Reciprocal control of Mycobacterium avium and Mycobacterium tuberculosis infections by the alleles of the classic Class II H2-Aβ gene in mice

Linge, Irina; Petrova, Ekaterina; Dyatlov, Alexander; Kondratieva, Tatiana; Логунова, Н. Н.; Majorov, Konstantin; Kondratieva, Elena; Апт, А. С.

doi:10.1016/j.meegid.2019.103933

Cited by 4 publications

(2 citation statements)

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“…The B6.Sst1 carries the susceptibility allele of the Scl11a1. In addition, it carries the MHC class II allele b of the H2-Aβ that has been also associated with increased lung pathology in M.av-infected mice (49).…”

Section: Discussionmentioning

confidence: 99%

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Rosenbloom

Gavrish

Seidel

et al. 2021

Preprint

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Pulmonary infections caused by the group of nontuberculosis mycobacteria (NTM), Mycobacterium avium complex (MAC), are increasing worldwide and a growing public health concern. Pulmonary granulomas are the hallmark of MAC lung infection, yet reliable correlates of granuloma progression and susceptibility in immunocompetent hosts are poorly defined. The development of mouse models that recapitulate the diversity of granulomas seen in MAC pulmonary disease in humans is crucial to study mechanisms of susceptibility in humans and for preclinical evaluation of therapeutics. Unlike widely used inbred mouse strains, mice that carry the mutant allele at the genetic locus sst1 develop human-like pulmonary tuberculosis featuring well-organized caseating granulomas. These mice became instrumental in pre-clinical testing of novel interventions. In this study, we tested whether the B6.Sst1S that carries the sst1 mutant allele on standard B6 background develop more advanced pulmonary infection with NTM M. avium spp. hominissuis (M.av). To assess pulmonary disease progression, we utilized traditional semi-quantitative histomorphological evaluation and fluorescent multiplex immunohistochemistry (fmIHC) in combination with whole slide imaging and digital image analysis. After infection with the laboratory M.av strain 101, the B6.Sst1S pulmonary lesions progressed 12 to 20 weeks post infection, although we did not observe the formation of necrotic granulomas during this interval. Using fmIHC, we determined that the disease progression was associated with a steadily increasing proportion of mycobacteria infected Arg1+ and double positive iNOS+Arg1+ macrophages. The B6.Sst1S granulomas had a greater proportion of Arg1+ and double positive iNOS+Arg1+ macrophages, and decreased T cell density, as compared to wild type B6 mice. Thus, the genetic composition of the B6.Sst1S mice renders them more susceptible to pulmonary M.av infection. In combination with more virulent clinical isolates of M.av these mice could provide an improved mouse model that recapitulates more severe pulmonary disease in humans. The Arg1 macrophage expression in this model combined with automated fmIHC could serve as a sensitive biomarker for the unbiased assessment of medical countermeasures against NTM infection.

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Section: Discussionmentioning

confidence: 99%

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Rosenbloom

Gavrish

Seidel

et al. 2021

Preprint

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show abstract

“…This mouse strain also carries the susceptibility allele of the Scl11a1 gene that has been identified as a major genetic factor controlling replication of taxonomically unrelated intracellular pathogens including M.av [ 40 ]. It also carries the MHC class II allele b of the H2-Aβ that has been associated with increased lung pathology in M.av-infected mice [ 41 ]. Therefore, we postulated that the genetic composition of the B6.Sst1S mice may provide a model of pulmonary NTM infections that better resembles destructive pulmonary NTM infections in immunocompetent, but susceptible humans.…”

Section: Introductionmentioning

confidence: 99%

Progression and Dissemination of Pulmonary Mycobacterium Avium Infection in a Susceptible Immunocompetent Mouse Model

Rosenbloom

Gavrish

Tseng

et al. 2022

IJMS

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Pulmonary infections caused by the group of nontuberculosis mycobacteria (NTM), Mycobacterium avium complex (MAC), are a growing public health concern with incidence and mortality steadily increasing globally. Granulomatous inflammation is the hallmark of MAC lung infection, yet reliable correlates of disease progression, susceptibility, and resolution are poorly defined. Unlike widely used inbred mouse strains, mice that carry the mutant allele at the genetic locus sst1 develop human-like pulmonary tuberculosis featuring well-organized caseating granulomas. We characterized pulmonary temporospatial outcomes of intranasal and left intrabronchial M. avium spp. hominissuis (M.av) induced pneumonia in B6.Sst1S mice, which carries the sst1 mutant allele. We utilized traditional semi-quantitative histomorphological evaluation, in combination with fluorescent multiplex immunohistochemistry (fmIHC), whole slide imaging, and quantitative digital image analysis. Followingintrabronchiolar infection with the laboratory M.av strain 101, the B6.Sst1S pulmonary lesions progressed 12–16 weeks post infection (wpi), with plateauing and/or resolving disease by 21 wpi. Caseating granulomas were not observed during the study. Disease progression from 12–16 wpi was associated with increased acid-fast bacilli, area of secondary granulomatous pneumonia lesions, and Arg1+ and double positive iNOS+/Arg1+ macrophages. Compared to B6 WT, at 16 wpi, B6.Sst1S lungs exhibited an increased area of acid-fast bacilli, larger secondary lesions with greater Arg1+ and double positive iNOS+/Arg1+ macrophages, and reduced T cell density. This morphomolecular analysis of histologic correlates of disease progression in B6.Sst1S could serve as a platform for assessment of medical countermeasures against NTM infection.

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Current topics of molecular mycobacteriology

Mokrousov

2019

Infection, Genetics and Evolution

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Reciprocal control of Mycobacterium avium and Mycobacterium tuberculosis infections by the alleles of the classic Class II H2-Aβ gene in mice

Cited by 4 publications

References 44 publications

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Dissemination and progression of pulmonaryMycobacterium aviuminfection in mouse model is associated with type 2 macrophage activation

Progression and Dissemination of Pulmonary Mycobacterium Avium Infection in a Susceptible Immunocompetent Mouse Model

Current topics of molecular mycobacteriology

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