In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…1d, Brains). However, consistent with previous reports 58,81 , the majority (80%) of BA.1 infected mice showed no symptoms, with no virus detected in the brains of symptom-free animals (Fig. 1d, Brains).…”

Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions

“…The viral protein and RNA of SARS‐CoV‐2 were detected scattered throughout the brain tissues of died and survived patients, and infected K18‐hACE2 mice 47,48 . Moreover, SARS‐CoV‐2 may employ olfactory neurons or other bundles to enter the central nervous system from the peripheral nervous system or through the blood–brain barrier 49,50 . Alterations in immune system might be responsible for fatigue, as SARS‐CoV‐2 could reach the hypothalamus via the olfactory pathway, which led to the production of pro‐inflammatory cytokines, and then caused headache and fatigue 25 .…”

“…The sustentacular cells in the olfactory epithelium highly express TMPRSS2, and omicron may have a low tropism on these cells, thereby reducing the frequency of anosmia 164 . The experiment based on human‐induced pluripotent stem cells (hiPSC) derived neurons culture, hACE2 transgenic mice and hamster infection model showed that compared with delta and D614G mutant, the neurotropism, neuro‐invasion, and neurovirulence of omicron are decreasing, 50 which may be explained by the less replication efficiency in the olfactory mucosa of omicron compared with earlier variants 50,166 . Nevertheless, some studies also declared that the neurological and psychiatric outcomes were similar between the delta and omicron infection 167 …”

“…164 The experiment based on human-induced pluripotent stem cells (hiPSC) derived neurons culture, hACE2 transgenic mice and hamster infection model showed that compared with delta and D614G mutant, the neurotropism, neuroinvasion, and neurovirulence of omicron are decreasing, 50 which may be explained by the less replication efficiency in the olfactory mucosa of omicron compared with earlier variants. 50,166 Nevertheless, some studies also declared that the neurological and psychiatric outcomes were similar between the delta and omicron infection. 167 SARS-CoV-2 infection causes liver injury, and current studies are mostly based on early strains and early variants.…”

“… 47 , 48 Moreover, SARS‐CoV‐2 may employ olfactory neurons or other bundles to enter the central nervous system from the peripheral nervous system or through the blood–brain barrier. 49 , 50 Alterations in immune system might be responsible for fatigue, as SARS‐CoV‐2 could reach the hypothalamus via the olfactory pathway, which led to the production of pro‐inflammatory cytokines, and then caused headache and fatigue. 25 SARS‐CoV‐2 was detected to infect brain vascular endothelial cells and cause brain damage in K18‐hACE2 transgenic mice and hamster model, indicating that SARS‐CoV‐2 crossed the blood–brain barrier to the brain, and led to neuronal damage and inflammatory response.…”