Different host defences are required to protect mice from primary systemic vs pulmonary infection with the facultative intracellular bacterial pathogen, Francisella tularensis LVS

Conlan, J. Wayne; KuoLee, Rhonda; Shen, Hua; Webb, Ann

doi:10.1006/mpat.2001.0489

Cited by 87 publications

(85 citation statements)

References 31 publications

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“…Consistent with previous reports, the present study shows that levels of inflammatory cytokines stimulated by LPS from E. coli were in the same range as those caused FtB when the macrophages were incubated continuously with the bacteria (8,16). FtB stimulated the secretion of TNF-α and IL-12p40 with a time course similar to that caused by LPS from E. coli (data not shown).…”

Section: Discussionsupporting

confidence: 92%

“…Thus, secretion of inflammatory cytokines during the early stages of an infection may limit bacterial proliferation by increasing the activation state of macrophages. Consistent with this hypothesis, it has been shown that administration of neutralizing antibodies against tumor necrosis factor-α (TNF-α) or interferon-γ (IFN-γ) results in early death or a decrease in LD50 of mice infected with F. tularensis (8,14,17,19,24). IFN-γ null mice are also more susceptible to F. tularensis infection than their wild type counterparts (11).…”

Section: Introductionmentioning

confidence: 87%

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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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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 87%

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 results of one study demonstrated that depletion of granulocytes with monoclonal antibodies markedly increases the lethality of LVS administered to mice via the dermis or the peritoneal cavity (111). Conversely, neutropenia does not exacerbate disease course when LVS is administered via the aerosol route (32). In this model, PMN depletion has no significant effect on bacterial burden in the lung and spleen, and the LVS load in the liver is only moderately elevated.…”

Section: Role Of Neutrophilsmentioning

confidence: 74%

Francisella tularensis:Taxonomy, Genetics, and Immunopathogenesis of a Potential Agent of Biowarfare

McLendon

Apicella

Allen

2006

Annu. Rev. Microbiol.

205

292

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Tularemia is a zoonosis of humans caused by infection with the facultative intracellular bacterium Francisella tularensis. Interest in F. tularensis has increased markedly in the past few years because of its potential use as an agent of bioterrorism. Five subspecies of this organism are found in the Northern hemisphere, but only F. tularensis subsp. tularensis and subsp. holarctica cause disease in humans. This review summarizes what is known about the pathogenesis of tularemia with a focus on bacterial surface components such as lipopolysaccharide and capsule as well as information obtained from the F. tularensis subsp. tularensis SCHU S4 genome. In particular, the mechanisms of action of recently identified virulence factors are discussed in the context of bacterial replication in macrophages and manipulation of the host inflammatory response. Throughout this report shared and unique features of F. tularensis subsp. tularensis, subsp. holarctica, and subsp. novicida are discussed.

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“…In this regard, it has been shown that, compared to systemic immunization, immunization of mice, monkeys, guinea pigs, and humans with LVS by aerosol or intranasal inoculation afforded better protection against subsequent respiratory challenge with type A F. tularensis [8,11,14,15]. However, LVS is much more virulent for humans and experimental animals when administered by the respiratory route than the dermal route [8,11,16].…”

Section: Introductionmentioning

confidence: 99%

Oral immunization of mice with the live vaccine strain (LVS) of Francisella tularensis protects mice against respiratory challenge with virulent type A F. tularensis

KuoLee

Harris

Conlan

et al. 2007

Vaccine

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Francisella tularensis is a gram-negative intracellular bacterium, and the causative agent of tularemia. The infection can be initiated by various routes and can manifest itself in several clinical forms with the disseminated typhoidal form initiated by inhalation being most fatal. The attenuated live vaccine strain (LVS), developed almost 50 years ago, remains the sole effective tularemia vaccine, which is still only available as an Investigational New Drug for at-risk individuals. This vaccine, when given by scarification, appears to provide solid protection against subsequent systemic infection with clinical strains of F. tularensis, but its efficacy against respiratory infection is less satisfactory. In this study, we evaluated the potential of oral immunization with LVS for eliciting protection against systemic and respiratory infection with virulent F. tularensis strains in a mouse model of tularemia. Oral LVS immunization was highly effective at protecting Balb/c mice against lethal systemic or respiratory challenges with type A and type B F. tularensis. Compared to shamimmunized mice, oral LVS-immunized mice showed significant reductions in burdens of virulent F. tularensis in the lung and spleen and milder tissue damage and inflammation in the liver. The immunization induced F. tularensis -specific antibody responses in the serum and bronchoalveolar lavage fluids, as well as antigen-specific splenocyte proliferation and IFN-γ and IL-2 production. The protective efficacy was related to the size of the immunizing dose but not the number of doses administered. Like other routes of LVS immunization in mice, the protective immunity induced by oral immunization was relatively short-lived. These results suggest that oral immunization should be explored further as an alternative vaccination strategy to combat tularemia.

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Different host defences are required to protect mice from primary systemic vs pulmonary infection with the facultative intracellular bacterial pathogen, Francisella tularensis LVS

Cited by 87 publications

References 31 publications

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

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

Francisella tularensis:Taxonomy, Genetics, and Immunopathogenesis of a Potential Agent of Biowarfare

Oral immunization of mice with the live vaccine strain (LVS) of Francisella tularensis protects mice against respiratory challenge with virulent type A F. tularensis

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