An engineered probiotic system locally delivers checkpoint blockade nanobodies to tumors for sustained therapeutic release.

Practical pathology of aging mice

Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome. It has been difficult to establish causal relationships between host genetics and the selection of the vast multitude of micro-organisms that live in and on us (i.e. the microbiota). Cystic fibrosis has been shown to be associated with changes in the fecal microbiome (the genetic constitution of the microbiota) although it was not evident whether mutation of CFTR, the gene mutated in CF, could drive this selection or whether the frequent use of antibiotics in this population was at fault. Here, by using a germfree (i.e. sterile, lacking all microbiota) mouse model of CF we clearly demonstrate that mutated CFTR alone can alter the microbiome. We also show an increase in an adaptive immune cell type (TH17 cells) in the mesenteric lymph nodes and spleens of CF mice compared to control mice. Our study provides new insights into the dominant role that CFTR plays in microbiome determination and suggests that therapies restoring CFTR function could also correct the microbial dysbiosis observed in CF.

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans. Much experimental work has been directed at understanding the host immune response to flavivirus infections such as West Nile virus (WNV) using mouse models of infection. While valuable information has certainly been secured using these methods, a limitation to studies with traditional inbred mouse models is that they lack the genetic diversity of the human population, and consequently this limits our ability to study particular states of disease that aren’t replicated in traditional inbred mice. For instance, despite reports of chronic WNV infection in humans, a mouse model of chronic infection is lacking. Here, we report the discovery of a mouse model of chronic WNV infection using the Collaborative Cross, a panel of reproducible recombinant inbred mouse strains with a high degree of standing genetic variation. Further, we find that chronic disease is associated with altered innate immunity and increased regulatory T cell frequency, and we find that chronically infected mice have lower expression of genes associated with cytolysis. Thus, in addition to discovery of a new chronic infection model that may be useful for other neuroinvasive infections, we provide an immunologic mechanism by which chronic virus infection can be established.

The phenotype of genetically engineered mice is a combination of both genetic and environmental factors that include the microflora of the mouse. The impact a particular microbe has on a mouse reflects the host–microbe interaction within the context of the mouse genotype and environment. Although often considered a confounding variable, many host–microbe interactions have resulted in the generation of novel model systems and characterization of new microbial agents. Microbes associated with overt disease in mice have been the historical focus of the laboratory animal medical and pathology community and literature. The advent of genetic engineering and the complex of mouse models have revealed previously unknown or disregarded agents that now oblige the attention of the biomedical research community. The purpose of this article is to describe and illustrate how phenotypes can be affected by microflora by focusing on the infectious diseases present in genetically engineered mouse (GEM) colonies of our collective institutions and by reviewing important agents that are rarely seen in most research facilities today. The goal is to introduce the concept of the role of microflora on phenotypes and in translational research using GEM models.

Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.