Repository logo

Browsing by Issue Date, starting with "2017-07-19"

Filter results by year or month
Now showing 1 - 2 of 2
  • Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis
    Publication . Santarino, Inês B.; Viegas, Michelle S.; Domingues, Neuza S.; Ribeiro, Ana M.; Soares, Miguel P.; Vieira, Otília V.
    Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.
    2017-07-19Journal article Open access Show more
  • The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution
    Publication . Ormond, Louise; Liu, Ping; Matuszewski, Sebastian; Renzette, Nicholas; Bank, Claudia; Zeldovich, Konstantin; Bolon, Daniel N.; Kowalik, Timothy F.; Finberg, Robert W.; Jensen, Jeffrey D.; Wang, Jennifer P.
    Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated.
    2017-07-19Journal article Open access Show more