Biology subjects

Sutton, M.

Publications and source records attributed to Sutton, M..

3 recordsLinked to original sources

bioRxiv2023

Variability in the phytoplankton response to upwelling across an iron limitation mosaic within the California Current System

Coastal upwelling currents such as the California Current System (CCS) comprise some of the most productive biological systems on the planet. Diatoms, a distinct taxon of phytoplankton, dominate these upwelling events in part due to their rapid response to nutrient entrainment. In this region, they may also be limited by the micronutrient iron (Fe), an important trace element primarily involved in photosynthesis and nitrogen assimilation. The mechanisms behind how diatoms physiologically acclimate to the different stages of the upwelling conveyor belt cycle with respect to Fe limitation remains largely uncharacterized. Here, we explore their physiological and metatranscriptomic response to the upwelling cycle with respect to the Fe limitation mosaic that exists in the CCS. Subsurface, natural plankton assemblages that would potentially seed surface blooms were examined over wide and narrow shelf regions. The initial biomass and physiological state of the phytoplankton community had a large impact on the overall response to simulated upwelling. Following on-deck incubation under varying Fe physiological states, our results suggest that diatoms quickly dominated the blooms by "frontloading" nitrogen assimilation genes prior to upwelling. However, diatoms subjected to induced Fe limitation exhibited reductions in carbon and nitrogen uptake and decreasing biomass accumulation. Simultaneously, they exhibited a distinct gene expression response which included increased expression of Fe-starvation induced proteins and decreased expression of nitrogen assimilation and photosynthesis genes. These findings may have significant implications for upwelling events in future oceans, where changes in ocean conditions are projected to amplify the gradient of Fe limitation in coastal upwelling regions.

plant biology↗

bioRxiv2023

Protective intravenous BCG vaccination induces enhanced immune signaling in the airways

Intradermal (ID) Bacillus Calmette-Guerin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis (Mtb) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF- signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-{gamma} response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge.

immunology↗

bioRxiv2022

The First Inhibitor of Meso-Diaminopimelate Biosynthesis with Antibacterial Activity Against Multi-Drug Resistant Bacteria

Antibiotic resistance represents one of the biggest threats to global health. While several of our current antibiotics target the peptidoglycan within the bacterial cell wall, only a fraction of its components has been explored for antibiotic development. A component that remains under-exploited is meso-diaminopimelate (meso-DAP), a constituent of the cross-linking peptide in Gram-negative bacteria. In this study, we employed a high throughput chemical screen to identify the first inhibitor of meso-DAP biosynthesis with antibacterial activity. Indeed, the compound was shown to have minimum inhibitory concentration values of 8-16 g/mL against a panel of multi-drug resistant Acinetobacter baumannii strains, including those resistant to the last resort antibiotic carbapenem. Importantly, the compound targets the meso-DAP biosynthesis pathway specifically, with no off-target effects observed in human cell lines, and no resistance exhibited upon continuous treatment, under the conditions tested. Furthermore, we revealed for the first time that meso-DAP biosynthesis inhibition prevents biofilm formation and disrupts established biofilms in A. baumannii. Using a Galleria mellonella model, we showed that this compound improves survival rates against A. baumannii infection by up to 40% relative to the no treatment controls. Lastly, we determined that the inhibitor potentiates the activity of several antibiotic classes, including carbapenems. Thus, this study provides proof-of-concept that meso-DAP biosynthesis represents a promising target for the development of standalone antibacterial agents with a new mode of action as well as adjuvants to be used in combinatorial regimens to rejuvenate our current antibiotic arsenal to combat resistance. ImportanceResistance levels to available antibiotics continues to rise, with a growing number of Gram-negative bacterial infections, in particular A. baumannii infections, becoming life-threatening. Despite this, there have been no new classes of antibiotics against Gram-negative bacteria introduced to the market over the last 40 years. Hence, new targets and therapeutics are urgently required to combat these clinically important pathogens. One such target is meso-DAP, a critical component of the cross-linking peptides in the cell walls of Gram-negative bacteria. Here, we describe the first inhibitor of bacterial meso-DAP biosynthesis, with antibacterial activity against multi-drug resistant Gram-negative bacterial strains, including carbapenem-resistant A. baumannii. We also reveal that meso-DAP biosynthesis inhibition affects biofilm stability and potentiates the activity of several antibiotic classes. This study highlights the need to further explore meso-DAP biosynthesis and other unexploited targets in the search for antibiotics with new modes of action.

microbiology↗