Work

The La Crosse virus M segment determines virus isolate cell-to-cell spread and virulence

Year: 2026

Type: preprint

Abstract: La Crosse virus (LACV) is an orthobunyavirus spread by mosquitoes in North America and can cause severe neurological disease. Despite this burden, there is a lack of LACV antiviral treatments as our fundamental understanding of how LACV spreads and causes disease remains incomplete. To investigate LACV biology, we took advantage of two genetically similar LACV lineage I isolates (LACV 1960 and LACV 1978 ) where we found that LACV 1960 infects and replicates at a higher rate than LACV 1978 , while LACV 1978 exhibits enhanced cell-cell spread and in vivo virulence and dissemination. To investigate the genomic determinants behind these phenotypes, we generated reassortants between each isolate. We found that each genomic segment contributed to LACV pathogenesis with the M segment as a dominant determinant for LACV pathogenesis in vivo and plaque size and replication in vitro . To address which M segment protein contributes to plaque size and infectivity, we generated M segment chimeric viruses using a LACV 1978 background and swapping in regions of the LACV 1960 M segment. We found that the Gc head domain determined plaque size and infectivity, with the LACV 1960 Gc head chimera producing small plaques but having increased infectivity over the wild-type LACV 1978 . Finally, using natural LACV lineage isolates, we showed that plaque size is variable across and within lineages suggesting changes in the M segment may impact LACV in nature. In future studies, we will continue to investigate the mechanisms behind how cell-to-cell spread influences dissemination to better understand how LACV genome segments affect spread, infectivity, virulence, and viral fitness. Importance Orthobunyaviruses are significant global public health threats. However, our understanding of how these viruses spread and cause disease is not well-defined. In this study, we took advantage of two genetically similar La Crosse virus (LACV) strains that differ in their infectivity, cell-to-cell spread, and virulence. We used reassortant and chimeric LACVs to identify the M segment as a major virulence determinant that regulates cell-to-cell spread and infectivity through the Gc head domain. These studies highlight that different LACV strains behave differently and that the genomic M segment can regulate these phenotypes. Future studies to better dissect how the M segment impacts dissemination will provide important avenues for antiviral development.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.17.752448