The requirement for gamma Interferon in resistance of mice to experimental tularemia

Anthony, L. S. D.; Ghadirian, Esfandiar; Nestel, Frederick P.; Kongshavn, Patricia A. L.

doi:10.1016/0882-4010(89)90022-3

Cited by 101 publications

(90 citation statements)

References 26 publications

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“…Taken together, these findings suggest that the mglA-mediated pathogenicity of wild type F. novicida in the lung may be partly attributable to mitigated stimulation of the host innate immune system. IFN-γ is critically important in regulating macrophage responses to intracellular pathogens [23] and it is known to be essential for control of LVS infection [24,25]. Similarly, our data suggest that IFN-γ has an important role in containing ΔmglA replication within the first month of infection.…”

Section: Discussionsupporting

confidence: 62%

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

West

Pelletier

Majure

et al. 2008

Microbes and Infection

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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.

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Section: Discussionsupporting

confidence: 62%

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

West

Pelletier

Majure

et al. 2008

Microbes and Infection

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“…The parental strains are known to differ in response to many pathogens. [26][27][28][29] The other notable advantage of this particular panel of RI strains is that both parental strains have been sequenced. 30 This makes it possible to use reverse genetic methods to test modifier genes.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

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“…IFN-γ null mice are also more susceptible to F. tularensis infection than their wild type counterparts (11). Treatment of macrophages with IFN-γ allows these cells to limit the growth of F. tularensis (1,2,15,22). The ability of IFN-γ and TNF-α to limit the growth of intracellular pathogens in macrophages is often mediated by nitric oxide (6).…”

Section: Introductionmentioning

confidence: 99%

Francisella tularensis LVS grown in macrophages has reduced ability to stimulate the secretion of inflammatory cytokines by macrophages in vitro

Loegering

Drake

Banas

et al. 2006

Microbial Pathogenesis

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The virulence of Francisella tularensis LVS is determined in part by its ability to invade and replicate within macrophages and stimulate the production of inflammatory cytokines. The present study determined the effects of growing F. tularensis in macrophages on its ability to stimulate cytokine secretion by macrophages. F. tularensis grown in Mueller Hinton broth (FtB) stimulated the secretion of large amounts of TNF-α, IL-12p40, IL-6 and MCP-1/CCL2 when incubated with macrophages overnight. In contrast, F. tularensis released from infected macrophages (FtMac) stimulated very little secretion of these cytokines by primary cultures of murine peritoneal macrophages, human monocytes or macrophage cell lines. Stimulation of nitric oxide production by FtMac was also less than that elicited by FtB. FtMac killed with gentamicin or paraformaldehyde also stimulated low levels of cytokine secretion. FtMac recovered the ability to stimulate cytokine secretion after overnight culture in broth. Infection of macrophages with FtMac inhibited the cytokine response to subsequent stimulation with LPS from E. coli but did not affect Fcγ receptor-mediated phagocytosis. FtMac were ingested by macrophages at about half the rate of FtB however this did not account for the lower cytokine secretion. FtMac and FtB replicated at similar rates within macrophages. Finally, Mice infected with FtMac had a higher mortality rate than those infected with FtB. These results reveal that growth in macrophages causes a reversible phenotypic change in F. tularensis that is associated with decreased stimulation of cytokine secretion, inhibition of LPS-stimulated secretion of inflammatory cytokines by macrophages and increased lethality in mice.

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The requirement for gamma Interferon in resistance of mice to experimental tularemia

Cited by 101 publications

References 26 publications

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

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

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Francisella tularensis LVS grown in macrophages has reduced ability to stimulate the secretion of inflammatory cytokines by macrophages in vitro

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