Research output: Contribution to journal › Article › peer-review
Insight into blood proteinase-inhibitor system and pathogenesis of renal tuberculosis induced by phylogenomically different Mycobacterium tuberculosis strains in rabbit model. / Esmedlyaeva, D.; Mokrousov, I.; Alexeyeva, N.; Blum, N.; Dyakova, M.; Dogonadze, M.; Vyazovaya, A.; Polev, D.; Ariél, B.; Vinogradova, T.; Yablonsky, P.
In: BMC Nephrology, Vol. 26, No. 1, 473, 20.08.2025.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Insight into blood proteinase-inhibitor system and pathogenesis of renal tuberculosis induced by phylogenomically different Mycobacterium tuberculosis strains in rabbit model
AU - Esmedlyaeva, D.
AU - Mokrousov, I.
AU - Alexeyeva, N.
AU - Blum, N.
AU - Dyakova, M.
AU - Dogonadze, M.
AU - Vyazovaya, A.
AU - Polev, D.
AU - Ariél, B.
AU - Vinogradova, T.
AU - Yablonsky, P.
N1 - Export Date: 01 November 2025; Cited By: 0; Correspondence Address: D. Esmedlyaeva; St. Petersburg Research Institute of Phthisiopulmonology, St. Petersburg, 191036, Russian Federation; email: Diljara-e@yandex.ru; I. Mokrousov; St. Petersburg Pasteur Institute, St. Petersburg, 197101, Russian Federation; email: imokrousov@mail.ru
PY - 2025/8/20
Y1 - 2025/8/20
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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. © 2025 Elsevier B.V., All rights reserved.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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. © 2025 Elsevier B.V., All rights reserved.
KW - Adaptation
KW - Cystatin c
KW - Extracellular matrix
KW - Matrix metalloproteinases
KW - Mycobacterium tuberculosis
KW - Proteinase inhibitors
KW - Renal tuberculosis
KW - Virulence
KW - Whole genome sequencing
KW - albumin
KW - biological marker
KW - cefazolin
KW - ceruloplasmin
KW - creatinine
KW - genomic DNA
KW - matrix metalloproteinase
KW - proteinase inhibitor
KW - thiopental
KW - tiletamine plus zolazepam
KW - urea
KW - cystatin C
KW - anesthesia
KW - animal experiment
KW - animal model
KW - animal tissue
KW - Article
KW - bacterial strain
KW - bacterium culture
KW - biochemical analysis
KW - bioinformatics
KW - computer assisted tomography
KW - controlled study
KW - delayed hypersensitivity
KW - DNA extraction
KW - histology
KW - histopathology
KW - inflammation
KW - kidney biopsy
KW - kidney injury
KW - kidney parenchyma
KW - kidney tissue
KW - male
KW - nonhuman
KW - pathogenesis
KW - phylogenomics
KW - rabbit model
KW - real time polymerase chain reaction
KW - renal tuberculosis
KW - survival analysis
KW - urea nitrogen blood level
KW - whole genome sequencing
KW - article
KW - etiology
KW - extracellular matrix
KW - pharmacokinetics
UR - https://www.mendeley.com/catalogue/89f098ad-0717-3be0-9acc-aece569c3c13/
U2 - 10.1186/s12882-025-04411-w
DO - 10.1186/s12882-025-04411-w
M3 - статья
C2 - 40836283
VL - 26
JO - BMC Nephrology
JF - BMC Nephrology
SN - 1471-2369
IS - 1
M1 - 473
ER -
ID: 143196845