Insight into blood proteinase-inhibitor system and pathogenesis of renal tuberculosis induced by phylogenomically different Mycobacterium tuberculosis strains in rabbit model

This study aimed to evaluate the impact of different Mycobacterium tuberculosis strains on the blood proteinase-inhibitor system and structural changes in the renal parenchyma during the pathogenesis of renal tuberculosis in a rabbit model. Renal tuberculosis was modeled on 60 male Soviet Chinchilla rabbits. The susceptible virulent strain M. tuberculosis H37Rv (Euro-American lineage, group 1) and the low-lethal multidrug-resistant strain 5582 (Beijing Central Asian/Russian cluster; group 2) were injected into the cortex of the lower pole of the left kidney. Blood levels of biomarkers and enzymes were measured at baseline (pre-infection), and 2.5 and 22 weeks after infection. Morphological changes in nephron structures were assessed using 26 indicators at 22 weeks. Whole genome sequencing of M. tuberculosis DNA was performed on the DNBSEQ-G50 MGI platform. At 2.5 weeks, group 1 exhibited a significant increase in matrix metalloproteinases (MMP)-1/9 and cystatin C compared to group 2 (p = 0.02). After 22 weeks, group 1 showed elevated levels of MMP-9 and ceruloplasmin, alongside reduced levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), cystatin C, and albumin (p = 0.02). Group 1 demonstrated a larger area of specific inflammation and less severe fibrotic changes compared to group 2 (p = 0.02). Genome of clinical strain 5582 harboured 55 frameshift and 8 stop codon mutations some of which were in genes known to be involved in intracellular survival and pathogenesis. In quantitative terms, the structural changes observed in the kidneys of rabbits were inversely related to the virulence of the strains. Specifically, the more virulent strain (H37Rv) induces less pronounced structural changes. Renal tuberculosis induced by H37Rv is characterized by a pronounced imbalance in the MMP/TIMP-1 system, marked by increased MMP-1 and − 9 levels and decreased TIMP-1 levels in the blood. This imbalance is associated with structural kidney damage, including specific and paraspecific changes typical of an immediate hypersensitivity reaction. In contrast, infection with Beijing 5582 maintained a relative balance in the MMP/inhibitor system, with a significant increase in cystatin C and moderately pronounced productive changes in the renal parenchyma, consistent with a delayed hypersensitivity reaction.