Divergent low-density lipoprotein receptor (LDLR) linked to low VSV G-dependent viral infectivity and unique serum lipid profile in zebra finches

Abstract

The low-density lipoprotein receptor (LDLR) is key to cellular cholesterol uptake and is also the main receptor for the vesicular stomatitis virus glycoprotein (VSV G). Here we show that in songbirds LDLR is highly divergent and lacks domains critical for ligand binding and cellular trafficking, inconsistent with universal structure conservation and function across vertebrates. Linked to the LDLR functional domain loss, zebra finches show inefficient infectivity by lentiviruses (LVs) pseudotyped with VSV G, which can be rescued by the expression of human LDLR. Finches also show an atypical plasma lipid distribution that relies largely on high-density lipoprotein (HDL). These findings provide insights into the genetics and evolution of viral infectivity and cholesterol transport mechanisms in vertebrates.

Genomic loss of GPR108 disrupts AAV transduction in birds

“…This interpretation is also consistent with enhanced AAV2G9 transduction in the zebra finch brain seen with modifications of the heparin binding domain 13 . Together with our report on divergence of the avian homolog of the VSV G receptor LDLR 28 , our present findings point to multiple losses of functional viral receptors in avian genomes, consistent with a complex genomic landscape for host-viral interactions of relevance for emerging zoonotic viruses 32 .…”

Pseudotyped lentiviral vectors: Ready for translation into targeted cancer gene therapy?

“… 40 Consistently, in zebra finches who lose the LDLR functional domain, the infectivity by VSVG-pseudotyped LVs is inefficient. 64 Apart from LDLR, some regulators have also been shown to determine the infectivity of VSVG-pseudotyped LVs. The cholesterol represents one of them as its supplementation during viral production increases the infectivity of VSVG-pseudotyped LVs, although the detailed mechanisms require further clarification.…”

Induction of an immortalized songbird cell line allows for gene characterization and knockout by CRISPR-Cas9

“…However, these lines are difficult to maintain as culture stocks, compared to stable cell lines from other species, and have not been widely utilized across the avian science community. Primary cells have also been utilized 15 , 16 , though these cells have a limited lifetime in vitro. Primary cells also vary genetically between individuals and laboratories, risking issues with replicability between divergent zebra finch lab populations 17 .…”

“…Such approaches have not been previously reported in passerine birds despite constituting over half (~ 5000) of all bird species 25 , representing a major gap in the toolset for studying this clade’s cellular and molecular biology. As we learn more about both the convergent and unique biological properties of songbirds 16 , 26 , 27 , the need for immortalized cell lines becomes increasingly clear.…”