Genetic control of susceptibility to pulmonary infection with Chlamydia pneumoniae in the mouse

Min‐Oo, Gundula; Lindqvist, Lisa; Vaglenov, A.; Wang, C; Fortin, P.; Li, Y; Kaltenboeck, Bernhard; Gros, Philippe

doi:10.1038/sj.gene.6364450

Cited by 14 publications

(18 citation statements)

References 31 publications

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“…That observation was confirmed and extended in animal experiments (4,8,38). Inbred A/J and B6 mice differ profoundly in their inflammatory responses and susceptibilities to pulmonary infection with C. pneumoniae in regard to the lung chlamydial loads and lung pathology (30).…”

supporting

confidence: 49%

“…In contrast, B6 mice initially eliminate C. pneumoniae efficiently and mount an excessive inflammatory response that results in substantial lung disease (30). Min-Oo et al (38) mapped a recessive murine quantitative trait locus that accounts for ϳ30% of the variance in C. pneumoniae lung loads to a region on chromosome 17 that overlaps with the major histocompatibility complex locus.…”

mentioning

confidence: 99%

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Temporal Delay of Peak T-Cell Immunity DeterminesChlamydia pneumoniaePulmonary Disease in Mice

Wang¹,

Ginkel²,

Kim³

et al. 2008

Infect Immun

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Severe chlamydial disease typically occurs after previous infections and results from a hypersensitivity response that is also required for chlamydial elimination. Here, we quantitatively dissected the immune and disease responses to repeated Chlamydia pneumoniae lung infection by multivariate modeling with four dichotomous effects: mouse strain (A/J or C57BL/6), dietary protein content (14% protein and 0.3% L-cysteine-0.9% L-arginine, or 24% protein and 0.5% L-cysteine-2.0% L-arginine), dietary antioxidant content (90 IU ␣-tocopherol/kg body weight versus 450 IU ␣-tocopherol/kg and 0.1% g L-ascorbate), and time course (3 or 10 days postinfection). Following intranasal C. pneumoniae challenge, C57BL/6 mice on a low-protein/low-antioxidant diet, but not C57BL/6 mice on other diets or A/J mice, exhibited profoundly suppressed early lung inflammatory and pan-T-cell (CD3␦ ؉ ) and helper T-cell (CD45) responses on day 3 but later strongly exacerbated disease on day 10. Contrast analyses characterized severe C. pneumoniae disease as being a delayed-type hypersensitivity (DTH) response with increased lung macrophage and Th1 cell marker transcripts, increased Th1:Th2 ratios, and Th1 cytokine-driven inflammation. Results from functional analyses by DTH, enzymelinked immunospot, and immunohistofluorescence assays were consistent with the results obtained by transcript analysis. Thus, chlamydial disease after secondary infection is a temporal dysregulation of the T-cell response characterized by a profoundly delayed T-helper cell response that results in a failure to eliminate the pathogen and provokes later pathological Th1 inflammation. This delayed T-cell response is under host genetic control and nutritional influence. The mechanism that temporally and quantitatively regulates the host T-cell population is the critical determinant in chlamydial pathogenesis.

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supporting

confidence: 49%

mentioning

confidence: 99%

Temporal Delay of Peak T-Cell Immunity DeterminesChlamydia pneumoniaePulmonary Disease in Mice

Wang¹,

Ginkel²,

Kim³

et al. 2008

Infect Immun

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“…Although this region is usually associated with antigen-presenting H-2 genes of adaptive immunity, it also contains many genes associated with innate immune defense, including complement components, certain TNF family members, and stress-related proteins (15). Resistance of mice to a variety of pathogens including Plasmodium berghei (14), T. crassiceps (10), Chlamydia pneumoniae (30), and Streptococcus pyogenes (13) has been mapped to the MHC region. Similar to what we have found for Y. pestis, an early innate immune defense appears to be responsible for the observed resistance to S. pyogenes.…”

Section: Discussionmentioning

confidence: 99%

The Resistance of BALB/cJ Mice toYersinia pestisMaps to the Major Histocompatibility Complex of Chromosome 17

