Biology subjects

Massa, P.

Publications and source records attributed to Massa, P..

4 recordsLinked to original sources

bioRxiv2023

Gene expression is the main driver of purifying selection in large penguin populations

Purifying selection is the most pervasive type of selection, as it constantly removes deleterious mutations arising in populations, directly scaling with population size. Highly expressed genes appear to accumulate fewer deleterious mutations between divergent species lineages (known as E-R anticorrelation), pointing towards gene expression as an additional driver of purifying selection. However, estimates of the effect of gene expression on segregating deleterious variants in natural populations are scarce, as is an understanding of the relative contribution of population size and gene expression to purifying selection. Here, we analyse genomic and transcriptomic data from two natural populations of closely related sister species with different demographic histories, the Emperor penguin (Aptenodytes forsteri) and the King penguin (A. patagonicus), and show that purifying selection at the population-level depends on gene expression rate, resulting in very high selection coefficients at highly expressed genes. Leveraging realistic forward simulations, we estimate that the top 10% of the most highly expressed genes in a genome experience a selection pressure corresponding to an average selection coefficient of -0.1, which decreases to a selection coefficient of -0.01 for the top 50%. Gene expression rate can be regarded as a fundamental parameter of protein evolution in natural populations, maintaining selection effective even at small population size. We suggest it could be used as a proxy for gene selection coefficients, which are notoriously difficult to derive in non-model species under real-world conditions.

evolutionary biology↗

bioRxiv2023

Comparative pathogenesis of two lineages of Powassan virus reveals differing routes of neuroinvasion leading to distinct clinical outcome, neuropathology and inflammation

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlated with unique clinical presentation for each lineage. Comparative transcriptomics of infected brains demonstrates activation of different immune pathways and downstream host responses. Ultimately the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that different disease presentations would be occur in clinical cases due to the innate differences in the two lineages of Powassan virus. Author SummaryPowassan virus causes a nationally notifiable disease which can cause severe neurological disease in humans and has no approved vaccines or therapeutics. Although two distinct lineages circulate in North America, clinical differentiation is not typically performed, and pathology has been assumed to be similar between lineages. In this work, a direct comparison of lineage I (Powassan virus) and lineage II (deer tick virus) demonstrated distinct differences in the clinical presentation, pathology of the central nervous system, and immune response in immunocompetent mice. These differences suggest that deer tick virus and Powassan virus do not utilize the same mechanisms for neuroinvasion and dissemination within the CNS. This is clinically relevant as the development of treatment plans and therapeutics need to be evaluated for these virus lineages.

microbiology↗

bioRxiv2022

Goat PRP14 (gPRP14) has xeno-antigenic properties and works as a vaccine in preclinical models of cancer.

We studied the activity of recombinant goat PRP14 (gPRP14), a member of the RID protein family, as a xeno-antigen in preclinical models of cancer. Antisera from rabbits and mice immunized with gPRP14 showed strong reactivity against several tumor cell types, which was absent towards normal cells: the tumor selectivity was related to surface and intra-cellular expression in tumor cells, and to an exclusively intra-cellular localization in normal cells. In vitro, binding to tumor cells was followed by cytotoxicity which could be rescued by the addition of excess soluble antigen. In vivo, an anti-tumor activity of immunization with gPRP14 was observed in murine syngeneic models of breast cancer and melanoma: the anti-tumor response was present when gPRP14 was administered in a preventive setting, and persisted upon repeated challenges with tumor cells in long-term survivor mice. Finally, we showed that both the humoral and T-cell mediated responses are needed for the optimal anti-tumor effect in the murine melanoma model. Thus, we have performed an initial characterization of gPRP14 as a cancer vaccine, which -given the potential wide range of tumor cells positive for the antigen-appears as a promising, novel immunotherapy.

cancer biology↗

bioRxiv2021

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for Covid19, indiscriminately suppress both responses, possibly impairing viral clearance, and provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces the macrophage response to SARS-CoV2 seen in patients and allows quantitation of inflammatory and antiviral activities. We show that the NFKB-dependent inflammatory response can be selectively inhibited by ablating the lysine-demethylase LSD1, which additionally unleashed interferon-independent ISG activation and blocked viral egress through the lysosomal pathway. These results provide a rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment. One-Sentence SummaryTargeting a chromatin-modifying enzyme in coronavirus infections curbs tissue-damage without affecting antiviral response

immunology↗