Modeling CRISPR gene drives for suppression of invasive rodents using a supervised machine learning framework

Funding: This study was supported by funding from New Zealand’s Predator Free 2050 program under Predator Free 2050 Ltd. award SS/05/01 to PWM, and from National Institutes of Health award R01GM127418 to PWM. PG-D received funding from the New Zealand BioHeritage National Science Challenge (contract 1617-28-033 A to Manaaki Whenua – Landcare Research) and from Natural Environment Research Council grant NE/S011641/1 under the Newton Latam programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Resveratrol Demonstrates Antimicrobial Effects Against Propionibacterium acnes In Vitro

IntroductionResveratrol (3,5,4'-trihydroxystilbene) is an antioxidant that has multiple biologic effects including antimicrobial properties. Acne vulgaris is a disease of the pilosebaceous unit, characterized by an inflammatory host immune response to the bacteria Propionibacterium acnes (P. acnes). This study sought to determine whether resveratrol may be a potential treatment for acne vulgaris.MethodsColony-forming unit (CFU) assays together with transmission electron microscopy using P. acnes treated with resveratrol or benzoyl peroxide were used to assess antibacterial effects. Blood was drawn from healthy human volunteers, and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays were used to assess cytotoxicity in monocytes and keratinocytes.ResultsResveratrol demonstrated sustained antibacterial activity against P. acnes, whereas benzoyl peroxide, a commonly used antibacterial treatment for acne, demonstrated a short-term bactericidal response. A combination of resveratrol and benzoyl peroxide showed high initial antibacterial activity and sustained bacterial growth inhibition. Electron microscopy of P. acnes treated with resveratrol revealed altered bacterial morphology, with loss of membrane definition and loss of well-defined extracellular fimbrial structures. Resveratrol was less cytotoxic than benzoyl peroxide.ConclusionThe sustained antibacterial activity and reduced cytotoxicity versus benzoyl peroxide demonstrated by resveratrol in this study highlight its potential as a novel therapeutic option or adjuvant therapy in the treatment of acne vulgaris

Antimicrobial and anti-inflammatory activity of chitosan-alginate nanoparticles: a targeted therapy for cutaneous pathogens.

Advances in nanotechnology have demonstrated potential application of nanoparticles (NPs) for effective and targeted drug delivery. Here we investigated the antimicrobial and immunological properties and the feasibility of using NPs to deliver antimicrobial agents to treat a cutaneous pathogen. NPs synthesized with chitosan and alginate demonstrated a direct antimicrobial activity in vitro against Propionibacterium acnes, the bacterium linked to the pathogenesis of acne. By electron microscopy (EM) imaging, chitosan-alginate NPs were found to induce the disruption of the P. acnes cell membrane, providing a mechanism for the bactericidal effect. The chitosan-alginate NPs also exhibited anti-inflammatory properties as they inhibited P. acnes-induced inflammatory cytokine production in human monocytes and keratinocytes. Furthermore, benzoyl peroxide (BP), a commonly used antiacne drug, was effectively encapsulated in the chitosan-alginate NPs and demonstrated superior antimicrobial activity against P. acnes compared with BP alone while demonstrating less toxicity to eukaryotic cells. Together, these data suggest the potential utility of topical delivery of chitosan-alginate NP-encapsulated drug therapy for the treatment of dermatologic conditions with infectious and inflammatory components

Symbionts and gene drive: two strategies to combat vector-borne disease

Mosquitoes bring global health problems by transmitting parasites and viruses such as malaria and dengue. Unfortunately, current insecticide-based control strategies are only moderately effective because of high cost and resistance. Thus, scalable, sustainable, and cost-effective strategies are needed for mosquito-borne disease control. Symbiont-based and genome engineering-based approaches provide new tools that show promise for meeting these criteria, enabling modification or suppression approaches. Symbiotic bacteria like Wolbachia are maternally inherited and manipulate mosquito host reproduction to enhance their vertical transmission. Genome engineering-based gene drive methods, in which mosquitoes are genetically altered to spread drive alleles throughout wild populations, are also proving to be a potentially powerful approach in the laboratory. Here, we review the latest developments in both symbionts and gene drive-based methods. We describe some notable similarities, as well as distinctions and obstacles, relating to these promising technologies

Analysis of the surface, secreted, and intracellular proteome of Propionibacterium acnes

