific helical structure of VDR's hinge connects the 3′‐bound DBD with the 5′‐bound LBD and thereby serves as a conserved linker of defined length sensitive to mutational deletion.
The first cryo‐EM structure of the complete DNA‐bound retinoid X receptor (RXR)/vitamin D receptor (VDR) heterodimer, one of the smallest complexes studied with this technique, provides insight into cooperative DNA binding of a key representative of the nuclear receptor family of transcription factors.
Plant defensins are small, cationic peptides with a highly conserved 3D structure. They have been studied extensively in the past decades. Various biological activities have been attributed to plant ...defensins, such as anti-insect and antimicrobial activities, but they are also known to affect ion channels and display antitumor activity. This review focuses on the structure, biological activity and antifungal mode of action of some well-characterized plant defensins, with particular attention to their fungal membrane target(s), their induced cell death mechanisms as well as their antibiofilm activity. As plant defensins are, in general, not toxic to human cells, show in vivo efficacy and have low frequencies of resistance occurrence, they are of particular interest in the fight against fungal infections.
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