Intestinal damage precedes mucosal immune dysfunction in SIV infection

Area of Science:

• Immunology
• Virology
• Gastroenterology

Background:

• HIV and SIV infections cause mucosal dysfunction, including epithelial barrier damage, Th17 cell loss, neutrophil infiltration, and microbial translocation.
• The precise timing and sequence of these events remain unclear, hindering understanding of disease initiation.

Purpose of the Study:

• To longitudinally evaluate the kinetics of mucosal and systemic immune responses, microbial translocation, and epithelial changes after SIV infection.
• To determine if epithelial damage or immune dysfunction initiates the cycle of mucosal damage in SIV infection.

Main Methods:

• Rhesus macaques were infected intrarectally with SIV, and longitudinal assessments of T-cell activation, microbial translocation markers, Th17 cell and neutrophil frequencies were performed.
• Colon proteome analysis was conducted to identify early molecular pathway alterations.

Main Results:

• Increased T-cell activation (HLA-DR+) and reduced peripheral zonulin were observed 3-14 days post-infection.
• Microbial translocation was evident by 14 days post-infection.
• Epithelial structural protein pathways were downregulated by 3 days post-SIV, preceding Th17 cell depletion (14-28 days post-SIV) and gut neutrophil accumulation.

Conclusions:

• Epithelial damage, indicated by altered structural protein pathways, occurs before significant immune dysfunction like Th17 cell loss or neutrophil infiltration.
• These findings suggest that epithelial barrier damage is an early event that may initiate the cycle of mucosal dysfunction in SIV infection.