Dad. Scientist. Interested in how Cryptosoridium tricks its host cells!
Sebastian Shaw
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I would like to thank all co-authors, especially Gracyn who was a major driving force of this project!
@striepenlab.bsky.social @francoismayer.bsky.social @parasitesrule.org
Different C. parvum strains do not respond equally to clofazimine.
That difference gave us a way to genetically map resistance.
So… what does it clofazimean?
NDH2 heterogeneity may act as a metabolic rheostat, enhancing parasite adaptability.
Host diet, metabolism, microbiome, and immune pressure likely reshape parasite redox balance and drive allele dynamics.
Knocking out ndh2 caused high-level clofazimine resistance, and recombinant CpNDH2 directly reduced clofazimine.
In other words: NDH2 helps activate clofazimine, and losing NDH2 helps the parasite escape.
Bulk segregant analysis pointed to one sharp locus on chromosome 7.
At that locus we found ndh2, encoding type II NAD(P)H dehydrogenase. A small 2-bp deletion near the start of the gene became enriched under drug pressure.
The most surprising part: this resistance-associated ΔAA ndh2 allele is already widespread in C. parvum and C. hominis populations.
So Cryptosporidium may carry pre-existing genetic heterogeneity that lets it rapidly adjust under drug pressure.
We crossed a clofazimine-resistant strain with a susceptible one, selected recombinant progeny in mice, then treated with clofazimine.
The treatment suppressed parasite growth, but the infection rebounded. The surviving progeny became more resistant.
Excited to share our new paper, co-led by Gracyn Buenconsejo and me.
Why did a promising anti-#Cryptosporidium drug fail?
We asked whether the parasite itself might already be genetically prepared to escape treatment.
doi.org/10.1038/s415...
#Clofazimine #forwardgenetics
Sebastian Shaw
Sebastian Shaw
Sebastian Shaw
Forward and reverse genetics identifies the mode of action of clofazimine in the parasite Cryptosporidium. The genomic locus encoding the target is heterogeneous, and a resistance-conferring allele is...
