Biology subjects

Miller, K. A.

Publications and source records attributed to Miller, K. A..

6 recordsLinked to original sources

bioRxiv2026

Sulforaphane targets Leishmania promastigotes to inhibit parasite motility and alters host autophagy to suppress parasite replication in macrophages

Visceral leishmaniasis (VL) is a neglected tropical disease caused by the protozoan parasites Leishmania infantum (LI) and Leishmania donovani (LD). VL disproportionately affects populations that live in extreme poverty and those affected by climate change. Treatment options are limited, fiscally prohibitive, and toxic to some that receive treatment. In cases where VL remains untreated, death is inevitable. Although disease prevalence is increasing in affluent countries with robust research capabilities, there remains little economic incentive to search for new, more accessible non-toxic treatments, emphasizing the neglected tropical aspect of this disease. Our previous results indicate that sulforaphane (SFN) inhibits VL promastigote and amastigote growth through an unknown mechanism. The current study extends the anti-parasitic effects of SFN establishing SFN's efficacy against multiple Leishmania parasites including L. tropica, L. mexicana, L. panamensis and L. amazonesis. Moreover, SFN was an effective therapy post-infection as stably infected macrophages treated with SFN (10 M for 48 hours) had a significant reduction in the number of infected cells and the number of amastigotes per cell against Leishmania species that cause both VL and cutaneous leishmaniasis (CL). Moreover, SFN led to a reduction of motility within 6 hours of treatment indicating a direct interaction with the parasite. Alkynyl SFN (A-SFN) was subsequently synthesized to determine the specific binding target of SFN. Interestingly, A-SFN was more effective than SFN in decreasing parasite viability and inhibiting motility against VL and CL parasite species at equivalent concentrations. Immunofluorescence analysis utilizing click chemistry indicated A-SFN binds to cytosolic promastigote components and colocalized only minimally with KMP-11. The binding of SFN to KMP-11 could not be confirmed in vitro. In terms of intracellular host effects, SFN treatment increased the induction of nonselective macroautophagy by increased lysosomal acidification as quantified by DALGreen and FITC-dextran staining in infected macrophages. The induction of autophagy occurred simultaneously with the upregulation of expression of cytoprotective, antioxidant and autophagy-related genes via the NRF2 transcription factor. These data provide robust evidence that SFN is an excellent lead compound against Leishmania that initiates multiple innate immune pathways that enable enhanced parasite killing. Future studies will focus on the in vivo efficacy of SFN against CL.

microbiology↗

bioRxiv2026

The genomic basis of evolutionary stasis in the 500-million-year-old red seaweed genus Ahnfeltia

The red seaweed genus Ahnfeltia is an ancient lineage that has persisted for over 500 million years with remarkably limited diversification despite a global distribution in cold-temperate intertidal habitats. Compared to the highly diverse sister lineage, Rhodymeniophycidae, Ahnfeltia provides a unique system for investigating long-term evolutionary persistence in marine macroalgae. Here, we generated chromosome-scale genomes from five populations across three species and combined population genomics with paleogeographic niche modelling. Our results reveal remarkable genomic conservation, strong geographic isolation with limited gene flow, high homozygosity, and evidence of purifying selection. Niche projections indicate long-term stability and spatial connectivity of suitable cold-temperate habitats. These findings suggest that Ahnfeltias persistence and limited diversification are linked to genomic constraints and stable ecological niches over geological timescales. This study provides new insights into the genomic basis of evolutionary stasis in ancient marine lineages and highlights potential vulnerability to ongoing climate change affecting cold-water coastal ecosystems.

evolutionary biology↗

bioRxiv2025

Vibrio cholerae interaction with predatory bacteria on chitin suggests an alternative mode of biofilm formation in marine snow conditions

