T Cells from Lungs and Livers of<i>Francisella tularensis-</i>Immune Mice Control the Growth of Intracellular Bacteria

Collazo, Carmen M.; Meierovics, Anda I.; Pascalis, Roberto De; Wu, Terry; Lyons, C. Rick; Elkins, Karen L.

doi:10.1128/iai.01322-08

Cited by 28 publications

(37 citation statements)

References 41 publications

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“…The ability of LVS-immune splenocytes to control intracellular LVS growth relies on the production of IFN-␥, TNF-␣, and the resulting production of reactive nitrogen intermediates, including nitric oxide (RNI) (32)(33)(34)36). Supernatants were therefore collected from cocultures and assessed for levels of RNI.…”

Section: Characterization Of the Production And Role Of Il-6 During Pmentioning

confidence: 99%

“…Cocultures were performed in 24-or 48-well tissue culture plates as described previously (32)(33)(34)(35)(36)(37). Briefly, bone marrow macrophages (BMMØ) were cultured in complete Dulbecco's modified Eagle's medium (DMEM supplemented with 10% heat-inactivated FCS [HyClone, Logan, UT], 10% L-929-conditioned medium, 0.2 mM L-glutamine, 10 mM HEPES buffer, and 0.1 mM nonessential amino acids) in 24-well plates.…”

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confidence: 99%

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Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

Kurtz

Foreman

Bosio³

et al. 2013

Infect Immun

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We employed Francisella tularensis live vaccine strain (LVS) to study mechanisms of protective immunity against intracellular pathogens and, specifically, to understand protective correlates. One potential molecular correlate identified previously was interleukin-6 (IL-6), a cytokine with pleotropic roles in immunity, including influences on T and B cell functions. Given its role as an immune modulator and the correlation with successful anti-LVS vaccination, we examined the role IL-6 plays in the host response to LVS. IL-6-deficient (IL-6 knockout [KO]) mice infected with LVS intradermally or intranasally or anti-IL-6-treated mice, showed greatly reduced 50% lethal doses compared to wild-type (WT) mice. Increased susceptibility was not due to altered splenic immune cell populations during infection or decreased serum antibody production, as IL-6 KO mice had similar compositions of each compared to WT mice. Although LVS-infected IL-6 KO mice produced much less serum amyloid A and haptoglobin (two acute-phase proteins) than WT mice, there were no other obvious pathophysiological differences between LVS-infected WT and IL-6 KO mice. IL-6 KO or WT mice that survived primary LVS infection also survived a high-dose LVS secondary challenge. Using an in vitro overlay assay that measured T cell activation, cytokine production, and abilities of primed splenocytes to control intracellular LVS growth, we found that IL-6 KO total splenocytes or purified T cells were slightly defective in controlling intracellular LVS growth but were equivalent in cytokine production. Taken together, IL-6 is an integral part of a successful immune response to primary LVS infection, but its exact role in precipitating adaptive immunity remains elusive.

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Section: Characterization Of the Production And Role Of Il-6 During Pmentioning

confidence: 99%

mentioning

confidence: 99%

Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

Kurtz

Foreman

Bosio³

et al. 2013

Infect Immun

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“…To discover additional critical immune mechanisms, our group and others have employed an in vitro coculture system to investigate protection against Francisella tularensis and M. tuberculosis (21)(22)(23)(24). In this coculture assay, murine bone marrowderived macrophages (BMDM) are infected at a low multiplicity of infection.…”

mentioning

confidence: 99%

“…Cocultures were performed in 24-or 48-well tissue culture plates, as described previously (21,(28)(29)(30)(31)(32). Briefly, bone marrow-derived macrophages (BMDM) were cultured in complete Dulbecco's modified Eagle's medium (DMEM) (DMEM supplemented with 10% heat-inactivated FBS [HyClone, Logan, UT], 10% L-929-conditioned medium, 0.2 mM L-glutamine, 10 mM HEPES buffer, and 0.1 mM nonessential amino acids) in 24-well plates.…”

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confidence: 99%

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

Kurtz

Elkins

2015

Clin Vaccine Immunol

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A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses.A lthough it has been more than 90 years since the implementation of immunization with the Mycobacterium bovis BCG vaccine, Mycobacterium tuberculosis is as much of a public health threat today as ever (1). While it is clear that the BCG vaccine has shortcomings, the exact nature of its failure to fully protect adult populations against pulmonary disease still remains a mystery. The lack of understanding of the protective mechanisms needed for the successful control of M. tuberculosis impedes the design and testing of next-generation novel vaccine candidates (2-4).Much work has already been done to elucidate the protective mechanisms involved in the primary and secondary host responses to M. tuberculosis. Several immune components are integral to the primary immune response to M. tuberculosis, as has been demonstrated in both humans and mice. Interferon gamma (IFN-␥) is important for infection control in humans, as individuals with deficiencies in IFN-␥ signaling pathways are more susceptible to disseminated BCG and infections caused by nontuberculous mycobacteria (NTM) (5). In murine studies, IFN-␥ is essential for controlling the growth of the bacteria, as mice deficient in IFN-␥ succumb quickly to infection (6, 7).A primary source of IFN-␥ is activated CD4 ϩ T cells, which are themselves important for controlling M. tuberculosis infections. The role of CD4 ϩ T cells has been clearly demonstrated in humans in the context of HIV and associated T-cell deficiencies, as these patients are h...

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“…Regardless of the route of inoculation, the liver is one of the important targets for infection by F. tularensis (6,10,12,(31)(32)(33). Furthermore, F. tularensis invades and replicates to high numbers in hepatocytes (6,10,12,14,31,34), which constitute 70% of the cell number and 80% of the volume of the liver (35).…”

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FeoB-Mediated Uptake of Iron by Francisella tularensis

et al. 2013

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Francisella tularensis, the bacterial cause of tularemia, infects the liver and replicates in hepatocytes in vivo and in vitro. However, the factors that govern adaptation of F. tularensis to the intrahepatocytic niche have not been identified. Using cDNA microarrays, we determined the transcriptional profile of the live vaccine strain (LVS) of F. tularensis grown in the FL83B murine hepatocytic cell line compared to that of F. tularensis cultured in broth. The fslC gene of the fsl operon was the most highly upregulated. Deletion of fslC eliminated the ability of the LVS to produce siderophore, which is involved in uptake of ferric iron, but it did not impair its growth in hepatocytes, A549 epithelial cells, or macrophages. Therefore, we sought an alternative means by which F. tularensis might obtain iron. Deletion of feoB, which encodes a putative ferrous iron transporter, retarded replication of the LVS in iron-restricted media, reduced its growth in hepatocytic and epithelial cells, and impaired its acquisition of iron. Survival of mice infected intradermally with a lethal dose of the LVS was slightly improved by deletion of fslC but was not altered by loss of feoB. However, the ⌬feoB mutant showed diminished ability to colonize the lungs, liver, and spleen of mice that received sublethal inocula. Thus, FeoB represents a previously unidentified mechanism for uptake of iron by F. tularensis. Moreover, failure to produce a mutant strain lacking both feoB and fslC suggests that FeoB and the proteins of the fsl operon are the only major means by which F. tularensis acquires iron.

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T Cells from Lungs and Livers ofFrancisella tularensis-Immune Mice Control the Growth of Intracellular Bacteria

Cited by 28 publications

References 41 publications

Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

FeoB-Mediated Uptake of Iron by Francisella tularensis

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