2. Academic Validation
  3. Receptor affinity-selective differential dynamics of membrane fusion initiation govern deltacoronavirus cross-species transmission

Receptor affinity-selective differential dynamics of membrane fusion initiation govern deltacoronavirus cross-species transmission

  • Sci China Life Sci. 2025 Oct 24. doi: 10.1007/s11427-025-2985-1.
Da An 1,  Qi Peng 2,  Yong-Hao Ma 1 3,  Wenguang Hong 1,  Yi Pei 1,  Shiyu Liu 2,  Yan Li 1,  Jizong Li 2,  Yanke Shan 4 5,  Yulong Yin 6,  Bin Li 7 8,  Fei Liu 9 10
Affiliations

Affiliations

  • 1 Joint International Research Laboratory of Animal Health and Food Safety of Ministry of Education, Single Molecule Biochemistry & Biomedicine Laboratory (Sinmolab), Nanjing Agricultural University, Nanjing, 210095, China.
  • 2 Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Veterinary Medicine, Key Laboratory of Veterinary Biological Engineering and Technology, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China.
  • 3 Sanya Institute of Nanjing Agricultural University, Sanya, 572000, China.
  • 4 Joint International Research Laboratory of Animal Health and Food Safety of Ministry of Education, Single Molecule Biochemistry & Biomedicine Laboratory (Sinmolab), Nanjing Agricultural University, Nanjing, 210095, China. shanyk26@njau.edu.cn.
  • 5 Sanya Institute of Nanjing Agricultural University, Sanya, 572000, China. shanyk26@njau.edu.cn.
  • 6 Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China. yinyulong@isa.ac.cn.
  • 7 Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Veterinary Medicine, Key Laboratory of Veterinary Biological Engineering and Technology, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China. libinana@126.com.
  • 8 Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Jiangsu Key Laboratory of Zoonoses, Yangzhou University, Yangzhou, 225009, China. libinana@126.com.
  • 9 Joint International Research Laboratory of Animal Health and Food Safety of Ministry of Education, Single Molecule Biochemistry & Biomedicine Laboratory (Sinmolab), Nanjing Agricultural University, Nanjing, 210095, China. feiliu24@njau.edu.cn.
  • 10 Sanya Institute of Nanjing Agricultural University, Sanya, 572000, China. feiliu24@njau.edu.cn.
PMID: 41144156 DOI: 10.1007/s11427-025-2985-1
Abstract

Porcine deltacoronavirus (PDCoV) exploits both human Aminopeptidase N (hAPN) and porcine APN (pAPN) as receptors, with a higher affinity for hAPN than for pAPN through conserved interaction sites. However, despite this affinity, PDCoV is rarely pathogenic to humans, suggesting that the utilization dynamics of APN homologs by PDCoV are distinct, which is crucial in cross-species transmission but poorly understood. Here, we employed single-virus tracking to visualize and dissect the entry dynamics of PDCoV facilitated by APN. It was discovered that APN homologs bind PDCoV simultaneously, yet the times required for the initiation of membrane fusion and internalization differ significantly. Although high-affinity hAPN, rather than low-affinity pAPN, accompanies PDCoV during internalization, low-affinity pAPN initiates PDCoV internalization approximately 20 s faster than high-affinity hAPN, with caveolae-mediated endocytosis being more predominant and productive. Depending on the cell species, low-affinity pAPN induced a 5% to 25% greater proportion and a 0.6 to 4.3 min faster cell surface fusion, contributing to efficient Infection. In contrast, high-affinity hAPN resulted in a 5% to 25% greater proportion and a 5 to 15 min faster endosomal fusion, potentially promoting immune evasion. We further demonstrated that the binding affinities between the PDCoV receptor-binding domain (RBD) and APN homologs are key determinants of the differential kinetics, driving flexible transitions between the two fusion pathways. This receptor affinity-selective PDCoV entry kinetics evolves an optimal balance of immune evasion and rapid Infection, underscoring the potential for PDCoV interspecies transmission and the need for its vigilant surveillance.

Keywords

cross-species transmission; deltacoronavirus; differential dynamics; internalization; membrane fusion; single-virus tracking.

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