NK Cells and Gamma Interferon Coordinate the Formation and Function of Hepatic Granulomas in Mice Infected with the<i>Francisella tularensis</i>Live Vaccine Strain

Bokhari, Sirosh; Kim, Kee-Jun; Pinson, David M.; Slusser, Joyce G.; Yeh, Hung‐Wen; Parmely, Michael J.

doi:10.1128/iai.00745-07

Cited by 39 publications

(64 citation statements)

References 32 publications

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“…Thus, the pattern of Francisella sp. antigen staining and subsequent necrosis during acute infections in zebrafish (primarily within fish lymphoid tissue and the liver) largely parallels the pattern observed in mammalian tularemia (6,15). Francisella infection in other fish species has been reported to cause numerous granulomas in the spleen and kidney after much longer, chronic infections (47,48).…”

Section: Discussionmentioning

confidence: 84%

Host Immune Response and Acute Disease in a Zebrafish Model ofFrancisellaPathogenesis

et al. 2009

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Members of the bacterial genus Francisella are highly virulent and infectious pathogens. New models to study Francisella pathogenesis in evolutionarily distinct species are needed to provide comparative insight, as the mechanisms of host resistance and pathogen virulence are not well understood. We took advantage of the recent discovery of a novel species of Francisella to establish a zebrafish/Francisella comparative model of pathogenesis and host immune response. Adult zebrafish were susceptible to acute Francisella-induced disease and suffered mortality in a dose-dependent manner. Using immunohistochemical analysis, we localized bacterial antigens primarily to lymphoid tissues and livers of zebrafish following infection by intraperitoneal injection, which corresponded to regions of local cellular necrosis. Francisella sp. bacteria replicated rapidly in these tissues beginning 12 h postinfection, and bacterial titers rose steadily, leveled off, and then decreased by 7 days postinfection. Zebrafish mounted a significant tissue-specific proinflammatory response to infection as measured by the upregulation of interleukin-1␤ (IL-1␤), gamma interferon, and tumor necrosis factor alpha mRNA beginning by 6 h postinfection and persisting for up to 7 days postinfection. In addition, exposure of zebrafish to heat-killed bacteria demonstrated that the significant induction of IL-1␤ was highly specific to live bacteria. Taken together, the pathology and immune response to acute Francisella infection in zebrafish share many features with those in mammals, highlighting the usefulness of this new model system for addressing both general and specific questions about Francisella host-pathogen interactions via an evolutionary approach.

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Section: Discussionmentioning

confidence: 84%

Host Immune Response and Acute Disease in a Zebrafish Model ofFrancisellaPathogenesis

et al. 2009

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“…In contrast, IRS treatment reduced the bacterial burden and histopathology in the liver and, in doing so, may have preserved more liver functions in the infected rat. Similar passive immunization studies of mice with LVS point to a process that involves Fc receptor and gamma interferon (IFN-␥) (26,36), and the liver is one of the richest sources of NK cells that are capable of producing an IFN-␥ in response to F. tularensis infection (4,12). This may also explain the ability of immune serum to delay the death of athymic nude rats and mice (36), which express higher NK cell activity than wild-type animals (10,24).…”

Section: Vol 79 2011mentioning

confidence: 99%

“…Cells were harvested from the Percoll interface. All the cell preparations were treated with red blood cell lysis buffer (0.15 M NH 4 Cl, 1 mM KHCO 3 , 0.1 mM Na 2 -EDTA), washed with PBS, and resuspended in complete RPMI (RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1 mM nonessential amino acids, 1 mM L-glutamine, 1 mM sodium pyruvate) before staining. Cells were stained with biotinylated anti-CD8b (mouse IgG1, , clone 341) and anti-CD161a (mouse IgG1, , clone 10/78), fluorescein isothiocyanate (FITC)-conjugated anti-CD45R (mouse IgG2b, , clone HIS24), and allophycocyanin (APC)-conjugated anti-CD3 (mouse IgM, , clone iF4) antibodies from BD Biosciences (San Jose, CA) and phycoerythrin (PE)-conjugated anti-CD8b (mouse IgG1, , clone eBio341) and FITC-conjugated anti-CD4 (mouse IgG2a, clone OX-35) antibodies from eBiosciences (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A Francisella tularensis Strains

