Neuroinvasive flavivirus pathogenesis is restricted by host genetic factors in Collaborative Cross mice, independently of Oas1b

Abstract

Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive disease, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of Oas1b-null CC lines with POWV and observed a range of susceptibility phenotypes, indicating that host factors other than the well-characterized flavivirus restriction factor Oas1b modulate POWV pathogenesis in CC mice. Among Oas1b-null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071, and a single resistant line (78% survival), CC045. Susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we identified one line, CC006, that was resistant specifically to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replicated to higher titers in bone marrow-derived macrophages from CC071 mice compared to CC045 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days post-infection were equivalent between CC071 and CC045 mice, clearance of POWV from the serum was significantly slower in CC071 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days post-infection compared to CC071 mice, suggesting that reduced CNS infection contributes to the resistant phenotype of CC045 mice.

Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo

“…High viral load was found in CC071 mice after dengue infection [ 15 ]. Lethality after infection with West Nile virus [ 15 ] or Powassan virus [ 16 ] were also described, although there is likely contribution from the defective Oas1b allele that CC071 has inherited from 129S1/SvImJ. CC071 was also one of the most susceptible CC strains to Rift Valley Fever virus infection [ 17 ] and to hepacivirus with long-term viral persistence [ 21 ].…”

Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced byIrf3deficiencyin vitrobut requires other variantsin vivo, not linked to the type I interferon response

“…High viral load was found after dengue infection (15). Lethality after infection with WNV (15) or Powassan virus (36) were also described, although there is likely contribution from the defective Oas1b allele that CC071 has inherited from 129S1/SvImJ. CC071 was also one of the most susceptible CC strains to Rift Valley Fever virus infection (37) and to hepacivirus, with long-term viral persistence (38).…”

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

“…Interestingly, CC071 mice also have increased susceptibility to classical flaviviruses such as Zika virus (ZIKV), Powassan virus and West Nile virus but not to the bunyavirus Rift Valley fever virus indicating that this strain is particularly sensitive to the Flaviviridae [31][32][33] WT results in similar levels of STAT1 phosphorylation suggesting that defects in JAK/STAT signaling is not driving increased flavivirus susceptibility 32 . Neither CC046 nor CC071 appear to have a broad immune deficiency as they are not more susceptible to Salmonella Typhimurium infection than WT mice (i.e.…”

“…Here, we describe three genetically distinct mouse strains with a multitude of different hepacivirus infection phenotypes and disease trajectories. Interestingly, CC071 mice also have increased susceptibility to classical flaviviruses such as Zika virus (ZIKV), Powassan virus and West Nile virus but not to the bunyavirus Rift Valley fever virus indicating that this strain is particularly sensitive to the Flaviviridae 31-33 . JAK/STAT signaling, a key component of the interferon response, appears to function normally in CC071 as interferon treatment of MEFs from CC071 or WT results in similar levels of STAT1 phosphorylation suggesting that defects in JAK/STAT signaling is not driving increased flavivirus susceptibility 32 .…”