Biology subjects

Cagliani, R.

Publications and source records attributed to Cagliani, R..

6 recordsLinked to original sources

bioRxiv2024

Tangled genetic relationships within the Fusobacterium genus

Fusobacteria have been associated to different diseases, including colorectal cancer (CRC), but knowledge of which taxonomic groups contribute to specific conditions is incomplete. We analyzed the genetic diversity and relationships within the Fusobacterium genus. We report recent and ancestral recombination in core genes, indicating that fusobacteria have mosaic genomes and emphasizing that taxonomic demarcation should not rely on single genes/gene regions. Across databases, we found ample evidence of species miss-classification and of undescribed species, which are both expected to complicate disease association. By focusing on a lineage that includes F. periodonticum/pseudoperiodonticum and F. nucleatum, we show that genomes belong to four modern populations, but most known species/subspecies emerged from individual ancestral populations. Of these, the F. periodonticum/pseudoperiodonticum population experienced the lowest drift and displays the highest genetic diversity, in line with the less specialized distribution of these bacteria in oral sites. A highly drifted ancestral population instead contributed genetic ancestry to a new species, which includes genomes classified within the F. nucleatum animalis diversity in a recent CRC study. Thus, evidence herein calls for a re-analysis of F. nucleatum animalis features associated to CRC. More generally, our data inform future molecular profiling approaches to investigate the epidemiology of Fusobacterium-associated diseases.

microbiology↗

bioRxiv2022

Genomic clustering and sequence context of mutations in human monkeypox virus (hMPXV1) genomes

The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted in Nigeria. Analysis of genetic differences indicated that APOBEC-mediated editing might be responsible for the unexpectedly high number of mutations observed in hMPXV1 genomes. Here, using 1624 hMPXV1 publicly available sequences, we analyzed mutations that accrued since 2017 until the emergence of the current predominant variant (B.1), as well as those that that have been accumulating during the 2022 outbreak. We found that substitutions tend to cluster and mutational hot-spots are observed. Investigation of the sequence context of C to T changes indicated a preference for 5-TCA/G-3 motifs, suggesting APOBEC3F- or APOBEC3A-mediated editing. The sequence context has remained unchanged since 2017, indicating that the same mutational mechanism that is driving the accumulation of substitutions during the ongoing human-to-human transmission, was already operating before the virus left Africa. We suggest that APOBEC3A is the most likely candidate, given its expression in the skin and its known role in the editing of human papillomavirus.

genomics↗

bioRxiv2022

SARS-CoV-2 ORF3c impairs mitochondrial respiratory metabolism, oxidative stress and autophagic flow

Coronaviruses encode a variable number of accessory proteins that play a role in host-virus interactions, in the suppression of immune responses, or in immune evasion. Accessory proteins in SARS-CoV-2 consist of at least twelve viral proteins whose roles during infection have been extensively studied. Nevertheless, the role of the ORF3c accessory protein, an alternative open reading frame of ORF3a, has remained elusive. Herein, we characterized ORF3c in terms of cellular localization, hosts antiviral response modulation, and effects on mitochondrial metabolism. We show that ORF3c has a mitochondrial localization and alters mitochondrial metabolism, resulting in increased ROS production, block of the autophagic flux, and accumulation of autophagosomes/autolysosomes. Notably, we also found that ORF3c induces a shift from glucose to fatty acids oxidation and enhanced oxidative phosphorylation. This is similar to the condition observed in the chronic degenerative phase of COVID-19. Altogether these data suggest that ORF3c could be a key protein for SARS-CoV-2 pathogenesis and that it may play a role in disease progression.

microbiology↗

bioRxiv2022

Variola virus is as old as the earliest historical lines of evidence suggest

Archaeovirology efforts provided a rich portrait of the evolutionary history of variola virus (VARV), the causative agent of smallpox. These studies revealed frequent viral lineage extinction and a relatively recent origin of VARV as a human pathogen ([~] 1,700 years ago, ya). This contrasts with historical records suggesting the presence of smallpox as early as 3,500 ya. By performing an analysis of ancestry components in modern, historic, and ancient VARV genomes, we unveil the progressive drifting of VARV lineages from a common ancestral population and we show that a small proportion of Viking-Age ancestry persisted until the 18th century. After the split of the P-I and P-II lineages, which occurred before the onset of smallpox vaccination, the former (but not the latter) experienced a severe bottleneck. We suggest this was due to the distinct epidemiology of the two lineages, which display remarkably different disease severity. As for the emergence of VARV, we corrected time estimates by accounting for the time-dependent rate phenomenon. Using this approach, we estimate that VARV emerged earlier than 3,800 ya, thus supporting its presence in ancient societies, including Egypt, as pockmarked mummies suggest. ImportanceNow eradicated, smallpox was one of the most devastating human diseases, causing the death of at least 300 million people in the 20th century. Humans were the only known host of variola virus, but the time-frame of its emergence in our species has been a matter of debate. Specifically, molecular dating suggested a relatively recent origin, whereas historical sources indicated the presence of VARV in ancient societies. By applying population genetic methods, we analyzed the ancestry components in modern and historic VARV genomes, and we found a progressive drifting of VARV lineages from a common ancestral population. By accounting for the common observation that rates of viral evolution scale negatively with the time-frame of measurement, we estimated that VARV emerged earlier than 3800 years ago. Thus, out data settle a controversy and provide novel insight into the origin and evolution of one of the most historically relevant human pathogens.

evolutionary biology↗

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↗