2. Academic Validation
  3. Differential pathogenic and molecular features in neurological infection of SARS-CoV-2 Omicron BA.5.2 and BA.2.75 and Delta

Differential pathogenic and molecular features in neurological infection of SARS-CoV-2 Omicron BA.5.2 and BA.2.75 and Delta

  • J Med Virol. 2024 Jan;96(1):e29357. doi: 10.1002/jmv.29357.
Erlin Wang 1 2,  Qiao-Jiang Yang 3,  Xiang-Xiong Xu 2 4,  Qing-Cui Zou 3,  Yanghaopeng Long 3,  Guanqin Ma 2 4,  Zhong-Hua Deng 3,  Jie-Bin Zhao 2 4,  Ming-Hua Li 3,  Jianxiong Zeng 1 2 3 4 5
Affiliations

Affiliations

  • 1 Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 3 Kunming National High-level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 4 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 5 Yunnan Key Laboratory of Biodiversity Information, Kunming, Yunnan, China.
PMID: 38235532 DOI: 10.1002/jmv.29357
Abstract

The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global threat, exacerbated by the emergence of viral variants. Two variants of SARS-CoV-2, Omicron BA.2.75 and BA.5, led to global Infection peaks between May 2022 and May 2023, yet their precise characteristics in pathogenesis are not well understood. In this study, we compared these two Omicron sublineages with the previously dominant Delta variant using a human angiotensin-converting Enzyme 2 knock-in mouse model. As expected, Delta exhibited higher viral replication in the lung and brain than both Omicron sublineages which induced less severe lung damage and immune activation. In contrast, the Omicron variants especially BA.5.2 showed a propensity for cellular proliferation and developmental pathways. Both Delta and BA.5.2 variants, but not BA.2.75, led to decreased pulmonary lymphocytes, indicating differential adaptive immune response. Neuroinvasiveness was shared with all strains, accompanied by vascular abnormalities, synaptic injury, and loss of astrocytes. However, Immunostaining assays and transcriptomic analysis showed that BA.5.2 displayed stronger immune suppression and neurodegeneration, while BA.2.75 exhibited more similar characteristics to Delta in the cortex. Such differentially infectious features could be partially attributed to the weakened interaction between Omicron Spike protein and host proteomes decoded via co-immunoprecipitation followed by mass spectrometry in neuronal cells. Our present study supports attenuated replication and pathogenicity of Omicron variants but also highlights their newly infectious characteristics in the lung and brain, especially with BA.5.2 demonstrating enhanced immune evasion and neural damage that could exacerbate neurological sequelae.

Keywords

BA.2.75; BA.5.2; Delta; SARS-CoV-2; Spike protein; hACE2 knock-in mice; neurological dysfunction; γ-secretase.

Figures
Products