We are interested in molecular strategies utilized by intracellular pathogens to interact with their host cells, and on fundamental cell biological processes subverted by pathogens during infection. Our studies of the mechanism by which the protozoan Trypanosoma cruzi invades host cells uncovered a previously unrecognized, ubiquitous process of Ca2+ dependent mobilization and fusion of lysosomes with the plasma membrane. This Ca2+-regulated lysosome exocytosis pathway is subverted by the parasites as a strategy to form a membrane-bounded vacuole, through which they gain access to host cells. We also discovered that Ca2+-triggered lysosomal exocytosis plays a central role in the mechanism by which mammalian cells reseal after wounding. We are currently actively investigating the role of the lysosomal enzyme acid sphingomyelinase in triggering an endocytic process responsible for removing toxin pores and other lesions from the plasma membrane. In addition, we have several projects analyzing the molecular mechanisms of intracellular survival of the trypanosomatid Leishmania, a parasite that causes serious human disease worldwide.
Andrews, N.W. Solving the secretory acid sphingomyelinase puzzle: Insights from lysosome-mediated parasite invasion and plasma membrane repair. Cellular Microbiology, e13065. doi: 10.1111/cmi.13065, 2019.
Michailowsky, V., Li, H., Mittra, B., Iyer, S.R., Mazála, D.A.G., Corrotte, M., Wang, Y., Chin, E.R., Lovering, R.M. and Andrews, N.W. Defects in sarcolemma repair and skeletal muscle function after injury in a mouse model of Niemann-Pick Type A/B disease. Skeletal Muscle, 9(1):1.doi: 10.1186/s13395-018-0187-5, 2019.
Laranjeira-Silva, M.F., Wang, W., Samuel, T.K., Maeda, F.Y., Michailowsky, V., Hamza, I,. Liu, Z. and Andrews, N.W. A MFS-type plasma membrane transporter required for Leishmania virulence protects the parasites from iron toxicity. PLoS Pathogens, 14(6):e10077140. doi: 10.1371/journal.ppat.1007140, 2018.
Panicker, L.M., Srikanth, M.P., Castro-Gomes, T., Miller, D., Andrews, N.W. and Feldman, R.A. Gaucher disease iPSC-derived osteoblasts have developmental and lysosomal defects that impair bone matrix deposition. Hum. Mol. Genet. doi: 10.1093/hmg/ddx442, 2018.
Mittra, B., Laranjeira-Silva M.F., Miguel D.C, de Menezes J.P. and Andrews, N.W. The iron-dependent mitochondrial superoxide dismutase SODA regulates Leishmania virulence. J. Biol. Chem., pii: jbc.M116.772624. doi: 10.1074/jbc.M116.772624, 2017.
De Menezes, J.P., Koushik, A., Das, S,. Guven, C., Siegel, A., Laranjeira-Silva, M.F., Losert, W. and Andrews, N.W. Leishmania infection inhibits macrophage motility by altering F-actin dynamics and the expression of adhesion complex proteins. Cell. Microbiol., doi: 10.1111/cmi.12668, 2017.
Mittra, M., Bezerra de Menezes, J.P., Larangeira-Silva, M.F., Jensen, J., Michailowsky, V., and Andrews, N.W. A trypanosomatid iron transporter that regulates mitochondrial function is required for Leishmania amazonensis virulence. PLoS Pathogens, 12(1):e1005340, 2016.
Miller, H., Castro-Gomes, T., Corrotte, M., Tam, C., Maugel, T.K., Andrews, N.W. and Song, W. Lipid raft-dependent plasma membrane repair interferes with the activation of B-lymphocytes. J. Cell Biol., 211: 1193-1205, 2015.
Fernandes, M.C., Miguel, D.C., Tam, C. and Andrews, N.W. The exocyst is required for trypanosome invasion and the repair of large plasma membrane wounds. J. Cell Sci, 128:27-32, 2015.
Andrews, N.W., Almeida, P.E. and Corrotte, M. Damage control: cellular mechanisms of plasma membrane repair. Trends in Cell Biology 24:734-742, 2014.
Ben-Othman, R., Flannery, A.R., Miguel, D.C., Ward, D.M., Kaplan, J. and Andrews, N.W. Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PloS Pathogens, 10:e1003901. 2014.
Corrotte, M., Almeida P.E., Tam, C., Castro-Gomes, T., Fernandes, M.C., Millis, B.A., Cortez, M., Miller, H., Song, W., Maugel, T.K. and Andrews, N.W. Caveolae internalization repairs wounded cells and muscle fibers. eLife 2013:2:e00926, 2013.
Flannery, A.R., Renberg, R.L. and Andrews, N.W. Pathways of iron acquisition and utilization in Leishmania. Curr. Op. Microbiol. doi:pii: S1369-5274(13)00119-7. 10.1016/j.mib.2013.07.018, 2013.
Mittra, B., Cortez, M., Haydock, A., Ramasamy, G., Myler, P.J. and Andrews, N.W. Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. J. Exp. Med. 210: 401-416, 2013.
Corrotte, M., Fernandes, M.C., Tam, C. and Andrews, N.W. Toxin pores endocytosed during plasma membrane repair traffic into the lumen of MVBs for degradation. Traffic 13:483-494,
Huynh, C., Yuan, X., Miguel, M.C., Renberg, R.L., Potchenko, O., Philpott, C.C., Hamza, I. and Andrews, N.W. Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathogens, 8:e1002795. Epub 2012.
Cortez, M., Huynh, C., Fernandes, M.C., Kennedy, K.A., Aderem, A. and Andrews, N.W. Leishmania promotes its own virulence by inducing expression of host CD200. Cell Host & Microbe 9:463-471, 2011.
Flannery, A.R., Huynh, C., Mittra, B., Mortara R.A. and Andrews, N.W. The LFR1 ferric iron reductase of Leishmania amazonensis is essential for the generation of infective parasite forms. J. Biol. Chem. 286:23266-23279, 2011.
Fernandes, M.C, Cortez, M, Flannery A.R, Tam C, Mortara R.A. and Andrews, N.A. Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion. J. Exp. Med. 208:909-979, 2011.
Tam, C., Idone, V., Devlin, C, Fernandes, M.C., Flannery, A., He, X., Schuchman, E., Tabas, I and Andrews, N.W. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J. Cell Biol. 189:1027-38, 2010.
Flannery, A, Czibener, C. and Andrews, N.W. Palmitoylation-dependent association with CD63 targets the Ca2+ sensor synaptotagmin VII to lysosomes. J. Cell Biol. 191:599-613, 2010.
Burroughs Wellcome Molecular Parasitology Scholar Award and a MERIT award from the National Institutes of Health
Ph.D. University of Sao Paulo, Brazil, 1983