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Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium.

Kondratieva E, Logunova N, Majorov K, Averbakh M, Apt A - PLoS ONE (2010)

Bottom Line: The role of host genetics in granuloma formation is not well defined.Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts.The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.

ABSTRACT
Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i) characteristics of susceptibility to two infections in vivo; (ii) architecture of lung granulomata assessed by immune staining; and (iii) expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

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B6 mice are more resistant to M. tuberculosis infection compared to I/St mice.Their survival time (A, P<0.001, Gohen's criterion for survival curves) is longer and lung CFU counts (B, P<0.01-0.001 at different time points, ANOVA) are lower. Lung macrophages of I/St, but not of B6, mice inhibit multiplication of M. avium after in vitro infection within a high range of MOI (C). The rate of mycobacterial growth was measured by [3H]-uracil uptake at 72 h after establishing co-cultures. 1 µCi/well [3H]-uracil was added for the last 18 h of incubation. The wells containing mycobacteria alone at numbers corresponding to each MOI served as controls. Results obtained in one of three similar experiments are expressed as mean CPMs ± SD for triplicate cultures; interstrain differences are statistically significant (P<0.01, Mann-Whitney's U-test).
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pone-0010515-g001: B6 mice are more resistant to M. tuberculosis infection compared to I/St mice.Their survival time (A, P<0.001, Gohen's criterion for survival curves) is longer and lung CFU counts (B, P<0.01-0.001 at different time points, ANOVA) are lower. Lung macrophages of I/St, but not of B6, mice inhibit multiplication of M. avium after in vitro infection within a high range of MOI (C). The rate of mycobacterial growth was measured by [3H]-uracil uptake at 72 h after establishing co-cultures. 1 µCi/well [3H]-uracil was added for the last 18 h of incubation. The wells containing mycobacteria alone at numbers corresponding to each MOI served as controls. Results obtained in one of three similar experiments are expressed as mean CPMs ± SD for triplicate cultures; interstrain differences are statistically significant (P<0.01, Mann-Whitney's U-test).

Mentions: Previously we have demonstrated that I/St and B6 mice display, respectively, resistant and susceptible phenotype when infected with M. avium [15]. Using several infection routes and doses, we have shown also that I/St mice are susceptible to M. tuberculosis [14], [16], [17] and that their interstitial lung macrophages display an impaired capacity to inhibit M. tuberculosis growth [18]. Since not B6, but A/Sn, mice were always used in our previous TB studies as the resistant counterpart, in this work we directly compared disease progression in I/St and B6 mice after aerosol M. tuberculosis challenge. Groups of corresponding animals were infected with ∼102 CFU of M. tuberculosis H37Rv, and lung CFU counts and survival of animals were assessed. I/St mice developed substantially more severe course of the disease, compared to B6 mice, both in terms of survival time (Fig. 1A, P<0.001, Gohen's criterion for survival curves) and CFU counts (Fig. 1B, P<0.01-0.001 at different time points, ANOVA).


Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium.

Kondratieva E, Logunova N, Majorov K, Averbakh M, Apt A - PLoS ONE (2010)

B6 mice are more resistant to M. tuberculosis infection compared to I/St mice.Their survival time (A, P<0.001, Gohen's criterion for survival curves) is longer and lung CFU counts (B, P<0.01-0.001 at different time points, ANOVA) are lower. Lung macrophages of I/St, but not of B6, mice inhibit multiplication of M. avium after in vitro infection within a high range of MOI (C). The rate of mycobacterial growth was measured by [3H]-uracil uptake at 72 h after establishing co-cultures. 1 µCi/well [3H]-uracil was added for the last 18 h of incubation. The wells containing mycobacteria alone at numbers corresponding to each MOI served as controls. Results obtained in one of three similar experiments are expressed as mean CPMs ± SD for triplicate cultures; interstrain differences are statistically significant (P<0.01, Mann-Whitney's U-test).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865535&req=5

pone-0010515-g001: B6 mice are more resistant to M. tuberculosis infection compared to I/St mice.Their survival time (A, P<0.001, Gohen's criterion for survival curves) is longer and lung CFU counts (B, P<0.01-0.001 at different time points, ANOVA) are lower. Lung macrophages of I/St, but not of B6, mice inhibit multiplication of M. avium after in vitro infection within a high range of MOI (C). The rate of mycobacterial growth was measured by [3H]-uracil uptake at 72 h after establishing co-cultures. 1 µCi/well [3H]-uracil was added for the last 18 h of incubation. The wells containing mycobacteria alone at numbers corresponding to each MOI served as controls. Results obtained in one of three similar experiments are expressed as mean CPMs ± SD for triplicate cultures; interstrain differences are statistically significant (P<0.01, Mann-Whitney's U-test).
Mentions: Previously we have demonstrated that I/St and B6 mice display, respectively, resistant and susceptible phenotype when infected with M. avium [15]. Using several infection routes and doses, we have shown also that I/St mice are susceptible to M. tuberculosis [14], [16], [17] and that their interstitial lung macrophages display an impaired capacity to inhibit M. tuberculosis growth [18]. Since not B6, but A/Sn, mice were always used in our previous TB studies as the resistant counterpart, in this work we directly compared disease progression in I/St and B6 mice after aerosol M. tuberculosis challenge. Groups of corresponding animals were infected with ∼102 CFU of M. tuberculosis H37Rv, and lung CFU counts and survival of animals were assessed. I/St mice developed substantially more severe course of the disease, compared to B6 mice, both in terms of survival time (Fig. 1A, P<0.001, Gohen's criterion for survival curves) and CFU counts (Fig. 1B, P<0.01-0.001 at different time points, ANOVA).

Bottom Line: The role of host genetics in granuloma formation is not well defined.Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts.The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.

ABSTRACT
Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i) characteristics of susceptibility to two infections in vivo; (ii) architecture of lung granulomata assessed by immune staining; and (iii) expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

Show MeSH
Related in: MedlinePlus