Investigating the Role of Nucleic Acid Sensing in the Pathogenesis of Chronic Viral Infection-Induced Chronic Kidney Disease and Autoimmunity

Abstract

Patients with chronic HIV infections, are at increased risk of developing comorbidities, with chronic kidney disease (CKD) such as immune complex glomerulonephritis (ICGN) being particularly common. Diagnosis of ICGN typically involves kidney biopsies, revealing significant deposition of immunoglobulins (Igs) and complements in the kidney glomeruli. The molecular mechanisms underlying HIV-associated CKD remain poorly understood, partly due to the lack of appropriate animal models. <br /> Our clinical study identified increased levels of autoantibodies and circulating free DNA in the HIV patients with CKD compared to those without CKD, along with a strong IFN-I response. These pathological features can be reproduced in a mouse model of neoLCMV infection. In this model, neonates of C57BL6/J mice infected with WE-LCMV develop persistent infection and displayed strong deposition of Igs and complements in the kidney glomeruli, similar to what is observed in CKD positive HIV patients. This makes the neoLCMV mouse model a valuable tool to study RNA-viral infection-associated CKD. <br /> Moreover, neoLCMV infection seems to drive the immune response towards an extrafollicular (ExFO) pathway of B cell activation. In the absence of TLR7, CKD in neoLCMV-infected mice is alleviated, accompanied with decreased autoantibodies production and a reduction in CXCR3⁺MHCII^hi ExFO plasma cells and ICOS^hiCXCR4⁺ ExFO T helper cells (ExFO-Th). <br /> Disease amelioration was also obtained by specifically deleting TLR7 signaling in B cells using TLR7^flxCD19^cre/WT mice. These mice exhibited reduced B cell differentiation and altered ExFO-Th to Treg ratios, suggesting a novel intrinsic role of TLR7 in the B and T cell activation beyond its function as an RNA sensor. Our data also showed, that IL-10 and IL-6 production, which are strongly expressed in neoLCMV mice developing CKD, were significantly reduced in the absence of TLR7 signaling in B cells. Overall, these findings highlight the crucial role of TLR7 signaling in the CKD pathogenesis during chronic RNA viral infections and suggest that targeting TLR7 could be a potential strategy for treating of preventing HIV-associated CKD.