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

ABSTRACT 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...

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Autores principales:	Sherry L. Kurtz, Amy P. Rossi, Gillian L. Beamer, Dan M. Gatti, Igor Kramnik, Karen L. Elkins
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Mycobacterium tuberculosis animal models Diversity Outbred immunization tuberculosis vaccines vaccines Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cddfce89436a43de9a56f36b303402dc
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spelling	oai:doaj.org-article:cddfce89436a43de9a56f36b303402dc2021-11-15T15:29:16ZThe Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection10.1128/mSphere.00097-202379-5042https://doaj.org/article/cddfce89436a43de9a56f36b303402dc2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00097-20https://doaj.org/toc/2379-5042ABSTRACT 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.Sherry L. KurtzAmy P. RossiGillian L. BeamerDan M. GattiIgor KramnikKaren L. ElkinsAmerican Society for MicrobiologyarticleMycobacterium tuberculosisanimal modelsDiversity Outbredimmunizationtuberculosis vaccinesvaccinesMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis animal models Diversity Outbred immunization tuberculosis vaccines vaccines Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis animal models Diversity Outbred immunization tuberculosis vaccines vaccines Microbiology QR1-502 Sherry L. Kurtz Amy P. Rossi Gillian L. Beamer Dan M. Gatti Igor Kramnik Karen L. Elkins The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
description	ABSTRACT 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.
format	article
author	Sherry L. Kurtz Amy P. Rossi Gillian L. Beamer Dan M. Gatti Igor Kramnik Karen L. Elkins
author_facet	Sherry L. Kurtz Amy P. Rossi Gillian L. Beamer Dan M. Gatti Igor Kramnik Karen L. Elkins
author_sort	Sherry L. Kurtz
title	The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
title_short	The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
title_full	The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
title_fullStr	The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
title_full_unstemmed	The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection
title_sort	diversity outbred mouse population is an improved animal model of vaccination against tuberculosis that reflects heterogeneity of protection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/cddfce89436a43de9a56f36b303402dc
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The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

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