Embracing the heterogeneity of natural viruses in mouse studies

Fiege, Jessica K.; Langlois, Ryan A.

doi:10.1099/jgv.0.001758

Cited by 5 publications

(5 citation statements)

References 68 publications

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“…All methods were in agreements regarding their size distribution—centered between 25Kbp and 75Kbp (Figure 6C). This is in accordance with known sizes of DNA viruses infecting Bacteria and Archaea that are likely the most abundant hosts in the gut microbiome obtained from fecal samples (53–55). This suggests that if viruses are the targeted diversity for a study, the addition of long-reads may not substantially improve results.…”

Section: Resultssupporting

confidence: 86%

A comparison of short-read, HiFi long-read, and hybrid strategies for genome-resolved metagenomics

Eisenhofer,

Nesme,

Santos-Bay

et al. 2023

Preprint

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Shotgun metagenomics enables the reconstruction of complex microbial communities at a high level of detail. Such an approach can be conducted using both short-read and long-read sequencing data, as well as a combination of both. To assess the pros and cons of these different approaches, we used 22 faecal DNA extracts collected weekly for 11 weeks from two respective lab mice to study seven performance metrics over four combinations of sequencing depth and technology: i) 20 Gbp of Illumina short-read data, ii) 40 Gbp of short-read data, iii) 20 Gbp of PacBio HiFi long-read data, and iv) 40 Gbp of hybrid (20 Gbp of short-read + 20 Gbp of long-read) data. No strategy was best for all metrics, but instead, each one excelled across different metrics. The long-read approach yielded the best assembly statistics, with the highest N50 and lowest number of contigs. The 40 Gbp short-read approach yielded the highest number of refined bins. Finally, the hybrid approach yielded the longest assemblies, and the highest mapping rate to the bacterial genomes. Our results suggest that while long-read sequencing significantly improves the quality of reconstructed bacterial genomes, it is more expensive and requires deeper sequencing than short-read approaches to recover a comparable amount of reconstructed genomes. The most optimal strategy is study-specific, and depends on how researchers assess the tradeoff between the quantity and quality of recovered genomes.ImportanceOur understanding of microbial communities is limited by the technologies we employ. Here, we test several different DNA sequencing techniques to better understand the pros and cons of each. Long read DNA sequencing allowed for the reconstruction of higher quality and even complete microbial genomes, however, the cost was greater than commonly used short-read DNA sequencing. We suggest researchers consider the trade-offs between each method and decide based on the goals of their research question/s.

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Section: Resultssupporting

confidence: 86%

A comparison of short-read, HiFi long-read, and hybrid strategies for genome-resolved metagenomics

Eisenhofer,

Nesme,

Santos-Bay

et al. 2023

Preprint

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“…This model thus permits specific dissection of the microbial factors and host pathways that contribute to these immune phenotypes. While the variable exposures achieved via cohousing of SPF mice with wild or pet shop mice may better model the breadth of immune exposures experienced by humans (14), intentional exposures that appropriately mimic the "average" exposures experienced by humans in HICs or LMICs also could inform our understanding of the diversity of human immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Cohousing of SPF mice with wild or pet shop-derived mice, rewilding by exposing SPF mice to a natural environment, and "wildling" models in which transferred lab mouse embryos are sired by wild mothers (6,(8)(9)(10)(11)(12), have provided critical comparisons between "exposed" and naïve SPF mice. These alternative "dirty" models reproduce natural microorganism exposures including bacteria, eukaryotic viruses, bacteriophages, fungi, helminths and/or mites (13,14), and exhibit fundamental shifts in their immune systems, improving their ability to recapitulate essential aspects of human immunity (5,6,9). Co-housing laboratory mice results in the replication of immune phenotypes and transcriptional signatures found in wild mice or humans, including altering T cell differentiation and modulating susceptibility to new pathogens (6).…”

Section: Introductionmentioning

confidence: 99%

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

Li,

Molleston,

Kim

et al. 2023

Preprint

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Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond these immune responses changes, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight their potential importance of considering prior microbial exposures when investigating vaccine responses.

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“…We and others have previously shown that SPF mice do not recapitulate human immune responses to vaccination and that introducing microbial experiences yields vaccine responses that better recapitulate those observed in humans ( 6 , 7 ). There are several models that have been developed to reintroduce natural mouse and environmental pathogens to laboratory mice to better recapitulate the human immune system ( 10 ). However, no one model can capture the complexity of human exposures across space and time.…”

Section: Observationmentioning

confidence: 99%

Comparison of mouse models of microbial experience reveals differences in microbial diversity and response to vaccination

Sanders,

Arnesen,

Shepherd

et al. 2024

mSphere

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Specific pathogen-free (SPF) laboratory mice dominate preclinical studies for immunology and vaccinology. Unfortunately, SPF mice often fail to accurately model human responses to vaccination and other immunological perturbations. Several groups have taken different approaches to introduce additional microbial experience to SPF mice to better model human immune experience. How these different models compare is unknown. Here, we directly compare three models: housing SPF mice in a microbe-rich barn-like environment (feralizing), adding wild-caught mice to the barn-like environment (fer-cohoused), or cohousing SPF mice with pet store mice in a barrier facility (pet-cohoused); the two latter representing different murine sources of microbial transmission. Pet-cohousing mice resulted in the greatest microbial exposure. Feralizing alone did not result in the transmission of any pathogens tested, while fer-cohousing resulted in the transmission of several picornaviruses. Murine astrovirus 2, the most common pathogen from pet store mice, was absent from the other two model systems. Previously, we had shown that pet-cohousing reduced the antibody response to vaccination compared with SPF mice. This was not recapitulated in either the feralized or fer-cohoused mice. These data indicate that not all dirty mouse models are equivalent in either microbial experience or immune responses to vaccination. These disparities suggest that more cross model comparisons are needed but also represent opportunities to uncover microbe combination-specific phenotypes and develop more refined experimental models. Given the breadth of microbes encountered by humans across the globe, multiple model systems may be needed to accurately recapitulate heterogenous human immune responses. IMPORTANCE Animal models are an essential tool for evaluating clinical interventions. Unfortunately, they can often fail to accurately predict outcomes when translated into humans. This failure is due in part to a lack of natural infections experienced by most laboratory animals. To improve the mouse model, we and others have exposed laboratory mice to microbes they would experience in the wild. Although these models have been growing in popularity, these different models have not been specifically compared. Here, we directly compare how three different models of microbial experience impact the immune response to influenza vaccination. We find that these models are not the same and that the degree of microbial exposure affects the magnitude of the response to vaccination. These results provide an opportunity for the field to continue comparing and contrasting these systems to determine which models best recapitulate different aspects of the human condition.

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Embracing the heterogeneity of natural viruses in mouse studies

Cited by 5 publications

References 68 publications

A comparison of short-read, HiFi long-read, and hybrid strategies for genome-resolved metagenomics

A comparison of short-read, HiFi long-read, and hybrid strategies for genome-resolved metagenomics

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination

Comparison of mouse models of microbial experience reveals differences in microbial diversity and response to vaccination

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