Biology subjects

Holland, S.

Publications and source records attributed to Holland, S..

2 recordsLinked to original sources

bioRxiv2021

Genetically diverse mouse models of SARS-CoV-2 infection model clinical variation and cytokine responses in COVID-19

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18- hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity. One Sentence SummaryGenetically diverse mice model a spectrum of clinically relevant innate immune responses to SARS-CoV-2 infection.

microbiology↗

bioRxiv2020

Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17

After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal and distal axon degeneration were previously thought to be controlled by two distinct pathways, involving activation of the kinase DLK and loss of the axon survival factor NMNAT2, respectively. However, we found that mutual palmitoylation by the palmitoyl acyltransferase ZDHHC17 couples the DLK and NMNAT2 signals, which together form a "trust, but verify system". In healthy optic nerves, ZDHHC17-dependent palmitoylation ensures NMNAT-dependent distal axon integrity, while following ONC, ZDHHC17-dependent palmitoylation is critical for DLK-dependent somal degeneration. We found that ZDHHC17 also controls survival-versus-degeneration decisions in sensory neurons and identified motifs in NMNAT2 and DLK that govern their ZDHHC17-dependent regulation. These findings suggest that the control of somal and distal axon integrity should be considered as a single, holistic process, involving two palmitoylation-dependent pathways acting in concert.

neuroscience↗