Using Mouse Genetics to Understand Infectious Disease Pathogenesis

Dietrich, William F.

doi:10.1101/gr.173101

Cited by 14 publications

(8 citation statements)

References 101 publications

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“…Although the defective Tlr4 likely plays a role in susceptibility to bacterial infections in models using C3H/HeJ mice, the studies reported here strongly indicate the presence of multiple genetic factors in host defense against infections caused by E. coli and, potentially, other types of bacteria. This view is consistent with the multigenic nature of susceptibility or resistance to infections documented in several mouse models (17). Thus, it is important to consider genes acting individually or together with Tlr4 when using C3H/HeJ mice in models of infectious diseases.…”

Section: Introductionsupporting

confidence: 88%

Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

Suhs

Marthaler

Welch

et al. 2011

mBio

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Toll-like receptor 4 is thought to have a primary role in host defense against Escherichia coli bladder colonization, based on mouse models of urinary tract infection using C3H/HeJ female mice. This strain carries a point mutation in the Tlr4 gene, which renders the mice unresponsive to lipopolysaccharide (LPS) and thus limits the bladder inflammatory response and infection resolution. The importance of Tlr4 as the sole genetic determinant of resistance or susceptibility can be questioned, however, by the observation that C3H/HeOuJ female mice with a functional Tlr4 do not effectively resolve E. coli bladder infections. The present study further examined this inconsistency by investigating the association of Tlr4 Lpsd and Lpsn alleles with bladder infection susceptibility by using genetic crosses of C3H/HeJ mice with Tlr4 (Lpsn/Lpsn) or (Lpsn/Lpsd) mice. Heterozygous offspring of C3H/HeJ (Lpsd/Lpsd) × BALB/cAnN (Lpsn/Lpsn) mice successfully resolved bladder infections induced by a uropathogenic E. coli strain, while heterozygous mice from a C3H/HeJ (Lpsd/Lpsd) × C3H/HeOuJ (Lpsn/Lpsn) cross had severe infections. A backcross of C3H/HeJ (Lpsd/Lpsd) with (BALB/cAnN × C3H/HeJ)F1 (Lpsn/Lpsd) produced mice that were either resistant or susceptible to E. coli bladder infections and had Lpsd/Lpsd or Lpsn/Lpsd Tlr4 genotypes. The Lpsd/Lpsd or Lpsn/Lpsd genotypes were present in individual mice with unresolved bladder infections, and the Lpsd/Lpsd genotype was found in infection-resistant mice. These results indicate that at least one gene other than Tlr4 strongly influences susceptibility to E. coli bladder infections in C3H/HeJ mice.

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Section: Introductionsupporting

confidence: 88%

Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

Suhs

Marthaler

Welch

et al. 2011

mBio

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“…In contrast, mouse models are well-controlled experimental tools to address TB immunity [3]–[7]. Studies in gene-targeted mice have identified several cell subsets (e.g., CD4 and CD8 T cells) and molecules (e.g., IFN-γ, TNF-α) whose deficiency results in extremely severe TB and suggested that active TB develops as a result of inefficient antibacterial responses [4]–[7].…”

Section: Introductionmentioning

confidence: 99%

In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

et al. 2010

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BackgroundInfection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.Methodology/Principal FindingsTo address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-γ, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1β, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1β and IL-11. TNF-α had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80+ cells) and granulocytes (Gr-1hi/Ly-6Ghi cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1dim cells that could contribute to TB progression.Conclusions/SignificanceIn a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1dim cells is a newly identified feature of progressing TB. High expression of IL-1β and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.

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“…Indeed, for many pathogens, classical mouse genetics has served as a valuable tool for the dissection of host factors involved in the response to infection. 20,21 In an effort to apply the host genetics approach to Chlamydia pathogenesis, and to identify novel genes involved in resistance or susceptibility to Chlamydia, we have adapted a systemic model of C. trachomatis infection for use in genetic analysis. 22 In this model, mice are injected intravenously with C. trachomatis L2, and the ensuing infection is monitored in the spleen during the acute phase of the infection.…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of susceptibility to Chlamydia trachomatis in mouse

et al. 2006

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Chlamydia trachomatis is a bacterial pathogen that is a major cause of blindness and infertility in diverse populations across the world. In an effort to model genetic complexities that are observed in human populations and to identify novel genes involved in susceptibility to C. trachomatis, we have adapted a murine model of systemic infection for use in genetic analysis. In this model, chlamydial colonization and replication is measured in the spleens of mice shortly after intravenous delivery of C. trachomatis L2. Here, we show that C57BL/6J and C3H/HeJ inbred mice are differentially susceptible to this systemic infection. Additionally, fibroblasts cultured from C57BL/6J and C3H/HeJ embryos are differentially permissive for chlamydial replication. We have taken advantage of this natural variation to map quantitative trait loci on Chromosomes 2, 3, and 11 that segregate with the bacterial load in F2 cross progeny during the acute phase of C. trachomatis infection in vivo. To validate our mapping results, we also generated mice that are congenic for a portion of Chromosome 11 from the susceptible parent. This congenic interval confers increased susceptibility to C. trachomatis, both in vivo and in vitro, suggesting that our screen identified at least one gene that is involved in cellular resistance to C. trachomatis replication.

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Using Mouse Genetics to Understand Infectious Disease Pathogenesis

Cited by 14 publications

References 101 publications

Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

Genetic analysis of susceptibility to Chlamydia trachomatis in mouse

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Using Mouse Genetics to Understand Infectious Disease Pathogenesis

Cited by 14 publications

References 101 publications

Lack of Association between theTlr4(Lpsd/Lpsd) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

Lack of Association between theTlr4(Lpsd/Lpsd) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

Genetic analysis of susceptibility to Chlamydia trachomatis in mouse

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Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice

Lack of Association between theTlr4(Lps^d/Lps^d) Genotype and Increased Susceptibility to Escherichia coli Bladder Infections in Female C3H/HeJ Mice