CD163 SRCR5 Mutations to Block PRRSV Genotype 2 Entry
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Solution Overview
Problem
Current methods are inadequate in providing resistance to porcine reproductive and respiratory syndrome virus (PRRSV) infection, particularly for genotype 2 strains, as they do not effectively target the specific domains of the CD163 receptor required for viral entry.
Innovation Solution
Mutations in the CD163 receptor, specifically deletions and insertions in domains such as SRCR5, PSTII, and disulfide bonds, are introduced to prevent PRRSV infection by disrupting the viral recognition and entry process, including the use of proline-arginine insertions and alanine substitutions to alter the protein structure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatment methods are used, then general protection against PRRSV is provided, but resistance to genotype 2 strains is insufficient
Solution Approach 1:
The patent applies local quality by introducing specific mutations at precise locations within the CD163 receptor protein, particularly in the SRCR5 domain and disulfide bond regions. These localized modifications alter the protein's structure and function specifically to resist genotype 2 PRRSV while maintaining overall receptor functionality. The targeted approach focuses changes on specific domains rather than the entire protein structure.
Solution Approach 2:
The patent employs parameter changes by modifying amino acid sequences, adding proline-arginine insertions, and altering disulfide bond configurations in the CD163 receptor. These parameter modifications change the physical and chemical properties of the receptor protein, enabling it to resist genotype 2 PRRSV infection while preserving its ability to bind and internalize the virus.
2Object-affected harmful factors
If CD163 receptor is modified to resist PRRSV infection, then viral entry is blocked, but cell susceptibility to infection increases
Solution Approach 1:
The patent converts the harmful effect of PRRSV binding to CD163 into a beneficial resistance mechanism. By introducing specific mutations that prevent viral attachment while maintaining the receptor's natural functions (hemoglobin-haptoglobin complex internalization), the patent transforms the vulnerability into protection. The modified receptor becomes resistant to genotype 2 strains while preserving essential cellular functions.
Solution Approach 2:
The patent segments the CD163 receptor analysis into distinct functional domains (SRCR1-SRCR9, PSTII region, disulfide bonds) and identifies specific regions critical for viral entry. By focusing modifications on the SRCR5 domain and specific disulfide bonds, the patent selectively blocks viral attachment while preserving other domains' functions, thereby maintaining cell viability and normal receptor activities.
3Reliability
If multiple mutations are introduced in CD163, then resistance to PRRSV increases, but protein structure stability may be compromised
Solution Approach 1:
The patent applies beforehand cushioning by carefully selecting and testing multiple mutation combinations before final implementation. The research systematically evaluates various amino acid substitutions, proline-arginine insertion positions, and disulfide bond modifications to predict and ensure protein stability. This preliminary testing and selection process cushions against potential structural instability that could result from multiple mutations.
Solution Approach 2:
The patent creates a composite modified CD163 protein structure that integrates multiple types of modifications (amino acid substitutions, proline-arginine insertions, disulfide bond alterations) into a cohesive functional unit. The modified receptor combines these different mutation types in specific combinations that collectively provide resistance to genotype 2 PRRSV while maintaining overall protein folding, structural integrity, and functional capability.
Data Source
AI summary
The present disclosure provides compositions and methods for decreasing permissiveness to infection by PRRSV. The methods involve inserting peptides or oligopeptides into the CD163 SRCR domain 5 to disrupt the protein structure and thereby prevent PRRSV infection. The deletion of the exon 13 region of PSTII eliminates infection. The replacement of cysteine residues with alanines in SRCR5 as a means to disrupt disulfide bond formation. The final method is the deletion of, or amino acid substitution within the SRCR4-5 interdomain region.