Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process

Area of Science:

• Virology
• Molecular Biology
• Genomics

Background:

• Marburgvirus (MARV) and Ravn virus (RAVV) infections are typically lethal in humans and nonhuman primates.
• Establishing lethal MARV/RAVV infections in mice requires serial passage to select for virulent variants.

Purpose of the Study:

• To investigate the genomic alterations and molecular mechanisms underlying the adaptation of MARV and RAVV to cause lethal infections in mice.
• To identify specific mutations and viral RNA changes associated with increased virulence and altered tissue tropism.

Main Methods:

• Serial transfer (passage) of nonlethal MARV/RAVV into immunocompetent BALB/c mice.
• Genomic analysis of viral RNA to identify mutations and track their history during passage.
• Comparative analysis of wild-type and selected lethal mouse variants, including tissue tropism studies.

Main Results:

• The VP40:D184N mutation, previously seen in lethal guinea pig MARV, was the earliest mutation in both MARV and RAVV mouse variants.
• Biased hypermutation was observed in the RAVV variant genome.
• Identical mutations, VP40:Y19H (in the PPPY motif) and VP40:D184N (in a loop structure), were found in lethal mouse MARV and RAVV variants.
• Passage selected for viral variants with distinct genotypes compared to wild-type viruses.
• A lethal mouse RAVV variant exhibited altered tissue tropism compared to its wild-type counterpart.

Conclusions:

• Serial passage selects for specific Marburgvirus variants with distinct genomic profiles and virulence characteristics.
• Identified mutations, particularly in the VP40 protein, are crucial for MARV/RAVV adaptation and lethality in mice.
• Understanding these adaptive mechanisms provides insights into Marburgvirus pathogenesis and potential targets for antiviral strategies.