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 and HIV albeit with different mechanisms. Since 2003, however, the research group was proficient in quickly redirecting its research interest to emerging viral diseases when outbreaks of a new disease (Severe Acute Respiratory Syndrome, SARS) caused by a human pathogenic coronavirus became a global threat. Our group provided the first clinical isolate in Italy of SARS-CoV and pursued research on this virus until 2008. Then, we became involved in research of pandemic influenza A virus and, in 2016, on Zika virus, a neurotropic virus causing severe damages in fetal brain. This previous experience has been instrumental to cope with the global COVID-19 emergency caused by a SARS-CoV related, yet distinct, coronavirus named SARS-CoV-2, that, in 2020, has redirected the research activity to studying its in vitro interaction with host target cells, but also to identify candidate antiviral agents and sanitation tools.
The Viral Pathogenesis and Bioasafety Group discovered that TRIM22 restricts influenza A viruses by interacting with the viral nucleoprotein (np) thereby promoting its polyubiquitination and degradation by the proteasome. The study of TRIM22-nucleoprotein interaction has highlighted critical np amino acid residues that have evolved during the last hundred years of influenza A virus circulation in the direction of viral attenuation. The group had earlier reported that TRIM22 restricts HIV-1 replication, albeit by an E3-independent mechanism, i.e. via inhibition of proviral transcription. In this regard, 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.
Since 2016, we have been focusing our research on Zika virus (ZIKV), a neurotropic flavivirus responsible of the microcephaly outbreak in newborns observed in Brazil in 2015. We have investigated the susceptibility to viral infection and replication of cells of the female genital tract (since infection can be acquired also by the sexual route) and, more recently, of the peripheral and central nervous systems. We have reported that heparin (an anticoagulant administered to pregnant women to prevent improper clotting) protects neural progenitor cells from ZIKV-induced cell death without affecting the virus replicative capacity. Based on these observations we are currently investigating the cellular pathways involved in ZIKV-induced cell death and its potential persistence in different neuronal and non-neuronal cells.
Since 2020, we engaged in SARS-CoV-2 research projects aimed at studying host-pathogen interactions by using in vitro models relevant for in vivo infection such as air-liquid interface epithelial cultures of primary airway tissues. In addition to searching for host factors capable of interfering with virus replication, we are currently testing different candidate antiviral agents for their capacity to interfere with viral infection at entry and post-entry levels.
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Bertini, S., et al., Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro: insights into structural requirements for binding. Thromb Haemost, 2022.
Davies, S.P., et al., The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models. Front Pharmacol, 2021. 12: p. 660490.
Rovere-Querini, P., et al. Biobanking for COVID-19 research. Panminerva Med, 10, S0031-0808, 2020.
Mycroft-West, C. J., et al. Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin. Thrombosis and Haemostasis 2020, 120(12), 1700-1715.
Armengaud, J., et al. The importance of naturally attenuated Sars‐Cov‐2 in the fight against Covid‐19. Environmental microbiology 2020 22(6), 1997-2000.
Turrini, F., et al. Interferon-inducible TRIM22 contributes to maintenance of HIV-1 proviral latency in T cell lines. Virus research 2019 269, 197631.
Volpi, V. G., et al. Zika virus replication in dorsal root ganglia explants from interferon receptor1 knockout mice causes myelin degeneration. Scientific reports 2018, 8(1), 1-9.
Pagani, I., et al. Mutations conferring increased sensitivity to tripartite motif 22 restriction accumulated progressively in the nucleoprotein of seasonal influenza A (H1N1) viruses between 1918 and 2009. Msphere 2018, 3(2).
Pagani I, et al. Human endometrial stromal cells are highly permissive to productive infection by zika virus. Scientific Reports 2017 Mar 10;7:44286.