Immunology, Transplantation and Infectious diseases
Viral pathogens and biosafety
The focus of this research Unit has always been the study of human viral pathogens with the ultimate goal of contributing to prevention and treatment of their related diseases. In particular, the group has focused on TRIM22, an E3- ubiquitin ligase induced by type I interferon, that restricts influenza A virus by promoting ubiquitination and degradation of the viral nucleoprotein. More recently, the unit has oriented its research towards the spread of Zika virus. In 2015 the neurotropic Zika virus (ZIKV) surfaced in Brazil with compelling evidence linking the infection to an outbreak of microcephaly in newborns. Taking advantage of the IRCCS Ospedale San Raffaele multidisciplinary research expertise, the group investigated the pathogenesis of ZIKV infection by studying its tropism for cells of the female genital tract.
Research activity
Viral pathogens and bionafety Unit discovered that TRIM22 restriction of influenza virus is likely acquired by a selection force that involves the cytotoxic T lymphocyte response. The group had earlier reported that TRIM22 restricts HIV-1 replication, albeit by an E3-independent mechanism, i.e. via inhibition of proviral transcription. Indeed, it is believed that TRIM22 or its interactors could be exploited in therapeutic strategies of “Shock and Kill” aiming at purging the HIV reservoir or “Lock of HIV transcription” in order to permanently silence it.
Moreover, the unit has demonstrated that ZIKV productively infects human endometrial stromal cells particularly in condition of decidualization, a physiological condition induced by progesterone during the secretory phase of the menstrual cycle. Regarding therapeutic approaches for ZIKV infection, for which there are no specific agents, this group found serendipitously that heparin decouples ZIKV replication from virus-induced cell death, an effect that group researchers are currently investigating in greater detail.
Moreover, the unit has demonstrated that ZIKV productively infects human endometrial stromal cells particularly in condition of decidualization, a physiological condition induced by progesterone during the secretory phase of the menstrual cycle. Regarding therapeutic approaches for ZIKV infection, for which there are no specific agents, this group found serendipitously that heparin decouples ZIKV replication from virus-induced cell death, an effect that group researchers are currently investigating in greater detail.
Wang J, Bardelli M, Pedotti M, Ng TS, Bianchi S, Espinosa D, Simonelli L, Lim EXY, Barca T, Foglierini M, Cavalli A, Vanzetta F, Jaconi S, Beltramello M, Cameroni E, Kostyuchenko VA, Shi J, Barca T, Pagani I, Rubio A, Broccoli V, Vicenzi E, Graham V, Pullan S, Dowall S, Hewson R, Jurt S, Zerbe O, Stettler K, Lanzavecchia A, Sallusto F, Harris E, Mei Lok S, Varani L, Corti D. A human bi-specific antibody against Zika virus with high therapeutic potential. Cell 2017 Sep 21;171(1):229-241.e15.
Pagani I, Ghezzi S, Ulisse A, Rubio A, Turrini F, Garavaglia E, Candiani M, Castilletti C, Ippolito G, Poli G, Broccoli V, Panina-Bordignon P, Vicenzi E. Human endometrial stromal cells are highly permissive to productive infection by zika virus. Scientific Reports 2017 Mar 10;7:44286.
Ghezzi S, Cooper L, Rubio A, Pagani I, Capobianchi MR, Ippolito G, Pelletier J, Meneghetti MCZ, Lima MA, Skidmore MA, Broccoli V, Yates EA, Vicenzi E. Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells. Antiviral Research 2017 Apr;140:13-17.
F. Turrini, S. Marelli, A. Kajaste-Rudnitski, M. Lusic, C. Lint, A. T. Das, A. Harwig, B. Berkhout, and E. Vicenzi. HIV-1 transcriptional silencing caused by TRIM22 inhibition of Sp1 binding to the viral promoter, Retrovirology 2015 Dec 18;12:104.
Pappas L, Foglierini M, Piccoli L, Kallewaard NL, Turrini F, Silacci C, Fernandez-Rodriguez B, Agatic G, Giacchetto-Sasselli I, Pellicciotta G, Sallusto F, Zhu Q, Vicenzi E, Corti D, Lanzavecchia A. Rapid development of broadly influenza neutralizing antibodies through redundant mutations. Nature 2014 Dec 18;516(7531):418-22.
Vicenzi E, Liò P, Poli G. The puzzling role of CXCR4 in human immunodeficiency virus infection.Theranostics 2013;3(1):18-25.
Di Pietro A, Kajaste-Rudnitski A, Oteiza A, Nicora L, Towers GJ, Mechti N, Vicenzi E. TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation. Journal of Virology 2013; 87(8):4523–4533.
Ghezzi S, Galli L, Kajaste-Rudnitski A, Turrini F, Marelli S, Toniolo D, Casoli C, Riva A, Poli G, Castagna A, Vicenzi E. Identification of TRIM22 single nucleotide polymorphisms associated with loss of inhibition of HIV-1 transcription and advanced HIV-1 disease. AIDS 2013 Sep 24;27(15):2335-44.
A. Kajaste-Rudnitski, S. Marelli, C. Pultrone, T. Pertel, P.D. Uchil, N. Mechti, W. Mothes, G. Poli, J. Luban and E.Vicenzi. TRIM22 inhibits HIV-1 transcription independently of its E3-ubiquitin ligase activity, Tat and NF-{kappa}B responsive LTR elements. J Virol. 2011; 85(10):5183-96.
Kajaste-Rudnitski A, Galli L, Nozza S, Tambussi G, Di Pietro A, Pellicciotta G, Monti A, Mascagni P, Moro M, Vicenzi E. Induction of protective antibody response by MF59-adjuvanted 2009 pandemic A/ H1N1v Influenza Vaccine in HIV-1 Infected Individuals. AIDS 2011 Jan 14;25(2):177-83.
