Mabbutt, A. | bioRxiv Science

bioRxiv2024

Enforced MYC expression selectively redirects transcriptional programs during human plasma cell differentiation

MYC provides a rheostat linking cell growth and division during plasma cell (PC) differentiation. Precise control of MYC is central to the network controlling differentiation. Deregulation of MYC drives transformation in aggressive B-cell neoplasms and is often accompanied by apoptotic protection conferred by BCL2. We assess how MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. Under permissive conditions for PC differentiation we find such deregulation does not transform cells. While driving loss of normal PC surface phenotype, MYC deregulation has little impact on components of regulatory circuitry controlling B-cell identity. This contrasts with profound impact on initiation of secretory output and secretory reprogramming, coupled to dampening of XBP1 and immunoglobulin gene enhancement and a shift toward distinct metabolic programs. The establishment of this aberrant state depends on MYC homology boxes (MB0 and MBII). Dependence on MBII is profound and resolves to residue W135.

cell biology↗

bioRxiv2020

Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19.

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques, resembling the mild clinical cases of COVID-19 in humans. Immune responses against SARS-CoV-2 were also similar in both species and equivalent to those reported in milder infections and convalescent human patients. Importantly, we have devised a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the optimal study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of novel and repurposed interventions against SARS-CoV-2. Accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

microbiology↗