Biology subjects

Sironi, M.

Publications and source records attributed to Sironi, M..

3 recordsLinked to original sources

bioRxiv2020

Simplexviruses successfully adapt to their host by fine-tuning immune responses

Primate herpes simplex viruses are relatively harmless to their natural hosts, whereas cross-species transmission can result in severe disease. We performed a genome-wide scan for signals of adaptation of simplexviruses to hominins. We found evidence of positive selection in three glycoproteins, with selected sites located in antigenic determinants. Positively selected non-core proteins were involved in different immune-escape mechanisms. By expressing mutants of one of these proteins (ICP47), we show that the amino acid status at the positively selected sites is sufficient to induce HLA-G. HSV-1/HSV-2 ICP47 induced HLA-G when mutated to recapitulate residues in B virus, whereas the mutated version of B virus ICP47 failed to determine HLA-G expression. Thus, the evolution of ICP47 in HSV-1/HSV-2 determined the loss of an immunosuppressive effect, suggesting that simplexviruses tune immune responses to promote successful co-existence with their hosts. These results also help explain the high pathogenicity of B virus in humans.

microbiology↗

bioRxiv2020

Antigenic variation of SARS-CoV-2 in response to immune pressure

The ongoing evolution of SARS-CoV-2 is expected to be at least partially driven by the selective pressure imposed by the human immune system. We exploited the availability of a large number of high-quality SARS-CoV-2 genomes, as well as of validated epitope predictions, to show that B cell epitopes in the spike glycoprotein (S) and in the nucleocapsid protein (N) have higher diversity than non-epitope positions. Similar results were obtained for other human coronaviruses. Conversely, in the SARS-CoV-2 population, epitopes for CD4+ and CD8+ T cells were not more variable than non-epitope positions. A significant reduction in epitope variability was instead observed for some of the most immunogenic proteins (S, N, ORF8, and ORF3a). Analysis over longer evolutionary time-frames indicated that this effect is not due to differential constraints. These data indicate that SARS-CoV-2 is evolving to elude the host humoral immune response, whereas recognition by T cells might benefit the virus.

microbiology↗

bioRxiv2020

Substrate Recognition by γ-Glutamyltransferase: A Molecular Dynamics Simulations Study

{gamma}-glutamyltransferase (GGT) is an enzyme that uses {gamma}-glutamyl compounds as substrate and catalyzes their transfer into a water molecule or an acceptor substrate with varied physiological-function in bacteria, plants and animals. Crystal structures of GGT are known for different species and in different states of the chemical reaction; however, structural dynamics of the substrate binding to the catalytic site of GGT is unknown. Here, we modeled Escherichia Coli GGTs glutamine binding by using a swarm of accelerated molecular dynamics (aMD) simulations. Characterization of multiple binding events identified three structural binding motifs composed of polar residues in the binding pocket that govern glutamine binding into the active site. Simulated open and closed conformations of a lid-loop protecting the binding cavity suggests its role as a gating element by allowing or blocking substrates entry into the binding pocket. Partially open states of the lid-loop are accessible within thermal fluctuations, while the estimated free energy cost of a complete open state is 2.4 kcal/mol. Our results suggest that both specific electrostatic interactions and GGT conformational dynamics dictate the molecular recognition of substrate-GGT complexes.

biophysics↗