Abstract Work with human specific viruses will greatly benefit from the use of an in vivo system that provides human target cells and tissues in a physiological setting. In this regard humanized mice ...(hu-Mice) have played an important role in our understanding of viral pathogenesis and testing of therapeutic strategies. Limitations with earlier versions of hu-Mice that lacked a functioning human immune system are currently being overcome. The new generation hu-Mouse models are capable of multilineage human hematopoiesis and generate T cells, B cells, macrophages and dendritic cells required for an adaptive human immune response. Now any human specific pathogen that can infect humanized mice can be studied in the context of ongoing infection and immune responses. Two leading humanized mouse models are currently employed: the hu-HSC model is created by transplantation of human hematopoietic stem cells (HSC), whereas the BLT mouse model is prepared by transplantation of human fetal liver, thymus and HSC. A number of human specific viruses such as HIV-1, dengue, EBV and HCV are being studied intensively in these systems. Both models permit infection by mucosal routes with viruses such as HIV-1 thus allowing transmission prevention studies. Cellular and humoral immune responses are seen in both the models. While there is efficient antigen specific IgM production, IgG responses are suboptimal due to inefficient immunoglobulin class switching. With the maturation of T cells occurring in the autologous human thymus, BLT mice permit human HLA restricted T cell responses in contrast to hu-HSC mice. However, the strength of the immune responses needs further improvement in both models to reach the levels seen in humans. The scope of hu-Mice use is further broadened by transplantation of additional tissues like human liver thus permitting immunopathogenesis studies on hepatotropic viruses such as HCV. Numerous studies that encompass antivirals, gene therapy, viral evolution, and the generation of human monoclonal antibodies have been conducted with promising results in these mice. For further improvement of the new hu-Mouse models, ongoing work is focused on generating new strains of immunodeficient mice transgenic for human HLA molecules to strengthen immune responses and human cytokines and growth factors to improve human cell reconstitution and their homeostatic maintenance.
We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the ...current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development.
Alzheimer's Disease affects approximately 33 million people worldwide and is characterized by progressive loss of memory at the cognitive level. The formation of toxic amyloid oligomers, ...extracellular amyloid plaques and amyloid angiopathy in brain by amyloid beta peptides are considered a part of the identified mechanism involved in disease pathogenesis. The optimal treatment approach leads toward finding a chemical compound able to form a noncovalent complex with the amyloid peptide thus blocking the process of amyloid aggregation. This direction gained an increasing interest lately, many studies demonstrating that mass spectrometry is a valuable method useful for the identification and characterization of such molecules able to interact with amyloid peptides. In the present review we aim to identify in the scientific literature low molecular weight chemical compounds for which there is mass spectrometric evidence of noncovalent complex formation with amyloid peptides and also there are toxicity reduction results which verify the effects of these compounds on amyloid beta toxicity towards cell cultures and transgenic mouse models developing Alzheimer's Disease.
Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide ...(TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.
Recent human and animal studies suggest that gut microbes can influence atherosclerosis via generation of trimethylamine N-oxide (TMAO).
Cecal microbial transplantation from atherosclerosis-prone versus -resistant inbred strains of mice transmitted enhanced choline diet-dependent atherosclerosis and TMAO levels.
Atherosclerosis susceptibility can be transmitted with gut microbial transplantation.
Gut microbes participate in atherosclerosis susceptibility and are thus a potential therapeutic target.
The International Knockout Mouse Consortium (IKMC) introduces its targeted constructs into C57BL/6N embryonic stem cells. However, breeding with a Cre-recombinase and/or Flp-recombinase mouse is ...required for the generation of a null allele with the IKMC cassette. Many recombinase strains are in the C57BL/6J background, resulting in knockout animals on a mixed strain background. This can lead to variability in metabolic data and the use of improper control groups. While C57BL/6N and C57BL/6J are derived from the same parental C57BL/6 strain, there are key genotypic and phenotypic differences between these substrains. Many researchers may not even be aware of these differences, as the shorthand C57BL/6 is often used to describe both substrains. We found that 58% of articles involving genetically modified mouse models did not completely address background strain. This review will describe these two substrains and highlight the importance of separate consideration in mouse model development. Our aim is to increase awareness of this issue in the diabetes research community and to provide practical strategies to enable researchers to avoid mixed strain animals when using IKMC knockout mice.
Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate ...microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract–supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression.
