Inhalation of Francisella novicida ΔmglA causes replicative infection that elicits innate and adaptive responses but is not protective against invasive pneumonic tularemia

Abstract

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 ΔmglA in the lung in vivo. Aerosolized ΔmglA 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 hours. Early containment of ΔmglA infection was partially dependent on myeloid differentiation factor 88 and interferon-γ but did not require B or T cells. However, lymphocytes were necessary for subsequent bacterial clearance. Infection with ΔmglA elicited specific IgG1-predominant antibodies and variable interferon-γ recall responses to wild type F. novicida. Inoculation of mice with aerosolized ΔmglA afforded no protection against a subsequent low-dose aerosol challenge with wild type F. novicida. These findings establish that inhalation of F. novicida ΔmglA results in replicative infection that elicits innate and adaptive immune responses but not protective immunity against invasive pneumonic tularemia.

Genome-Wide Screen in Francisella novicida for Genes Required for Pulmonary and Systemic Infection in Mice

“…The protection afforded by primary infection with the atpC mutant against secondary airborne challenge with wild-type Francisella is not a universal result with attenuated mutants: previous reports have shown that infection with an iglC mutant is protective against nasal challenge (28), whereas infection with an mglA mutant was not protective (44). In contrast, lipid A mutant strains provided protection against lethal wild-type Francisella infection via both pulmonary and subcutaneous routes of infection (18), and some purine mutants elicited protective immunity in a systemic challenge model (30).…”

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

“…infection (18). Other studies have shown that prior administration of known TLR agonists reduces overall organ burdens and increases survival following subsequent F. tularensis infection (46)(47)(48). However, other properties likely also contribute to the limited systemic replication of the ⌬0831 bacteria, since the Schu S4 ⌬0831 strain also failed to replicate in the spleens and livers of mice when administered systemically via i.p.…”

Live attenuated tularemia vaccines: Recent developments and future goals

“…We have learned that phagosomal escape is required for intramacrophage replication and is critical to a mutant’s ability to confer protection [38, 39]. While we would expect that an inability to survive or replicate intracellularly would correlate with in vivo attenuation (and many reports support this hypothesis (see tables)), some reports have also shown that mutant strains can demonstrate significant in vivo attenuation even without demonstrated defects in intracellular replication.…”