et al. 2011

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Pneumonic tularemia is a life-threatening disease caused by inhalation of the highly infectious intracellular bacterium Francisella tularensis. The most serious form of the disease associated with the type A strains can be prevented in experimental animals through vaccination with the attenuated live vaccine strain (LVS). The protection is largely cell mediated, but the contribution of antibodies remains controversial. We addressed this issue in a series of passive immunization studies in Fischer 344 (F344) rats. Subcutaneous LVS vaccination induced a robust serum antibody response dominated by IgM, IgG2a, and IgG2b antibodies. Prophylactic administration of LVS immune serum or purified immune IgG reduced the severity and duration of disease in naïve rats challenged intratracheally with a lethal dose of the virulent type A strain SCHU S4. The level of resistance increased with the volume of immune serum given, but the maximum survivable SCHU S4 challenge dose was at least 100-fold lower than that shown for LVS-vaccinated rats. Protection correlated with reduced systemic bacterial growth, less severe histopathology in the liver and spleen during the early phase of infection, and bacterial clearance by a T cell-dependent mechanism. Our results suggest that treatment with immune serum limited the sequelae associated with infection, thereby enabling a sterilizing T cell response to develop and resolve the infection. Thus, antibodies induced by LVS vaccination may contribute to the defense of F344 rats against respiratory infection by type A strains of F. tularensis.

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“…Subsequently, sections were probed with the primary antibodies (rat anti-mouse F4/80 [1:50; Santa Cruz or Serotec] and rabbit anti-F. tularensis [1:500; BD]) that had been diluted in the blocking solution for at least 1 h at 4°C. Although small subsets of dendritic cells and eosinophils have been reported to express this antigen (33,37), F4/80 has been used as a pan-macrophage marker in many laboratories (24,38), including those used by researchers in the F. tularensis field (6,63). The antibody isotype controls that had been used were rat IgG2b (BD Pharmingen) and normal rabbit IgG (Calbiochem) (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

Horzempa¹,

O’Dee²,

Shanks

et al. 2010

Infect Immun

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The pathogenesis of Francisella tularensis has been associated with this bacterium's ability to replicate within macrophages. F. tularensis can also invade and replicate in a variety of nonphagocytic host cells, including lung and kidney epithelial cells and hepatocytes. As uracil biosynthesis is a central metabolic pathway usually necessary for pathogens, we characterized ⌬pyrF mutants of both F. tularensis LVS and Schu S4 to investigate the role of these mutants in intracellular growth. As expected, these mutant strains were deficient in de novo pyrimidine biosynthesis and were resistant to 5-fluoroorotic acid, which is converted to a toxic product by functional PyrF. The F. tularensis ⌬pyrF mutants could not replicate in primary human macrophages. The inability to replicate in macrophages suggested that the F. tularensis ⌬pyrF strains would be attenuated in animal infection models. Surprisingly, these mutants retained virulence during infection of chicken embryos and in the murine model of pneumonic tularemia. We hypothesized that the F. tularensis ⌬pyrF strains may replicate in cells other than macrophages to account for their virulence. In support of this, F. tularensis ⌬pyrF mutants replicated in HEK-293 cells and normal human fibroblasts in vitro. Moreover, immunofluorescence microscopy showed abundant staining of wild-type and mutant bacteria in nonmacrophage cells in the lungs of infected mice. These findings indicate that replication in nonmacrophages contributes to the pathogenesis of F. tularensis.

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NK Cells and Gamma Interferon Coordinate the Formation and Function of Hepatic Granulomas in Mice Infected with theFrancisella tularensisLive Vaccine Strain

Cited by 39 publications

References 32 publications

Host Immune Response and Acute Disease in a Zebrafish Model ofFrancisellaPathogenesis

Host Immune Response and Acute Disease in a Zebrafish Model ofFrancisellaPathogenesis

Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A Francisella tularensis Strains

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

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