Propionibacterium acnes, plays an important role in acne vulgaris and other diseases. However, understanding of the exact mechanisms of P. acnes pathogenesis is limited. Few studies have investigated its proteome, which is essential for vaccine development. Here, we comprehensively investigate the proteome of P. acnes strain ATCC 6919, including secreted, cell wall, membrane, and cytosolic fractions in three types of growth media. A total of 531 proteins were quantified using an Orbitrap mass spectrometer and bioinformatically categorized for localization and function. Several, including PPA1939, a highly expressed surface and secreted protein, were identified as potential vaccine candidates. Keywords: Acne, Proteomics, Mass spectrometry, Cell wal

Proteomic Analysis of Pathogenic Fungi Reveals Highly Expressed Conserved Cell Wall Proteins

We are presenting a quantitative proteomics tally of the most commonly expressed conserved fungal proteins of the cytosol, the cell wall, and the secretome. It was our goal to identify fungi-typical proteins that do not share significant homology with human proteins. Such fungal proteins are of interest to the development of vaccines or drug targets. Protein samples were derived from 13 fungal species, cultured in rich or in minimal media; these included clinical isolates of Aspergillus, Candida, Mucor, Cryptococcus, and Coccidioides species. Proteomes were analyzed by quantitative MSE (Mass Spectrometry—Elevated Collision Energy). Several thousand proteins were identified and quantified in total across all fractions and culture conditions. The 42 most abundant proteins identified in fungal cell walls or supernatants shared no to very little homology with human proteins. In contrast, all but five of the 50 most abundant cytosolic proteins had human homologs with sequence identity averaging 59%. Proteomic comparisons of the secreted or surface localized fungal proteins highlighted conserved homologs of the Aspergillus fumigatus proteins 1,3-β-glucanosyltransferases (Bgt1, Gel1-4), Crf1, Ecm33, EglC, and others. The fact that Crf1 and Gel1 were previously shown to be promising vaccine candidates, underlines the value of the proteomics data presented here

Chitosan against cutaneous pathogens

Propionibacterium acnes and Staphylococcus aureus are cutaneous pathogens that have become increasingly resistant to antibiotics. We sought to determine if chitosan, a polymer of deacetylated chitin, could be used as a potential treatment against these bacteria. We found that higher molecular weight chitosan had superior antimicrobial properties compared to lower molecular weights, and that this activity occurred in a pH dependent manner. Electron and fluorescence microscopy revealed that chitosan forms aggregates and binds to the surface of bacteria, causing shrinkage of the bacterial membrane from the cell wall. Of special relevance, clinical isolates of P. acnes were vulnerable to chitosan, which could be combined with benzoyl peroxide for additive antibacterial effect. Chitosan also demonstrated significantly less cytotoxicity to monocytes than benzoyl peroxide. Overall, chitosan demonstrates many promising qualities for treatment of cutaneous pathogens

Chitosan against cutaneous pathogens.

Propionibacterium acnes and Staphylococcus aureus are cutaneous pathogens that have become increasingly resistant to antibiotics. We sought to determine if chitosan, a polymer of deacetylated chitin, could be used as a potential treatment against these bacteria. We found that higher molecular weight chitosan had superior antimicrobial properties compared to lower molecular weights, and that this activity occurred in a pH dependent manner. Electron and fluorescence microscopy revealed that chitosan forms aggregates and binds to the surface of bacteria, causing shrinkage of the bacterial membrane from the cell wall. Of special relevance, clinical isolates of P. acnes were vulnerable to chitosan, which could be combined with benzoyl peroxide for additive antibacterial effect. Chitosan also demonstrated significantly less cytotoxicity to monocytes than benzoyl peroxide. Overall, chitosan demonstrates many promising qualities for treatment of cutaneous pathogens

Different Propionibacterium acnes Phylotypes Induce Distinct Immune Responses and Express Unique Surface and Secreted Proteomes.

Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne vulgaris and other infections. Recent work revealed that P. acnes clinical isolates can be classified into distinct phylotypes, several of which have associations with healthy skin or acne. We sought to determine if these phylotypes induce different immunological responses and express protein factors that may contribute to their disease associations. We found that acne-associated P. acnes phylotypes induced 2- to 3-fold higher levels of IFN-γ and IL-17 in peripheral blood mononuclear cells compared with healthy phylotypes. On the other hand, P. acnes phylotypes associated with healthy skin induced 2- to 4-fold higher levels of IL-10. Comparative proteomic analysis of P. acnes phylotypes revealed a differential expression of several proteins, including an adhesion protein that was expressed at least 10-fold higher in acne-associated phylotypes and a cell surface hydrolase expressed in all phylotypes except those associated with healthy skin. Taken together, our data provide insight into how specific P. acnes phylotypes influence immune responses and the pathogenesis of acne