PhD Candidate Rutgers Grad. Sch. of Biomed. Sci. New Brunswick, New Jersey, United States
Disclosure(s):
Sainetra Sridhar, BA: No financial relationships to disclose
Introduction/Rationale: O’nyong-nyong virus (ONNV) is a mosquito-transmitted alphavirus closely related to chikungunya virus (CHIKV) that causes fever and debilitating polyarthritis in humans. To dissect immunopathogenic mechanisms driving ONNV-induced disease, we modeled infection in C57BL/6 mice. During the subacute phase (10 days post-infection), persistent viral RNA in the footpad coincided with a CXCL10-dominated chemokine milieu and pronounced infiltration of CD4+ T cells displaying an effector (CD44+CD62L-) phenotype, whereas CD8+ T cell recruitment was restricted. We sought to further explore the role of CXCL10 in this early phase of the disease.
Methods: We used C57Bl/6 mice to model ONNV infection, inoculating mice with 10^5 PFU of the virus through footpad injections. To perturb CXCL10 signaling we intraparitoneally administered an anti-cxcl10 antibody or atorvastatin. We collected infected footpads, draining lymph nodes and spleens at 10 days post infection to profile cellular composition and phenotype via flow cytometry and the expression of inflammatory markers by RT-qPCR.
Results: In the draining popliteal lymph node, CD4+ but not CD8+ T cells upregulated CXCR3 and activation markers, consistent with selective chemotactic responsiveness to CXCL10. Functional perturbation of this axis, using a CXCL10-neutralizing antibody or pharmacologic downregulation via atorvastatin, significantly reduced CD4+ and monocyte accumulation within the infected footpad, while enhancing activation and functional markers on lymph node CD8+ T cells. Atorvastatin treatment also decreased local viral burden, implicating CXCL10-driven inflammation in sustaining viral persistence
Conclusion: These findings identify the CXCL10-CXCR3 signaling axis as a key immunoregulatory node that skews the local immune response toward pathogenic CD4-driven inflammation at the expense of cytotoxic antiviral immunity. Modulating this chemokine circuit may recalibrate local immunity and mitigate alphavirus-associated arthritic disease.
