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Human SCARB2 Acts as a Cellular Associator for Helping Coxsackieviruses A10 Infection
Shu-Ling Yu1,2, Nai-Hsiang Chung1,3,4, Yu-Ching Lin1
1Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan.
Viruses
|April 28, 2023
Summary
Coxsackievirus A10 (CVA10) uses human SCARB2 (hSCARB2) as an entry receptor, causing severe disease in transgenic mice. This finding aids in developing CVA10 treatments and understanding its pathogenesis.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Coxsackievirus A10 (CVA10) causes hand, foot, and mouth disease (HFMD) and herpangina, potentially leading to severe neurological complications in children.
- Unlike enterovirus 71 (EV71), CVA10 does not primarily utilize the human SCARB2 (hSCARB2) receptor for infection, instead employing receptors like KREMEN1.
Purpose of the Study:
- To investigate the role of human SCARB2 (hSCARB2) in Coxsackievirus A10 (CVA10) infection and pathogenesis.
- To establish a mouse model for studying CVA10-induced disease and evaluating potential therapeutics.
Main Methods:
- Infection assays using mouse cells expressing human SCARB2 (3T3-SCARB2) and parental NIH3T3 cells.
- siRNA-mediated knockdown of hSCARB2 and KREMEN1 in human cells to assess their role in CVA10 entry.
- Co-immunoprecipitation to confirm physical interactions between CVA10 capsid protein VP1 and cellular receptors.
- Challenge studies in 12-day-old hSCARB2-transgenic mice and wild-type littermates with CVA10.
- Histopathological examination and viral load quantification in infected tissues.
- Vaccination studies using formalin-inactivated CVA10 to assess protective immunity.
Main Results:
- CVA10 efficiently infected and replicated in 3T3-SCARB2 cells but not in NIH3T3 cells, indicating hSCARB2 facilitates CVA10 entry.
- Knockdown of hSCARB2 and KREMEN1 significantly inhibited CVA10 infection in human cells.
- Co-immunoprecipitation confirmed direct interaction between CVA10 VP1 and both hSCARB2 and KREMEN1.
- hSCARB2-transgenic mice exhibited severe limb paralysis, high mortality, and extensive viral replication in muscles, spinal cords, and brains following CVA10 challenge.
- Vaccination with formalin-inactivated CVA10 conferred protective immunity, reducing disease severity and viral loads.
Conclusions:
- Human SCARB2 (hSCARB2) acts as an essential co-receptor, significantly aiding Coxsackievirus A10 (CVA10) infection.
- hSCARB2-transgenic mice provide a valuable model for studying CVA10 pathogenesis and for the preclinical evaluation of anti-CVA10 therapeutics.
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