Resilience to Bacterial Infection: Difference between Species Could Be Due to Proteins in Serum

Warren, H. Shaw; Fitting, Catherine; Hoff, Eva; Adib‐Conquy, Minou; Beasley-Topliffe, Laura K.; Tesini, Brenda; Liang, Xueya; Valentine, Catherine; Hellman, Judith; Hayden, Douglas; Cavaillon, Jean‐Marc

doi:10.1086/649557

Cited by 229 publications

(185 citation statements)

References 37 publications

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“…Recent articles have highlighted tradeoffs that species make to balance often opposing evolutionary strategies for resistance vs. tolerance or resilience to infection (26,27). Relative to the human response, mice are highly resilient to inflammatory challenge (28,29). For example, the lethal dose of endotoxin is 5-25 mg/kg for most strains of mice, whereas a dose that is 1,000,000-fold less (30 ng/kg) has been reported to cause shock in humans (30).…”

Section: Discussionmentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,554

1,921

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A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1-3). However, few of these human trials have shown success (4-7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8-11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3,12,13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14-18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16-18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.In this article, we report on a systematic comparison of the genomic respo...

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Section: Discussionmentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,554

1,921

View full text Add to dashboard Cite

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“…Most parameters of human NK cells have been acquired from cells derived from the blood compartment, whereas murine NK cells are mostly derived from spleen. It is interesting to note that the blood environment in mice and humans are greatly different, with murine plasma favoring the resilience of mice to bacterial infection (27).…”

Section: Antibacterial Innate Immunitymentioning

confidence: 99%

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

Souza-Fonseca-Guimarães

Adib‐Conquy

Cavaillon

2011

Mol Med

134

125

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Natural killer (NK) cells were first described as immune leukocytes that could kill tumor cells and soon after were reported to kill virus-infected cells. In the mid-1980s, 10 years after their discovery, NK cells were also demonstrated to contribute to the fight against bacterial infection, particularly because of crosstalk with other leukocytes. A wide variety of immune cells are now recognized to interact with NK cells through the production of cytokines such as interleukin (IL)-2, IL-12, IL-15 and IL-18, which boost NK cell activities. The recent demonstration that NK cells express pattern recognition receptors, namely Toll-like and nucleotide oligomerization domain (NOD)-like receptors, led to the understanding that these cells are not only under the control of accessory cells, but can be directly involved in the antibacterial response thanks to their capacity to recognize pathogen-associated molecular patterns. Interferon (IFN)-γ is the predominant cytokine produced by activated NK cells. IFN-γ is a key contributor to antibacterial immune defense. However, in synergy with other inflammatory cytokines, IFN-γ can also lead to deleterious effects similar to those observed during sepsis. Accordingly, as the main source of IFN-γ in the early phase of infection, NK cells display both beneficial and deleterious effects, depending on the circumstances.

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“…We have recently shown that gnotobiotic IL-10 −/− mice generated by broad-spectrum antibiotic treatment are excellently suited as C. jejuni infection model to study host-pathogen interactions in vivo [10][11][12]. It is well known that rodents are 1000 times more resistant to Toll-like receptor-4 agonists such as lipopolysaccharide (LPS) and lipooligosacharide (LOS) than humans [13]. In addition, IL-10 −/− mice are much more sensitive to LPS and LOS as compared to wildtype mice [10].…”

Section: Introductionmentioning

confidence: 99%

Selective gelatinase inhibition reduces apoptosis and pro-inflammatory immune cell responses inCampylobacter jejuni-infected gnotobiotic IL-10 deficient mice

Alutis

Grundmann²,

Fischer³

et al. 2014

European Journal of Microbiology and Immunology

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Increased levels of the matrix metalloproteinases-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in intestinal inflammation. We have recently shown that selective gelatinase blockage by the synthetic compound RO28-2653 ameliorates acute murine ileitis and colitis. We here investigated whether RO28-2653 exerts anti-inflammatory effects in acute Campylobacter jejuni-induced enterocolitis of gnotobiotic IL-10 −/− mice generated following antibiotic treatment. Mice were perorally infected with C. jejuni (day 0) and either treated with RO28-2653 (75 mg/kg body weight/day) or placebo from day 1 until day 6 post infection (p.i.) by gavage. Irrespective of the treatment, infected mice displayed comparable pathogen loads within the gastrointestinal tract. Following RO28-2653 administration, however, infected mice exhibited less severe symptoms such as bloody diarrhea as compared to placebo controls. Furthermore, less distinct apoptosis but higher numbers of proliferating cells could be detected in the colon of RO28-2653-treated as compared to placebo-treated mice at day 7 p.i. Remarkably, gelatinase blockage resulted in lower numbers of T-and B-lymphocytes as well as macrophages and monocytes in the colonic mucosa of C. jejuni-infected gnotobiotic IL-10 −/− mice. Taken together, synthetic gelatinase inhibition exerts anti-inflammatory effects in experimental campylobacteriosis.

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Resilience to Bacterial Infection: Difference between Species Could Be Due to Proteins in Serum

Cited by 229 publications

References 37 publications

Genomic responses in mouse models poorly mimic human inflammatory diseases

Genomic responses in mouse models poorly mimic human inflammatory diseases

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

Selective gelatinase inhibition reduces apoptosis and pro-inflammatory immune cell responses inCampylobacter jejuni-infected gnotobiotic IL-10 deficient mice

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