Caught in a trap: How pre-clinical studies in laboratory mice exaggerate vaccine responses

Coughlan, Lynda

doi:10.1016/j.xcrm.2021.100484

Cited by 3 publications

(4 citation statements)

References 10 publications

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“…This might be a consequence of the fact that the sequential infection included chronic pathogens. A second possibility, consistent with studies in young “dirty” mice, is that there is little effect of antigenic history on the primary immune response to influenza virus, as shown in one ( 15 , 49 ) but not all ( 47 ) studies. Because an effect of prior Ag exposure was seen on vaccination, resulting in compromised responses to heterosubtypic challenge of young mice ( 15 ), additional studies in “dirty” aged mice are needed to assess the innate, humoral, and cellular responses to primary infection and vaccination.…”

Section: Discussionsupporting

confidence: 55%

“…These data contribute an aging perspective to the literature comparing the immune response of “clean,” SPF-maintained laboratory mice and “dirty” mice, generated by a variety of methods, including sequential infection, cohousing with pet store or wild mice, or transfer of microbiota from wild mice ( 14–17 , 20–24 , 47 ). The published literature on immunity in dirty mice has shown variable results, with some studies showing enhanced immunity ( 17 , 47 , 48 ) and others showing depressed immunity ( 15 , 49 ) or no effect ( 48 ). Variations in these results likely reflect differences in the manner of inducing antigenic experience, the pathogen used to assess immunity, the type of immune responses analyzed, and the time points and/or age at which the assessments were undertaken.…”

Section: Discussionmentioning

confidence: 99%

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Sequential Early-Life Infections Alter Peripheral Blood Transcriptomics in Aging Female Mice but Not the Response to De Novo Infection with Influenza Virus or M. tuberculosis

et al. 2023

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To determine the impact of accumulating Ag exposure on immunity in the aging mouse, and to develop a model more relevant to humans who are exposed to multiple pathogens during life, we sequentially infected young female mice with four distinct pathogens at 8-wk intervals: murine γ-herpesvirus 68, Sendai virus, murine CMV, and Heligmosomoides polygyrus. Mock-infected mice received PBS. After aging the sequentially infected and mock-infected mice to 18–25 mo under specific pathogen-free conditions, we analyzed multiple immune parameters. We assessed transcriptional activity in peripheral blood, T cell phenotype, the diversity of influenza epitopes recognized by CD8 T cells, and the response of the animals to infection with influenza virus and Mycobacterium tuberculosis. Our data show enhanced transcriptional activation in sequentially infected aged mice, with changes in some CD8 T cell subsets. However, there was no measurable difference in the response of mock-infected and sequentially infected aged mice to de novo infection with either influenza virus or M. tuberculosis at 18–21 mo. Unexpectedly, a single experiment in which 25-mo-old female mice were challenged with influenza virus revealed a significantly higher survival rate for sequentially infected (80%) versus mock-infected (20%) mice. These data suggest that although exposure to a variety of pathogen challenges in the mouse model does not overtly impact cellular markers of immunity in aged female mice following de novo respiratory infection, subtle changes may emerge in other compartments or with increasing age.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Sequential Early-Life Infections Alter Peripheral Blood Transcriptomics in Aging Female Mice but Not the Response to De Novo Infection with Influenza Virus or M. tuberculosis

et al. 2023

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“…Specific pathogen free (SPF) male C57BL/6J mice were born and bred at the Laboratory Animal Centre of Sun Yat-sen University. SPF mice are free from a defined list of pathogens by routine testing and housed in clean conditions that minimize exposure to pathogens (Coughlan, 2021). Therefore, nonspecific microorganisms and parasites are allowed in SPF mice.…”

Section: Animal Experimentsmentioning

confidence: 99%

Microbiota affects mitochondria and immune cell infiltrations via alternative polyadenylation during postnatal heart development

Liu,

Shao,

Han

et al. 2024

Front. Cell Dev. Biol.

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There is a growing body of evidence supporting the significant impact of microbiota on heart development. Alternative polyadenylation (APA) is a crucial mechanism for gene expression regulation and has been implicated in postnatal heart development. Nonetheless, whether microbiota can influence postnatal heart development through the regulation of APA remains unclear. Therefore, we conducted APA sequencing on heart tissues collected from specific pathogen-free (SPF) mice and germ-free (GF) mice at three different developmental stages: within the first 24 h after birth (P1), 7-day-old SPF mice, and 7-day-old GF mice. This approach allowed us to obtain a comprehensive genome-wide profile of APA sites in the heart tissue samples. In this study, we made a significant observation that GF mice exhibited noticeably longer 3ʹ untranslated region (3ʹ UTR) lengths. Furthermore, we confirmed significant alterations in the 3ʹ UTR lengths of mitochondria-related genes, namely Rala, Timm13, and Uqcc3. Interestingly, the GF condition resulted in a marked decrease in mitochondrial cristae density and a reduction in the level of Tomm20 in postnatal hearts. Moreover, we discovered a connection between Rala and Src, which further implicated their association with other differentially expressed genes (DEGs). Notably, most of the DEGs were significantly downregulated in GF mice, with the exceptions being Thbs1 and Egr1. Importantly, the GF condition demonstrated a correlation with a lower infiltration of immune cells, whereby the levels of resting NK cells, Th17 cells, immature dendritic cells, and plasma cells in GF mice were comparable to those observed in P1 mice. Furthermore, we established significant correlations between these immune cells and Rala as well as the related DEGs. Our findings clearly indicated that microbiota plays a vital role in postnatal heart development by affecting APA switching, mitochondria and immune cell infiltrations.

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“…Following our reductionist tendencies, the character and make up of mouse microbiota is being intensively defined and simplified as specific-pathogen-free facilities are increasingly used (493,494). Normalizing the microbiome to one that more closely resembles wild mice leads to several substantial changes in immune response (495)(496)(497)(498). Thus, colonization with comparatively non-immunogenic microbiota may be yet another factor that needs to be accounted for when modeling human autoimmune disease in mice.…”

Section: Microbiota/pet Store Micementioning

confidence: 99%

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

2022

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Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor via a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal (especially murine) models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.

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Caught in a trap: How pre-clinical studies in laboratory mice exaggerate vaccine responses

Cited by 3 publications

References 10 publications

Sequential Early-Life Infections Alter Peripheral Blood Transcriptomics in Aging Female Mice but Not the Response to De Novo Infection with Influenza Virus or M. tuberculosis

Sequential Early-Life Infections Alter Peripheral Blood Transcriptomics in Aging Female Mice but Not the Response to De Novo Infection with Influenza Virus or M. tuberculosis

Microbiota affects mitochondria and immune cell infiltrations via alternative polyadenylation during postnatal heart development

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

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