Mammalian Lipopolysaccharide Receptors Incorporated into the Retroviral Envelope Augment Virus Transmission

Area of Science:

• Virology
• Immunology
• Microbiome research

Background:

• The mouse mammary tumor virus (MMTV) is an orally transmitted retrovirus dependent on the gut microbiota for persistence.
• Virion-associated lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), promoting IL-10 production and MMTV immune evasion.
• Mechanisms of MMTV-LPS association were previously unknown.

Purpose of the Study:

• To elucidate the mechanisms by which MMTV associates with LPS.
• To investigate how MMTV utilizes host factors and bacterial ligands for transmission.
• To understand how MMTV modifies bacterial components to enhance immune stimulation.

Main Methods:

• Analysis of MMTV virions for the presence of LPS-binding factors.
• Isolation and characterization of MMTV from mice lacking specific LPS-binding proteins (LBPs).
• Assessment of MMTV's ability to bind LPS and stimulate TLR4 in vitro and in vivo.

Main Results:

• MMTV virions possess mammalian LPS-binding factors: CD14, TLR4, and MD-2.
• LPS-binding protein (LBP) facilitates LPS binding to MMTV, augmenting viral transmission.
• MMTV lacking LBPs exhibit impaired LPS engagement and TLR4 stimulation, with a transmission defect.
• MMTV enhances the immunostimulatory capacity of weak LPS agonists from Bacteroides species.

Conclusions:

• MMTV captures and incorporates host LPS-binding factors, including CD14, TLR4, and MD-2.
• LBP is crucial for MMTV-LPS association and subsequent TLR4 activation, facilitating viral transmission.
• MMTV actively modifies bacterial ligands to enhance TLR4 stimulation, optimizing its transmission and immune evasion strategies.