Biology subjects

Martin, M. C.

Publications and source records attributed to Martin, M. C..

5 recordsLinked to original sources

bioRxiv2026

Genetic background determines allele-specific Pfkelch13-mediated artemisinin tolerance and persistence in Plasmodium falciparum

Artemisinin-based combination therapies are the frontline treatment for Plasmodium falciparum malaria, but their efficacy is threatened by Artemisinin partial resistance (ARTR). ARTR in Plasmodium falciparum is mediated by Pfkelch13 (k13) mutations but remains rare in West Africa. A critical question is whether short-term drug survival intrinsically predicts long-term evolutionary persistence. Here, using CRISPR-Cas9 editing, and nanopore-assisted allele tracking in a contemporary Senegalese isolate, we evaluated ARTR receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ARTR survival and drug-free persistence are biologically separable traits. While the WHO-validated Asian I543T mutation conferred the RSA phenotype, it was rapidly counter-selected during drug-free growth. In contrast, emerging African alleles (R561H, M579I) and a regional novel variant (C473S) establish stable resistance without a competitive penalty. These findings reveal that a parasite's genetic background acts as a strict evolutionary filter, uncoupling short-term tolerance from long-term persistence and establishing that genomic context determines allele-specific resistance trajectories.

microbiology↗

bioRxiv2026

Hailey-Hailey disease models identify synergistic therapeutic effects of MEK and ROCK inhibition

Hailey-Hailey disease (HHD) is a genetic skin blistering disorder lacking approved treatments despite linkage to ATP2C1 variants 25 years ago. Since knockout mice did not replicate HHD, we ablated ATP2C1 in human keratinocytes or chemically inhibited its encoded Golgi calcium pump SPCA1. In organotypic epidermis, SPCA1 deficiency or inhibition reproduced HHD pathology, disrupting desmosomal cadherins and severing cell-cell junctions, termed acantholysis. RNA sequencing of heterozygous cells identified dysregulation of actin and Rho GTPases along with EGF receptor signaling as potential pathogenic drivers. Accordingly, SPCA1-depleted organotypic epidermis and HHD biopsies exhibited cortical actin disorganization and hyper-phosphorylation of the Rho kinase (ROCK) target, myosin light chain. Rho activation was sufficient to induce acantholysis, while ROCK inhibition partially restored heterozygous keratinocyte cohesion. A fluorescent biosensor demonstrated ERK hyper-activation in heterozygous cells along with desmosomal cadherin mis-localization. Importantly, treating SPCA1-deficient keratinocyte sheets with MEK and ROCK inhibitors together fully restored their integrity. Our results show HHD blistering is driven by desmosome and cortical actin dysfunction that was mitigated by targeting MEK and ROCK with repurposed drugs, offering a viable treatment strategy. Moreover, our model provides a blueprint for replicating genetic epidermal disorders to delineate pathogenic mechanisms and vet therapeutics for other orphan skin diseases. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/726679v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@b2de6aorg.highwire.dtl.DTLVardef@128411borg.highwire.dtl.DTLVardef@1ca760forg.highwire.dtl.DTLVardef@10cd6c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Cellular and molecular basis of PfCoronin function in artemisinin resistance in Plasmodium falciparum

Artemisinin-based therapies are central to malaria treatment, but their efficacy is threatened by the emergence of resistant Plasmodium falciparum strains. While the role of Pfkelch13 mutations in clinical resistance is well established, recent reports from Africa implicate Pfcoronin mutations in treatment failure, adding to the complexity of resistance mechanisms. Here, we show that PfCoronin, a non-essential actin regulator active during the ring-stage, facilitates efficient hemoglobin uptake. We demonstrate that resistance-associated Pfcoronin mutations disrupt PfCoronins interaction with PfActin and its ring-stage localization, leading to impaired endocytosis and reduced hemoglobin acquisition. PfCoronin and PfKelch13 function in distinct cellular regions; mutations in both converge to limit heme availability and artemisinin activation. Although PfCoronin is dispensable for parasite viability, our findings demonstrate that Pfcoronin mutations reduce endocytosis and modulate artemisinin susceptibility during the clinically relevant ring stage--highlighting how non-essential, temporally restricted proteins can shape antimalarial drug response and resistance.

cell biology↗

bioRxiv2023

Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake

Artemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations in Pfcoronin and Pfkelch13. Here, we describe the mechanism of Pfcoronin-mediated ART resistance. PfCoronin interacts with PfActin and localizes to the parasite plasma membrane (PPM), the digestive vacuole (DV) membrane, and membrane of a newly identified preDV compartment--all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV. Pfcoronin mutations alter PfActin homeostasis and impair the development and morphology of the preDV. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stage Plasmodium falciparum. Previous work has identified decreased hemoglobin uptake as the mechanism of Pfkelch13-mediated ART resistance. This work demonstrates that PfCoronin appears to act via a parallel pathway. For both Pfkelch13-mediated and Pfcoronin-mediated ART resistance, we hypothesize that the decreased hemoglobin uptake in ring stage parasites results in less heme-based activation of the artemisinin endoperoxide ring and reduced cytocidal activity. This study deepens our understanding of ART resistance, as well as hemoglobin uptake and development of the DV in early-stage parasites.

cell biology↗

bioRxiv2020

Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a "Dont burn down the house" strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.

microbiology↗