Retinol binding protein 4 enhances cellular cholesterol uptake to facilitate influenza A virus infection

TL;DR

This study shows that retinol-binding protein 4 helps influenza A virus infect cells by increasing cholesterol and sialic acid levels, offering a new target for antiviral therapies.

Contribution

The study identifies RBP4 as a novel host factor that enhances influenza A virus infection through cholesterol metabolism.

Findings

RBP4 deficiency impairs influenza A virus replication in cells and mice.

RBP4 increases cholesterol levels by promoting CD36 expression, which aids viral attachment.

Restoring CD36 in RBP4-deficient cells recovers influenza A virus replication.

Abstract

Viruses hijack host cell machinery to facilitate their own replication. Therefore, identifying key cellular factors and processes involved in viral infection is crucial for developing host-directed therapies. Herein, we demonstrate that retinol-binding protein 4 (RBP4), a lipocalin family member and major retinol carrier, is significantly induced by influenza A virus (IAV) infection in both cellular models and clinical patients. Moreover, RBP4 deficiency impairs IAV replication both in vitro and in vivo. Mechanistically, RBP4 promotes the expression of CD36, a cholesterol uptake receptor protein, thereby increasing cellular cholesterol levels. This elevation in cholesterol subsequently boosts cell-surface sialic acid levels, facilitating IAV attachment. Consequently, enforced expression of CD36 restores IAV replication in RBP4-deficient cells and mice. In summary, our study identifies RBP4 as a pivotal host factor that facilitates IAV infection by modulating cellular cholesterol homeostasis.

Cholesterol metabolism is critical in a variety of viral infections, and influenza A viruses (IAV) employ multiple strategies to hijack this metabolic pathway to evade host immunity. Here, we provide compelling evidence that retinol-binding protein 4 (RBP4) promotes the upregulation of CD36 expression, thereby enhancing cholesterol uptake and sialic acid receptor expression. This process facilitates IAV infection and replication. Our findings reveal a mechanism by which IAV exploits host factors to maintain its own replication and suggest that RBP4 may represent a promising target for the development of novel anti-IAV therapies.

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