Pasqualato, S. | bioRxiv Science

bioRxiv2021

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for Covid19, indiscriminately suppress both responses, possibly impairing viral clearance, and provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces the macrophage response to SARS-CoV2 seen in patients and allows quantitation of inflammatory and antiviral activities. We show that the NFKB-dependent inflammatory response can be selectively inhibited by ablating the lysine-demethylase LSD1, which additionally unleashed interferon-independent ISG activation and blocked viral egress through the lysosomal pathway. These results provide a rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment. One-Sentence SummaryTargeting a chromatin-modifying enzyme in coronavirus infections curbs tissue-damage without affecting antiviral response

immunology↗

bioRxiv2020

Epistasis, aneuploidy, and gain-of-function mutations underlie the evolution ofresistance to induced microtubule depolymerization

Microtubules, polymers of alpha- and beta-tubulin, are essential cellular components. When microtubule polymerization is hindered, cells are delayed in mitosis, but eventually they manage to proliferate with massive chromosome missegregation. Several studies have analyzed the first cell division upon microtubules impairing conditions. Here, we asked how cells cope on the long term. Taking advantage of mutations in beta-tubulin, we evolved in the lab for [~]150 generations 24 populations of yeast cells unable to properly polymerize microtubules. At the end of the evolution experiment, cells re-gained the ability to form microtubules, and were less sensitive to microtubule depolymerizing drugs. Whole genome sequencing allowed us to identify genes recurrently mutated (tubulins and kinesins) as well as the pervasive duplication of chromosome VIII. We confirmed that mutations found in these genes and disomy of chromosome VIII allow cells to compensate for the original mutation in beta-tubulin. The mutations we identified were mostly gain-of-function, likely re-allowing the proper use of the mutated form of beta-tubulin. When we analyzed the temporal order of mutations leading to resistance in independent populations, we observed multiple times the same series of events: disomy of chromosome VIII followed by one additional adaptive mutation in either tubulins or kinesins. Analyzing the epistatic interactions among different mutations, we observed that some mutations benefited from the disomy of chromosome VIII and others did not. Given that tubulins are highly conserved among eukaryotes, our results are potentially relevant for understanding the emergence of resistance to drugs targeting microtubules, widely used for cancer treatment.

cell biology↗