Effects and mechanism of Aβ1-42 on EV-A71 replication

  • Virol J. 2022 Sep 20;19(1):151. doi: 10.1186/s12985-022-01882-3.
Ming Zhong  1  2 ,  Huiqiang Wang  1  2 ,  Haiyan Yan  1  2 ,  Shuo Wu  1  2 ,  Kun Wang  1  2 ,  Lu Yang  1  2 ,  Boming Cui  1  2 ,  Mengyuan Wu  1  2 ,  Yuhuan Li  3  4
Affiliations
  • 1. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan xili, Beijing, 100050, China.
  • 2. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 3. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan xili, Beijing, 100050, China. [email protected].
  • 4. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. [email protected].
PMID: 36127711 DOI: 10.1186/s12985-022-01882-3
Abstract

Background: β-Amyloid (Aβ) protein is a pivotal pathogenetic factor in Alzheimer's disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aβ to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aβ exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against Other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic Enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aβ and Other virus infections, this study aimed to investigate the potent activity of Aβ on EV-A71 Infection and extended the potential function of Aβ in Other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases.

Methods: Aβ peptides 1-42 are a major pathological factor of senile plaques in Alzheimer's disease (AD). Thus, we utilized Aβ1-42 as a test subject to perform our study. The production of monomer Aβ1-42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aβ1-42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aβ1-42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay.

Results: We found that EV-A71 Infection induced Aβ production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aβ1-42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aβ1-42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aβ1-42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aβ1-42 to prevent viruses from infecting cells.

Conclusions: Our findings unveiled that Aβ1-42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aβ in Other non-envelope viruses linked to infectious neurological diseases.

Keywords
Capsid protein VP1; Enterovirus A 71; Scavenger receptor class B member 2; β-Amyloid protein.
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