A reaction norm perspective on reproducibility

Voelkl, Bernhard; Würbel, Hanno

doi:10.1007/s12064-021-00340-y

Cited by 21 publications

(12 citation statements)

References 42 publications

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“…However, responses among individual mice of the same dose group varied, and not all mice developed immunity. External and internal factors such as those reported in humans (Zimmermann and Curtis, 2019) and mice (Franklin and Ericsson, 2017;Voelkl et al, 2020;Voelkl and Würbel, 2021;Zhang et al, 2021) (i.e. stress, microbiota diversity, variation in vaccination dose) may cause this variability and need to be further evaluated.…”

Section: Discussionmentioning

confidence: 99%

Safety of a Novel Listeria monocytogenes-Based Vaccine Vector Expressing NcSAG1 (Neospora caninum Surface Antigen 1)

Pownall

Imhof

Trigo

et al. 2021

Front. Cell. Infect. Microbiol.

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Listeria monocytogenes (LM) has been proposed as vaccine vector in various cancers and infectious diseases since LM induces a strong immune response. In this study, we developed a novel and safe LM-based vaccine vector platform, by engineering a triple attenuated mutant (Lm3Dx) (ΔactA, ΔinlA, ΔinlB) of the wild-type LM strain JF5203 (CC 1, phylogenetic lineage I). We demonstrated the strong attenuation of Lm3Dx while maintaining its capacity to selectively infect antigen-presenting cells (APCs) in vitro. Furthermore, as proof of concept, we introduced the immunodominant Neospora caninum (Nc) surface antigen NcSAG1 into Lm3Dx. The NcSAG1 protein was expressed by Lm3Dx_SAG1 during cellular infection. To demonstrate safety of Lm3Dx_SAG1 in vivo, we vaccinated BALB/C mice by intramuscular injection. Following vaccination, mice did not suffer any adverse effects and only sporadically shed bacteria at very low levels in the feces (<100 CFU/g). Additionally, bacterial load in internal organs was very low to absent at day 1.5 and 4 following the 1st vaccination and at 2 and 4 weeks after the second boost, independently of the physiological status of the mice. Additionally, vaccination of mice prior and during pregnancy did not interfere with pregnancy outcome. However, Lm3Dx_SAG1 was shed into the milk when inoculated during lactation, although it did not cause any clinical adverse effects in either dams or pups. Also, we have indications that the vector persists more days in the injected muscle of lactating mice. Therefore, impact of physiological status on vector dynamics in the host and mechanisms of milk shedding requires further investigation. In conclusion, we provide strong evidence that Lm3Dx is a safe vaccine vector in non-lactating animals. Additionally, we provide first indications that mice vaccinated with Lm3Dx_SAG1 develop a strong and Th1-biased immune response against the Lm3Dx-expressed neospora antigen. These results encourage to further investigate the efficiency of Lm3Dx_SAG1 to prevent and treat clinical neosporosis.

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Section: Discussionmentioning

confidence: 99%

Safety of a Novel Listeria monocytogenes-Based Vaccine Vector Expressing NcSAG1 (Neospora caninum Surface Antigen 1)

Pownall

Imhof

Trigo

et al. 2021

Front. Cell. Infect. Microbiol.

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“…As a result, genotype-by-environment interactions throughout ontogeny can lead to phenotypic differences in morphology, physiology, and behavior between animals reared in different environments. Due to such phenotypic plasticity, researchers may fail to replicate research findings, even when using genetically homogeneous (inbred) animals [28][29][30]. Therefore, phenotypic plasticity may contribute to replication failure and conflicting findings in the scientific literature [13,25,31].…”

Section: Introductionmentioning

confidence: 99%

The rearing environment persistently modulates mouse phenotypes from the molecular to the behavioural level

