The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection.

Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize "disease" and "protection," with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people.IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.

Immune Correlates of Protection From West Nile Virus Neuroinvasion and Disease.

BACKGROUND: A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. METHODS: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. RESULTS: Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. CONCLUSIONS: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.