MALIHA ALIKHAN1, JULI JAW1,2, IONA SCHUSTER3, PEEMAPAT PRAKONGTHAM1, LANI SHOCHET1,2, PAMELA HALL1, CHUNNI LU1, MICHAEL HICKEY1, MARIAPIA DEGLI-ESPOSTI3, ARTHUR KITCHING1,2,4
1Monash University Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Australia, 2Department of Nephrology, Monash Health, Clayton, Australia, 3Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia, 4Department of Paediatric Nephrology, Monash Health, Clayton, Australia
Biography:
Professor Richard Kitching is a nephrologist physician-scientist working in translational and clinical research relating to vasculitis and immune kidney disease.
Aim:
To define the role of latent CMV infection in rapidly progressive glomerulonephritis (RPGN).
Background:
Latent CMV infection is associated with adverse outcomes in ANCA-associated vasculitis. Although CMV is renotropic, CMV’s role in native kidney disease has not been assessed.
Methods:
Mice were infected with murine (m)CMV, which was latent by 7 weeks. In vivo fluorescenated anti-CD45 antibodies distinguished intravascular (IV+) from tissue (IV-) intrarenal cells (flow cytometry). Commencing at week 7, anti-MPO autoimmunity after MPO immunisation, experimental anti-MPO GN, and nephrotoxic serum nephritis (NTN, days 21 and 35) were studied.
Results:
CMV infection led to a persistent increase in IV+ and IV- intrarenal leukocytes after the virus had entered latency (organ CMV plaque assay). Intrarenal mCMV-specific CD8+ cells were prominent (20.0±1.6% IV+, 14.9±0.8% IV-CD8+ cells, tetramer staining). In vivo multiphoton microscopy showed that CMV induced more intravascular T cells in glomeruli and CX3CR1+ interstitial CD8+ T cells. Latent CMV infection heightened autoimmunity after MPO immunization (increased MPO-stimulated IL-17A/IFNγ ELISPOT, days 10 and 21), but anti-ovalbumin responses were unaffected by infection. In experimental anti-MPO glomerulonephritis (day 4), latent infection increased intrarenal CD4+ and CD8+ T cells, and macrophages. Intrarenal T cells in mCMV-infected mice with glomerulonephritis exhibited heightened TNF/IFNγ production. CMV-infected mice with anti-MPO glomerulonephritis developed increased proteinuria, but similar histological injury. However, in the more prolonged NTN model, latent CMV infection aggravated crescent formation (4.4±1.3 vs 12.4±2.8% day 21, 4.4±2.0 vs 14.6±3.7% day 35, p<0.03), including more CD4+ and CD8+ T cells, and CD11b+Ly6C+ inflammatory monocytes.
Conclusion:
Latent CMV infection causes persistent pro-inflammatory intrarenal leukocyte accumulation. Systemic anti-MPO autoimmunity and renal inflammation are enhanced in latent infection, with the potential to aggravate human RPGN.