Turner¹,

McAllister

Xu³

et al. 2008

Infect Immun

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Yersinia pestis, the causative agent of plague, has been well studied at the molecular and genetic levels, but little is known about the role that host genes play in combating this highly lethal pathogen. We challenged several inbred strains of mice with Y. pestis and found that BALB/cJ mice are highly resistant compared to susceptible strains such as C57BL/6J. This resistance was observed only in BALB/cJ mice and not in other BALB/c substrains. Compared to C57BL/6J mice, the BALB/cJ strain exhibited reduced bacterial burden in the spleen and liver early after infection as well as lower levels of serum interleukin-6. These differences were evident 24 h postinfection and became more pronounced with time. Although a significant influx of neutrophils in the spleen and liver was exhibited in both strains, occlusive fibrinous thrombi resulting in necrosis of the surrounding tissue was observed only in C57BL/6J mice. In an effort to identify the gene(s) responsible for resistance, we measured total splenic bacteria in 95 F 2 mice 48 h postinfection and performed quantitative trait locus mapping using 58 microsatellite markers spaced throughout the genome. This analysis revealed a single nonrecessive plague resistance locus, designated prl1 (plague resistance locus 1), which coincides with the major histocompatibility complex of chromosome 17. A second screen of 95 backcrossed mice verified that this locus confers resistance to Y. pestis early in infection. Finally, eighth generation backcrossed mice harboring prl1 were found to maintain resistance in the susceptible C57BL/6J background. These results identify a novel genetic locus in BALB/cJ mice that confers resistance to Y. pestis.

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“…57 In addition to encoding proteins critical for antigen presentation to T cells, this region contains various immunity-related genes such as the complement cascade components C4a, C4b and C2, and the cytokines Tnf and Lta. This genomic region has been associated with susceptibility to various models of pulmonary infection including Chlamydia pneumoniae 58,59 and Mycobacterium tuberculosis. 60,61 One previous report of female H-2 congenic C57BL/10 strains bearing the H-2 k/k haplotype also demonstrated an increased cryptococcal burden in the liver 39 days following infection.…”

Section: Genetic Control Of Cryptococcal Pneumoniamentioning

confidence: 99%

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

et al. 2008

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Cryptococcus neoformans is a major cause of fungal pneumonia, meningitis and disseminated disease in the immune compromised host. Here we have used a clinically relevant model to investigate the genetic determinants of susceptibility to progressive cryptococcal pneumonia in C57BL/6J and CBA/J inbred mice. At 5 weeks after infection, the lung fungal burden was over 1000-fold higher in C57BL/6J compared to CBA/J mice. A genome-wide scan performed on 210 male and 203 female (CBA/J Â C57BL/6J) F2 progeny using lung colony-forming units as a quantitative trait revealed a sex difference in genetic architecture with three loci (designated Cnes1-Cnes3) associated with susceptibility to cryptococcal pneumonia. Single locus analysis identified significant loci on chromosomes 3 (Cnes1) and 17 (Cnes2) with logarithm of the odds (LOD) scores of 4.09 (P ¼ 0.0110) and 7.30 (Po0.0001) that explained 8.9 and 15.9% of the phenotypic variance, respectively, in female CBAB6F2 and one significant locus on chromosome 17 (Cnes3) with a LOD score of 4.04 (P ¼ 0.010) that explained 8.6% of the phenotypic variance in male CBAB6F2 mice. Genome-wide pair-wise analysis revealed significant quantitative trait locus interactions in both the female and male CBAB6F2 progeny that collectively explained 43.8 and 19.5% of phenotypic variance in each sex, respectively.

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Genetic control of susceptibility to pulmonary infection with Chlamydia pneumoniae in the mouse

Cited by 14 publications

References 31 publications

Temporal Delay of Peak T-Cell Immunity DeterminesChlamydia pneumoniaePulmonary Disease in Mice

Temporal Delay of Peak T-Cell Immunity DeterminesChlamydia pneumoniaePulmonary Disease in Mice

The Resistance of BALB/cJ Mice toYersinia pestisMaps to the Major Histocompatibility Complex of Chromosome 17

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

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