RAW_REF_TEXT Correction /RAW_REF_TEXT RAW_REF_TEXT Open Access /RAW_REF_TEXT RAW_REF_TEXT Published:14 July 2021 /RAW_REF_TEXT Correction to: A probiotic has differential effects on allergic airway ...inflammation in A/J and C57BL/6 mice and is correlated with the gut microbiome RAW_REF_TEXT Mateus B. Casaro1, /RAW_REF_TEXT RAW_REF_TEXT Andrew M. Thomas2,3,4, /RAW_REF_TEXT RAW_REF_TEXT Eduardo Mendes1, /RAW_REF_TEXT RAW_REF_TEXT Claudio Fukumori1, /RAW_REF_TEXT RAW_REF_TEXT Willian R. Ribeiro1, /RAW_REF_TEXT RAW_REF_TEXT Fernando A. Oliveira5, /RAW_REF_TEXT RAW_REF_TEXT Amanda R. Crisma6, /RAW_REF_TEXT RAW_REF_TEXT Gilson M. Murata7, /RAW_REF_TEXT RAW_REF_TEXT Bruna Bizzarro8, /RAW_REF_TEXT RAW_REF_TEXT Anderson Sá-Nunes8, /RAW_REF_TEXT RAW_REF_TEXT Joao C. Setubal4, /RAW_REF_TEXT RAW_REF_TEXT Marcia P. A. Mayer9, /RAW_REF_TEXT RAW_REF_TEXT Flaviano S. Martins10, /RAW_REF_TEXT RAW_REF_TEXT Angélica T. Vieira11, /RAW_REF_TEXT RAW_REF_TEXT Ana T. F. B. Antiorio12, /RAW_REF_TEXT RAW_REF_TEXT Wothan Tavares-de-Lima13, /RAW_REF_TEXT RAW_REF_TEXT Niels O. S. Camara8, /RAW_REF_TEXT RAW_REF_TEXT Rui Curi14, /RAW_REF_TEXT RAW_REF_TEXT Emmanuel Dias-Neto3,15 & /RAW_REF_TEXT RAW_REF_TEXT Caroline M. Ferreira 1 /RAW_REF_TEXT Microbiome volume 9, Article number: 159 (2021) Cite this article RAW_REF_TEXT 89 Accesses /RAW_REF_TEXT RAW_REF_TEXT 1 Altmetric /RAW_REF_TEXT RAW_REF_TEXT Metrics details /RAW_REF_TEXT The Original Article was published on 10 June 2021 Correction to: Fig. 4 figure1 A/J embryo implantation in C57BL/6 mothers resulted in experimental allergic airway inflammation similar to C57BL/6 offspring. a Schematic representation of the embryo transfer and OVA-inducing airway inflammation protocol. b Phylogenetic diversity in mice. All values were calculated using Adonis with 999 permutations on unweighted UniFrac distances. d Total and differential (Eos, eosinophils; Neut, neutrophils; Mono, mononuclear) number of cells in the bronchoalveolar lavage (BALF) of the A/J, C57BL/6, and A/J transplanted OVA groups (n = 3–5). e Levels of (pg/ml) of interleukin (IL)-4 and interferon (INF)-γ in the BALF of the A/J, C57BL/6, and A/J transplanted OVA groups (n = 3–5). Correction Open Access Published:14 July 2021 /RAW_REF_TEXT Correction to: A probiotic has differential effects on allergic airway inflammation in A/J and C57BL/6 mice and is correlated with the gut microbiome RAW_REF_TEXT Mateus B. Casaro1, Andrew M. Thomas2,3,4, Eduardo Mendes1, Claudio Fukumori1, Willian R. Ribeiro1, Fernando A. Oliveira5, Amanda R. Crisma6, Gilson M. Murata7, Bruna Bizzarro8, Anderson Sá-Nunes8, Joao C. Setubal4, Marcia P. A. Mayer9, Flaviano S. Martins10, Angélica T. Vieira11, Ana T. F. B. Antiorio12, Wothan Tavares-de-Lima13, Niels O. S. Camara8, Rui Curi14, Emmanuel Dias-Neto3,15 & Caroline M. Ferreira 1 /RAW_REF_TEXT Microbiome volume 9, Article number: 159 (2021) Cite this article RAW_REF_TEXT 89 Accesses 1 Altmetric Metrics details
Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major ...factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals.
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•Wild mice from Maryland are close relatives to standard laboratory mouse strains•Gut microbiota of wild mice and laboratory mice differ significantly•Wild mouse gut microbiota can be banked and maintained in a laboratory mouse colony•Natural gut microbiota improves outcome in viral infection and tumorigenesis models
Characterization of a wild mice reference microbiome opens a window of opportunity to understand how the gut microbiota affects aspects of host physiology that are important in the natural world outside the laboratory.
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