Lrp1 is essential for lethal Rift Valley fever hepatic disease in mice

Area of Science:

• Virology
• Hepatology
• Immunology

Background:

• Rift Valley fever virus (RVFV) is an emerging African arbovirus causing severe disease, particularly liver necrosis.
• Low-density lipoprotein receptor-related protein 1 (Lrp1) is a newly identified host factor for RVFV cellular entry.
• The in vivo role of Lrp1 in RVFV pathogenesis, especially in the liver, is not well understood.

Purpose of the Study:

• To investigate the biological significance of Lrp1 in Rift Valley fever pathogenesis in vivo.
• To determine the specific role of hepatocyte Lrp1 expression in RVFV-induced liver disease.

Main Methods:

• Development of a mouse model with specific deletion of Lrp1 in hepatocytes.
• Infection of these genetically modified mice with RVFV.
• Analysis of viral replication, tissue pathology, clinical signs, and survival rates.

Main Results:

• Mice lacking hepatocyte Lrp1 exhibited significantly reduced RVFV replication in the liver.
• Hepatocyte Lrp1 deletion led to a longer survival time and altered disease presentation towards neurological signs.
• RVFV infection levels in non-hepatic tissues were unaffected by the Lrp1 deletion in hepatocytes.

Conclusions:

• Hepatocyte Lrp1 is essential for the development of severe hepatic disease during Rift Valley fever virus infection in mice.
• Lrp1 plays a critical role in mediating RVFV pathogenesis within the liver, but not in other tissues.
• Targeting Lrp1 in hepatocytes could be a potential therapeutic strategy for Rift Valley fever.