Biology subjects

Porter, S. S.

Publications and source records attributed to Porter, S. S..

3 recordsLinked to original sources

bioRxiv2026

A High-Content Pseudotime Framework for Morphological Profiling of Dengue Virus Inhibitors from a Drug-Repurposing Library

Dengue virus (DENV) causes dengue fever, a globally prevalent, epidemic-prone disease with no FDA-approved antivirals. Additionally, the available vaccine for DENV can increase the risk of severe dengue fever for those who have never had a DENV infection due to antibody-dependent enhancement. Thus, there is an urgent need to identify DENV antivirals. Drug repurposing, high-content screening, and machine learning were leveraged to efficiently identify antivirals likely to inhibit DENV replication. Using high-content screening in a DENV infection model, we characterized the morphological patterns of NS4B and envelope (E) protein expression over time and developed a viral pseudotime model that predicts infection progression to aid in phenotypic interpretation of drug effects. We then developed a single cell infection classifier for antiviral efficacy and performed high-throughput drug screening of 960 compounds. We identified four concentration-dependent inhibitors of DENV with nanomolar-to-submicromolar potencies: esomeprazole, GW4064, pralatrexate, and LY411575. With our pseudotime machine learning model trained on data from the time-series assay, we scored the concentration-dependent inhibitors to map their mechanism of action onto time points in the viral life cycle. Our most notable results show that LY411575, a gamma secretase inhibitor, exhibited an IC of 72 nM and reduced percent infection to near the level of the mock infection control. Pseudotime inferences generated mechanistic predictions that were supported by time-of-addition experiments, indicating that LY411575 arrests DENV infection before the development of late-stage infection associated morphologies, while retaining activity when added after inoculation.

cell biology↗

bioRxiv2025

The evolutionary genomics of incipient endosymbiosis in wild rhizobia bacteria

The advent of endosymbiosis underlies evolutionary innovation and ecosystem function. However, whether free-living partners tend to benefit or exploit each other during incipient endosymbiosis remains a dilemma. Rhizobia bacteria are plant endosymbionts capable of initiating root nodules and fixing nitrogen due to genes carried on mobile genetic elements (MGEs) such as the symbiosis island (SI). We conjugated marked SIs into the genomes of nonnodulating strains, which was sufficient to generate de novo root nodule-forming endosymbionts. Most novel endosymbionts originated as commensals that incurred no detectable costs to host plants, in contrast to predictions of exploitation. In fact, a third of endosymbionts originated as nitrogen fixing mutualists. Consistent with phylogenetic limits to transfer of MGE function, novel endosymbionts derived from more closely related SI donor and recipient strains showed greater nitrogen fixation. However, we did not detect phylogenetic limits to SI transmission, which could reflect selfish selection for generalized horizontal transfer of this MGE. In fact, the SI was able to displace other genomic elements residing at its characteristic tRNA gene insertion site. We thus provide genetic, genomic, and functional evidence of how MGEs can potentiate and constrain major evolutionary transitions to expand bacterial niches, with cascading effects on host organisms.

evolutionary biology↗

bioRxiv2025

Mobile genetic elements shape the evolution of wild bacterial pangenomes in the face of biotic and abiotic selective pressures in the soil

Mobile genetic elements (MGEs) provide a critical reservoir of diversity that potentiates bacterial local adaptation. However, the degree to which natural populations of MGEs and the chromosomes that host them share congruent or divergent evolutionary histories remains an open question. MGE and host chromosome phylogenies could show congruence or independence, depending on rates of MGE gain and loss, costs and benefit of MGE carriage, compatibility, and gene flow. We investigated phylogenetic congruence for two critical niche-expanding MGEs and host chromosomes using 302 genomes of wild symbiotic nitrogen-fixing Mesorhizobium bacteria. The MGEs comprise: 1) a nickel resistance island (NRI), which confers adaptation to nickel-enriched serpentine soils across replicated natural populations, and 2) a more extensive symbiosis island (SI), which enables symbiotic nitrogen fixation with a host legume. We demonstrate that the NRI, like the SI, is transmissible and its acquisition confers nickel adaptation. NRI acquisition often incurs no detectable cost, consistent with conditional neutrality during MGE-mediated adaptation. Phylogenies for the NRI, SI, and chromosome are congruent across wild strains, consistent with a history of vertical co-inheritance and/or MGE transmission primarily among close relatives. This congruence does not appear to result from barriers to gene flow, as diverse MGE and host chromosome haplotypes are broadly distributed and co-occur. Thus, despite ample ecological opportunity for admixture, distant relatives rarely transmitted MGEs, consistent with selection to maintain co-adapted genomic compartments. The SI has stronger phylogenetic congruence with the chromosome than does the smaller NRI, supporting the hypothesis that MGE complexity limits horizontal transfer among more divergent lineages. However, rare horizontal NRI transmission events among distant relatives and NRI loss appear to occur when haplotypes migrate across environments. Thus, environmentally dependent selection on migrants may periodically disrupt co-adapted MGE and chromosome haplotypes and serve as an engine of diversity.

evolutionary biology↗