Jarić

Voelkl²,

Clerc³

et al. 2022

PLoS Biol

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The phenotype of an organism results from its genotype and the influence of the environment throughout development. Even when using animals of the same genotype, independent studies may test animals of different phenotypes, resulting in poor replicability due to genotype-by-environment interactions. Thus, genetically defined strains of mice may respond differently to experimental treatments depending on their rearing environment. However, the extent of such phenotypic plasticity and its implications for the replicability of research findings have remained unknown. Here, we examined the extent to which common environmental differences between animal facilities modulate the phenotype of genetically homogeneous (inbred) mice. We conducted a comprehensive multicentre study, whereby inbred C57BL/6J mice from a single breeding cohort were allocated to and reared in 5 different animal facilities throughout early life and adolescence, before being transported to a single test laboratory. We found persistent effects of the rearing facility on the composition and heterogeneity of the gut microbial community. These effects were paralleled by persistent differences in body weight and in the behavioural phenotype of the mice. Furthermore, we show that environmental variation among animal facilities is strong enough to influence epigenetic patterns in neurons at the level of chromatin organisation. We detected changes in chromatin organisation in the regulatory regions of genes involved in nucleosome assembly, neuronal differentiation, synaptic plasticity, and regulation of behaviour. Our findings demonstrate that common environmental differences between animal facilities may produce facility-specific phenotypes, from the molecular to the behavioural level. Furthermore, they highlight an important limitation of inferences from single-laboratory studies and thus argue that study designs should take environmental background into account to increase the robustness and replicability of findings.

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“…e.g. [ 114 ]), such that data from CH or improved housing conditions generate different conclusions. (A figure illustrating this distinction is presented in Additional file 21 ).…”

Section: Discussionmentioning

confidence: 99%

Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis

Cait

Scott

et al. 2022

BMC Biol

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Background Over 120 million mice and rats are used annually in research, conventionally housed in shoebox-sized cages that restrict natural behaviours (e.g. nesting and burrowing). This can reduce physical fitness, impair thermoregulation and reduce welfare (e.g. inducing abnormal stereotypic behaviours). In humans, chronic stress has biological costs, increasing disease risks and potentially shortening life. Using a pre-registered protocol (https://atrium.lib.uoguelph.ca/xmlui/handle/10214/17955), this meta-analysis therefore tested the hypothesis that, compared to rodents in ‘enriched’ housing that better meets their needs, conventional housing increases stress-related morbidity and all-cause mortality. Results Comprehensive searches (via Ovid, CABI, Web of Science, Proquest and SCOPUS on May 24 2020) yielded 10,094 publications. Screening for inclusion criteria (published in English, using mice or rats and providing ‘enrichments’ in long-term housing) yielded 214 studies (within 165 articles, using 6495 animals: 59.1% mice; 68.2% male; 31.8% isolation-housed), and data on all-cause mortality plus five experimentally induced stress-sensitive diseases: anxiety, cancer, cardiovascular disease, depression and stroke. The Systematic Review Center for Laboratory animal Experimentation (SYRCLE) tool assessed individual studies’ risks of bias. Random-effects meta-analyses supported the hypothesis: conventional housing significantly exacerbated disease severity with medium to large effect sizes: cancer (SMD = 0.71, 95% CI = 0.54–0.88); cardiovascular disease (SMD = 0.72, 95% CI = 0.35–1.09); stroke (SMD = 0.87, 95% CI = 0.59–1.15); signs of anxiety (SMD = 0.91, 95% CI = 0.56–1.25); signs of depression (SMD = 1.24, 95% CI = 0.98–1.49). It also increased mortality rates (hazard ratio = 1.48, 95% CI = 1.25–1.74; relative median survival = 0.91, 95% CI = 0.89–0.94). Meta-regressions indicated that such housing effects were ubiquitous across species and sexes, but could not identify the most impactful improvements to conventional housing. Data variability (assessed via coefficient of variation) was also not increased by ‘enriched’ housing. Conclusions Conventional housing appears sufficiently distressing to compromise rodent health, raising ethical concerns. Results also add to previous work to show that research rodents are typically CRAMPED (cold, rotund, abnormal, male-biased, poorly surviving, enclosed and distressed), raising questions about the validity and generalisability of the data they generate. This research was funded by NSERC, Canada.

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A reaction norm perspective on reproducibility

Cited by 21 publications

References 42 publications

Safety of a Novel Listeria monocytogenes-Based Vaccine Vector Expressing NcSAG1 (Neospora caninum Surface Antigen 1)

Safety of a Novel Listeria monocytogenes-Based Vaccine Vector Expressing NcSAG1 (Neospora caninum Surface Antigen 1)

The rearing environment persistently modulates mouse phenotypes from the molecular to the behavioural level

Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis

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