Vibrio cholerae is a ubiquitous marine microbe that solubilizes and consumes chitin in the marine water column. In both the marine environment and the intestinal track, V. cholerae forms biofilms; a key question regarding the lifestyle of V. cholerae is how do the diverse substrates that it encounters influence its biofilm formation and, in turn, shape its ecological interactions. Here, we use the predator-prey interaction between Bdellovibrio bacteriovorus and V. cholerae as a model to explore how the environmental chitin substrate alters V. cholerae biofilm formation and predator-prey interactions. We find that glass-bound biofilms provide strong protection for V. cholerae against predation while also allowing a population of predatory B. bacteriovorus to remain in place. In contrast, chitin-bound biofilms offer less protection against B. bacteriovorus predation and do not maintain a stable population of B. bacteriovorus. Using percolation and population dynamics models, we predict that these changes in predator-prey dynamics can be mostly explained by alterations in biofilm architecture between the two conditions, which changes the fraction of prey available to B. bacteriovorus. Performing targeted biofilm matrix deletions, we confirm this prediction by recapitulating key features of the chitin predator-prey interactions on glass surfaces. Following on this observation, we show that V. cholerae biofilms grown on chitin produce much less of the canonical biofilm matrix components and instead rely on other extracellular structures. Overall, our experiments detail how growth substrate can alter biofilm matrix composition and how these changes in biofilm architecture and cellular arrangement can impact higher-order ecological interactions.

microbiology↗

bioRxiv2022

SIRT-1 connects autophagy and release of virus-containing vesicles during picornavirus infection

Enterovirus D68 is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we show that the histone deacetylase, SIRT-1, is essential for autophagy and EV-D68 infection. Knockdown of SIRT-1 inhibits autophagy and reduces EV-D68 extracellular titers. The proviral activity of SIRT-1 does not require its deacetylase activity or functional autophagy. SIRT-1s proviral activity is, we demonstrate, mediated through the repression of ER stress. Inducing ER stress through thapsigargin treatment or SERCA2A knockdown in SIRT-1 knockdown cells had no additional effect on EV-D68 extracellular titers. Knockdown of SIRT-1 also decreases poliovirus and SARS-CoV-2 titers but not coxsackievirus B3. In non-lytic conditions, EV-D68 is primarily released in an enveloped form, and SIRT-1 is required for this process. Our data show that SIRT-1, through its translocation to the cytosol, is critical to promote the release of enveloped EV-D68 viral particles.

microbiology↗

bioRxiv2021

Cytosolic Sensor of Bacterial Lipopolysaccharide in Human Macrophages

Endotoxin - bacterial lipopolysaccharide (LPS) - is a driver of the lethal infection sepsis through activation of innate immune responses. When delivered to the cytosol of macrophages, LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has been doubted by many investigators, as caspases-4, -5, and -11 bind and activate LPS directly in vitro. Here we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS required for efficient activation of the caspase-4 inflammasome in human macrophages. NLRP11 is present in humans and other primates, but absent in mice, likely explaining why it has been missed in screens looking for innate immune signaling molecules, most of which have been carried out in mice. NLRP11 is a previously missing link and a component of the human caspase-4 inflammasome activation pathway. One Sentence SummaryDiscovery that human macrophages contain a cytosolic receptor for bacterial lipopolysaccharide.

microbiology↗

bioRxiv2019

Nervous System and Tissue Polarity Dynamically Adapt to New Morphologies in Planaria

The coordination of tissue-level polarity with organism-level polarity is crucial in development, disease, and regeneration. Exploiting the flexibility of the body plan in regenerating planarians, we used mirror duplication of the primary axis to show how established tissue-level polarity adapts to new organism-level polarity. Tracking of cilia-driven flow to characterize planar cell polarity of the epithelium revealed a remarkable reorientation of tissue polarity in double-headed planarians. This reorientation is driven by signals produced by the intact brain and is not hampered by radiation-induced removal of stem cells. The nervous system itself adapts its polarity to match the new organismal anatomy in these animals as revealed by distinct regenerative outcomes driven by polarized nerve transport. Thus, signals from the central nervous system can dynamically control and re-orient tissue-level polarity to match the organism-level anatomical configuration, illustrating a novel role of the nervous system in the regulation of patterning.

physiology↗