Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19

ABSTRACT Differences among individuals in susceptibility to infectious diseases can be modulated by host genetics. Much of the research in this field has aimed to identify loci within the host genome that are associated with these differences. In mice, A/J (AJ) and C57BL/6J (B6) mice show differenti...

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Autores principales:	Avner Fink, Musa A. Hassan, Nihal A. Okan, Michal Sheffer, Ana Camejo, Jeroen P. J. Saeij, Dennis L. Kasper
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/93e1f57b28df4c19b8f08d7f48160d00
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spelling	oai:doaj.org-article:93e1f57b28df4c19b8f08d7f48160d002021-11-15T15:41:41ZEarly Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 1910.1128/mBio.02243-152150-7511https://doaj.org/article/93e1f57b28df4c19b8f08d7f48160d002016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02243-15https://doaj.org/toc/2150-7511ABSTRACT Differences among individuals in susceptibility to infectious diseases can be modulated by host genetics. Much of the research in this field has aimed to identify loci within the host genome that are associated with these differences. In mice, A/J (AJ) and C57BL/6J (B6) mice show differential susceptibilities to various pathogens, including the intracellular pathogen Francisella tularensis. Because macrophages are the main initial target during F. tularensis infection, we explored early interactions of macrophages from these two mouse strains with F. tularensis as well as the genetic factors underlying these interactions. Our results indicate that bacterial interactions with bone marrow-derived macrophages (BMDMs) during early stages of infection are different in the AJ and B6 strains. During these early stages, bacteria are more numerous in B6 than in AJ macrophages and display differences in trafficking and early transcriptional response within these macrophages. To determine the genetic basis for these differences, we infected BMDMs isolated from recombinant inbred (RI) mice derived from reciprocal crosses between AJ and B6, and we followed early bacterial counts within these macrophages. Quantitative trait locus (QTL) analysis revealed a locus on chromosome 19 that is associated with early differences in bacterial counts in AJ versus B6 macrophages. QTL analysis of published data that measured the differential susceptibilities of the same RI mice to an in vivo challenge with F. tularensis confirmed the F. tularensis susceptibility QTL on chromosome 19. Overall, our results show that early interactions of macrophages with F. tularensis are dependent on the macrophage genetic background. IMPORTANCE Francisella tularensis is a highly pathogenic bacterium with a very low infectious dose in humans. Some mechanisms of bacterial virulence have been elucidated, but the host genetic factors that contribute to host resistance or susceptibility are largely unknown. In this work, we have undertaken a genetic approach to assess what these factors are in mice. Analyzing early interactions of macrophages with the bacteria as well as data on overall susceptibility to infection revealed a locus on chromosome 19 that is associated with both phenotypes. In addition, our work revealed differences in the early macrophage response between macrophages with different genetic backgrounds. Overall, this work suggests some intriguing links between in vitro and in vivo infection models and should aid in further elucidating the genetic circuits behind the host response to Francisella tularensis infection.Avner FinkMusa A. HassanNihal A. OkanMichal ShefferAna CamejoJeroen P. J. SaeijDennis L. KasperAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Avner Fink Musa A. Hassan Nihal A. Okan Michal Sheffer Ana Camejo Jeroen P. J. Saeij Dennis L. Kasper Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
description	ABSTRACT Differences among individuals in susceptibility to infectious diseases can be modulated by host genetics. Much of the research in this field has aimed to identify loci within the host genome that are associated with these differences. In mice, A/J (AJ) and C57BL/6J (B6) mice show differential susceptibilities to various pathogens, including the intracellular pathogen Francisella tularensis. Because macrophages are the main initial target during F. tularensis infection, we explored early interactions of macrophages from these two mouse strains with F. tularensis as well as the genetic factors underlying these interactions. Our results indicate that bacterial interactions with bone marrow-derived macrophages (BMDMs) during early stages of infection are different in the AJ and B6 strains. During these early stages, bacteria are more numerous in B6 than in AJ macrophages and display differences in trafficking and early transcriptional response within these macrophages. To determine the genetic basis for these differences, we infected BMDMs isolated from recombinant inbred (RI) mice derived from reciprocal crosses between AJ and B6, and we followed early bacterial counts within these macrophages. Quantitative trait locus (QTL) analysis revealed a locus on chromosome 19 that is associated with early differences in bacterial counts in AJ versus B6 macrophages. QTL analysis of published data that measured the differential susceptibilities of the same RI mice to an in vivo challenge with F. tularensis confirmed the F. tularensis susceptibility QTL on chromosome 19. Overall, our results show that early interactions of macrophages with F. tularensis are dependent on the macrophage genetic background. IMPORTANCE Francisella tularensis is a highly pathogenic bacterium with a very low infectious dose in humans. Some mechanisms of bacterial virulence have been elucidated, but the host genetic factors that contribute to host resistance or susceptibility are largely unknown. In this work, we have undertaken a genetic approach to assess what these factors are in mice. Analyzing early interactions of macrophages with the bacteria as well as data on overall susceptibility to infection revealed a locus on chromosome 19 that is associated with both phenotypes. In addition, our work revealed differences in the early macrophage response between macrophages with different genetic backgrounds. Overall, this work suggests some intriguing links between in vitro and in vivo infection models and should aid in further elucidating the genetic circuits behind the host response to Francisella tularensis infection.
format	article
author	Avner Fink Musa A. Hassan Nihal A. Okan Michal Sheffer Ana Camejo Jeroen P. J. Saeij Dennis L. Kasper
author_facet	Avner Fink Musa A. Hassan Nihal A. Okan Michal Sheffer Ana Camejo Jeroen P. J. Saeij Dennis L. Kasper
author_sort	Avner Fink
title	Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
title_short	Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
title_full	Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
title_fullStr	Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
title_full_unstemmed	Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19
title_sort	early interactions of murine macrophages with <named-content content-type="genus-species">francisella tularensis</named-content> map to mouse chromosome 19
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/93e1f57b28df4c19b8f08d7f48160d00
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Early Interactions of Murine Macrophages with <named-content content-type="genus-species">Francisella tularensis</named-content> Map to Mouse Chromosome 19

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