Dr. Pierre-Yves Lozach
Cell Biology of Arboviral Infections
Arthropod-borne viruses are better known by their acronym, arboviruses. This term refers to an exceptionally diverse group of viruses transmitted to humans and other vertebrates by multiple arthropod vectors such as fleas, flies, midges, mosquitoes, and ticks. Even with the diversity of vectors, these viruses share the characteristics of having a complex dual life cycle, involving replication in both vertebrate hosts and arthropod vectors. Arboviruses virtually exist in any known habitat, and thus far, over 500 isolates have been identified through many distinct viral families. Many arboviruses are important pathogens in livestock and humans, causing severe health problems, often fatal, such as acute hepatitis, encephalitis, and hemorrhagic fever. Outbreaks are no longer limited to tropical and developing countries. With international trade, travel, and climate change that favors the spread of vectors to new areas, arboviruses are emerging and re-emerging agents of disease that represent a global threat for agricultural productivity and public health. A recent illustration is the rapid spread of the mosquito-borne virus Zika, from Africa to Pacific and to both South and North America. As such, many arboviruses are listed as high-priority pathogens by the World Health Organization and the need to develop research, diagnostic, and therapeutic tools to combat epidemic and pandemic arboviral infections is urgent.
The overall aim of the Lozach group is to obtain a deep knowledge of the biology of viruses transmitted by mosquitoes and ticks, both in their arthropod vectors and in the mammalian host. Our goal is to fully understand the arthropod vector-to-mammal host transmission with the ultimate objective of identifying novel antiviral strategies. To this end, we employ cellular and molecular techniques in combination with quantitative OMICS technologies, electron microscopy, and high-end fluorescence-based methods to (i) characterize arboviruses in both arthropod vector cells and mammalian host cells, (ii) investigate how arboviruses target and enter cells, and (iii) define the viral and host factors responsible for virulence and lethality. Our main arbovirus models are the phleboviruses Rift valley fever, Toscana, and Uukuniemi and, the flaviviruses West Nile and Zika. Through this research program, we expect to gain a detailed picture of the molecular and cellular mechanisms subverted by these viruses to infect humans.
Figure 1 | Research Program
Figure 2 | Project i: Electron micrograph showing one particle of Uukuniemi virus.
Figure 3 | Project ii: Uukuniemi viral particles (red) within LAMP1-positive endosomes (green).
Figure 4 | Project iii: The nonstructural protein NSs (red) of Rift Valley fever virus analyzed by super resolution microscopy
Uckeley, Z.M., Moeller, R., Kühn, L.I., Nilsson, E., Robens, C., Lasswitz, L., Lindqvist, R., Lenman, A., Passos, V., Voß, Y., Sommerauer, C., Kampmann, M., Goffinet, C., Meissner, F., Överby, A.K., Lozach, P.Y.† and Gerold, G.†. (2019). Quantitative proteomics of Uukuniemi virus-host cell interactions reveals GBF1 as proviral host factor for phleboviruses. Mol. Cell. Proteomics in press, †designs corresponding authors.
Uckeley, Z.M., Koch, J., Tischler, N.D., Léger, P., Lozach, P.Y. (2019). Cell biology of phlebovirus entry. Virologie, 23(3):176–87.
Li, S., Zhu, X., Guan, Z., Huang, W., Kortekaas, J., Lozach, P.Y. and Peng, K. (2019). NSs filament formation is important but not sufficient for RVFV virulence in vivo. Viruses, 11(9).
Hoffmann, A., Mazelier, M., Léger, P., and Lozach, P.Y. (2018). Deciphering virus entry with fluorescently labeled viral particles. Methods Mol. Biol., 1836:159–183.
Lozach, P.Y. (2018). Early virus-host cell interactions. J. Mol. Biol., 430(17):2555–2556.
Ashtikar, M., Mäder, K., Klein, K., Wunderlich, K., Lozach, P.Y., Gao, F., Mende, S., Strasser, C., Dennison, T., Marenchino, M., Wacker, M.G. (2018). LOEWE workshop particle characterization in medicine and biology. Pharm. Front. 1: pii: e190002
Mazelier, M., Rouxel, R.N., Zumstein, M., Mancini, R., Bell-Sakyi, L., and Lozach, P.Y. (2016). Uukuniemi virus as a tick-borne virus model. J. Virol., 90:6784–98.
Albornoz, A.†, Hoffmann, A.†, Lozach, P.Y., Tischler, N.D. (2016). Early bunyavirus-host cell interactions. Viruses 8(5): pii: e143
Léger, P.†, Tetard, M.†, Youness, B., Cordes, N., Rouxel, R.N., Flamand, M., and Lozach, P.Y. (2016). Differential use of the C‑type lectins L‑SIGN and DC-SIGN for phlebovirus endocytosis. Traffic, 17:639–656.
Boulant, S.†, Stanifer, M., and Lozach, P.Y.† (2015). Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis. Viruses, 7:2794–2815.
Léger, P. and Lozach, P.Y. (2015). Bunyaviruses: from transmission by arthropods to entry into mammalian-host first-target cells. Future Virol., 10:859–881.
Meier, R., Mazelier, M., and Lozach, P.Y. (2015). High-throughput small interfering RNA screens: When small interfering RNAs behave like microRNA. Med. Sci., 31:247–249.
Acuña, R., Bignon, E., Mancini, R., Lozach, P.Y., and Tischler, N.D. (2015). Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer. J. Gen. Virol., 96:3192–7.
Meier, R., Franceschini, A., Horvath, P., Tetard, M., Mancini, R., von Mering, C., Helenius, A., and Lozach, P.Y. (2014). Genome-wide siRNA screens reveal VAMP3 as a novel host factor required for Uukuniemi virus late penetration. J. Virol., 88:8565–8578.
Acuña, R., Cifuentes-Muñoz, N., Marquez, C.L., Bulling, M., Klingström, J., Mancini, R., Lozach, P.Y., and Tischler, N.D. (2014). Hantavirus Gn and Gc glycoproteins self-assemble into virus-like particles. J. Virol., 88:2344–2348.
Goncalves, A.R., Moraz, M.L., Pasquato, A., Helenius, A., Lozach, P.Y., and Kunz, S. (2013). Role of DC-SIGN in Lassa virus entry into human dendritic cells. J. Virol., 87:11504–11515.
Mercer, J., and Lozach, P.Y. (2013). Cellular protein disposal system assists poxvirus genome uncoating. Med. Sci., 29:561–563.
Barriga, G.P., Martínez-Valdebenito, C., Galeno, H., Ferrés, M., Lozach, P.Y., and Tischler, N.D. (2013). A rapid method for infectivity titration of Andes hantavirus using flow cytometry. J. Virol. Methods, 193:291–294.
Lozach, P.Y.†, Kühbacher, A., Meier, R., Mancini, R., Bitto, D., Bouloy, M., and Helenius, A.† (2011). DC-SIGN as receptor for phleboviruses. Cell Host Microbe, 10:75–88.