Inhalation of Francisella novicida Delta mglA causes replicative infection that elicits innate and adaptive responses but is not protective against invasive pneumonic tularemia.
Francisella tularensis causes the zoonosis tularemia in humans, and inhaled F. tularensis ssp. novicida induces lethal murine tularemia. Transcription of virulence factors in F. novicida is regulated by macrophage growth locus A (mglA), a global regulator required for bacterial replication in macrophages in vitro. We examined the infectivity and immunogenicity of attenuated F. novicida Delta mglA in the lung in vivo. Aerosolized Delta mglA caused replicative pulmonary infection that peaked at 7 days and was cleared thereafter, without clinical evidence of disease. In contrast, inhalation of wild type F. novicida resulted in more rapid bacterial replication and dissemination leading to death within 96 h. Early containment of Delta mglA infection was partially dependent on myeloid differentiation factor 88 and interferon-gamma but did not require B or T cells. However, lymphocytes were necessary for subsequent bacterial clearance. Infection with Delta mglA elicited specific IgG1-predominant antibodies and variable interferon-gamma recall responses to wild type F. novicida. Inoculation of mice with aerosolized Delta mglA afforded no protection against a subsequent low-dose aerosol challenge with wild type F. novicida. These findings establish that inhalation of F. novicida Delta mglA results in replicative infection that elicits innate and adaptive immune responses but not protective immunity against invasive pneumonic tularemia.
West
T Eoin
TE
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Box 359640, Seattle, WA 98104-2499, USA. tewest@u.washington.edu
Pelletier
Mark R
MR
Majure
Melanie C
MC
Lembo
Annalisa
A
Hajjar
Adeline M
AM
Skerrett
Shawn J
SJ
D000280:Administration, Inhalation; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines / Q000235:genetics* / Q000276:immunology*; D015169:Colony Count, Microbial; D005604:Francisella tularensis / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D017353:Gene Deletion; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014406:Tularemia / Q000517:prevention & control*; D014613:Vaccines, Attenuated; D037521:Virulence Factors / Q000235:genetics
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D014613:Vaccines, Attenuated; D037521:Virulence Factors; D007371:Interferon-gamma