scholarly journals Aim2 and Nlrp3 Are Dispensable For Vaccine-Induced Immunity Against Francisella tularensis Live Vaccine Strain

2021 ◽  
Author(s):  
Maha Alqahtani ◽  
Zhuo Ma ◽  
Kayla Fantone ◽  
Meenakshi Malik ◽  
Chandra Shekhar Bakshi
Keyword(s):  
Immune Responses ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Nlrp3 Inflammasome ◽  
Live Vaccine ◽  
Innate Immune ◽  
Live Vaccine Strain ◽  
Innate Immune Responses ◽  
Lethal Challenge ◽  
Induced Immunity

Francisella tularensis (F. tularensis) is a facultative intracellular, Gram-negative bacterium that causes a fatal disease known as tularemia. Due to its extremely high virulence, ease of spread by aerosolization, and the potential to be used as a bioterror agent, F. tularensis is classified by the CDC as a Tier 1 Category A Select Agent. Previous studies have demonstrated the roles of inflammasome sensors; absent in melanoma 2 (AIM2) and NLRP3, in the generation of innate immune responses to F. tularensis infection. However, contributions of both the AIM2 and NLRP3 in the development of vaccine-induced adaptive immune responses against F. tularensis are not known. This study determined the contributions of Aim2 and Nlrp3-inflammasome sensors in vaccine-induced immune responses in a mouse model of respiratory tularemia. We developed a model to vaccinate the Aim2 and Nlrp3-deficient mice (Aim2-/- and Nlrp3-/-) using the emrA1 mutant of F. tularensis live vaccine strain (LVS). The results demonstrate that the innate immune responses in Aim2-/- and Nlrp3-/- mice vaccinated with the emrA1 mutant differ from their wild-type counterparts. However, despite these differences in the innate immune responses, both Aim2-/- and Nlrp3-/- mice are fully protected against an intranasal lethal challenge dose of F. tularensis LVS. Moreover, the lack of both Aim2 and Nlrp3 inflammasome sensors does not affect the production of the vaccination-induced antibody and cell-mediated responses. Overall, this study reports a novel finding that both Aim2 and Nlrp3 are dispensable for vaccination-induced immunity against respiratory tularemia caused by F. tularensis.

Dominance of human innate immune responses in primary Francisella tularensis live vaccine strain vaccination

2006 ◽  
Vol 117 (5) ◽  
pp. 1186-1188 ◽  
Author(s):  
Claudette L. Fuller ◽  
Katherine C. Brittingham ◽  
Matthew J. Hepburn ◽  
James W. Martin ◽  
Patricia L. Petitt ◽  
...  
Keyword(s):  
Immune Responses ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Innate Immune ◽  
Live Vaccine Strain ◽  
Innate Immune Responses

scholarly journals Diverse Myeloid and Lymphoid Cell Subpopulations Produce Gamma Interferon during Early Innate Immune Responses to Francisella tularensis Live Vaccine Strain

2008 ◽  
Vol 76 (9) ◽  
pp. 4311-4321 ◽  
Author(s):  
Roberto De Pascalis ◽  
Betsy C. Taylor ◽  
Karen L. Elkins
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Nk Cells ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Innate Immune ◽  
Live Vaccine Strain ◽  
Ifn Γ ◽  
Cell Subpopulations

ABSTRACT Francisella tularensis, a small gram-negative intracellular bacterium responsible for causing tularemia, is highly pathogenic and classified as a category A agent of bioterrorism. As for other intracellular pathogens, successful protective immune responses to Francisella tularensis require rapid and efficient induction of gamma interferon (IFN-γ) production. Studies using intracellular bacteria such as Listeria monocytogenes as well as Francisella suggest that natural killer (NK) and T cells are important sources of IFN-γ. However, comprehensive characterization of specific sources of IFN-γ produced during Francisella infection in vivo remains incomplete, and depletion of NK cells before infection of mice with the F. tularensis live vaccine strain (LVS) has little impact on the course or outcome of infection. In this study, we determined the cell subpopulations that respond quickly to intradermal F. tularensis LVS infection of mice by producing IFN-γ within hours to a few days. Splenic and liver lymphocytes were obtained from LVS-infected mice and analyzed for IFN-γ mRNA by reverse transcription-PCR, for intracellular cytokine expression by multiparameter flow cytometry, and for ex vivo production of IFN-γ protein by enzyme-linked immunosorbent assay. Cells producing IFN-γ were readily detectable by day 3 after infection, and numbers progressively increased through days 5 to 7. Importantly, the cell types responsible for IFN-γ production were much more varied than expected: these included not only NK cells and T cells, which might be predicted, but also other cells, including dendritic cells (DCs), “NK DCs,” NK T cells, and neutrophils. Most importantly, since RAG-1 knockout mice appeared to exhibit a frequency of IFN-γ-producing cells comparable to that of intact wild-type mice, early IFN-γ production by innate immune cells does not depend on the presence of T or B cells.

scholarly journals TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

2014 ◽  
Vol 82 (5) ◽  
pp. 2068-2078 ◽  
Author(s):  
Christopher R. Doyle ◽  
Ji-An Pan ◽  
Patricio Mena ◽  
Wei-Xing Zong ◽  
David G. Thanassi
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Host Cell ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Type I ◽  
Content Type ◽  
Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

scholarly journals Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination

2007 ◽  
Vol 44 (12) ◽  
pp. 3173-3184 ◽  
Author(s):  
Claudette L. Fuller ◽  
Katherine C. Brittingham ◽  
Mark W. Porter ◽  
Matthew J. Hepburn ◽  
Patricia L. Petitt ◽  
...  
Keyword(s):  
Immune Responses ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Transcriptome Analysis ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Human Immune

scholarly journals Construction and Characterization of an Attenuated Purine Auxotroph in a Francisella tularensis Live Vaccine Strain

2006 ◽  
Vol 74 (8) ◽  
pp. 4452-4461 ◽  
Author(s):  
Roger Pechous ◽  
Jean Celli ◽  
Renee Penoske ◽  
Stanley F. Hayes ◽  
Dara W. Frank ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Defined Medium ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Lethal Challenge ◽  
Significant Attenuation ◽  
Infected Cells

ABSTRACT Francisella tularensis is a facultative intracellular pathogen and is the etiological agent of tularemia. It is capable of escaping from the phagosome, replicating to high numbers in the cytosol, and inducing apoptosis in macrophages of a variety of hosts. F. tularensis has received significant attention recently due to its potential use as a bioweapon. Currently, there is no licensed vaccine against F. tularensis, although a partially protective live vaccine strain (LVS) that is attenuated in humans but remains fully virulent for mice was previously developed. An F. tularensis LVS mutant deleted in the purMCD purine biosynthetic locus was constructed and partially characterized by using an allelic exchange strategy. The F. tularensis LVS ΔpurMCD mutant was auxotrophic for purines when grown in defined medium and exhibited significant attenuation in virulence when assayed in murine macrophages in vitro or in BALB/c mice. Growth and virulence defects were complemented by the addition of the purine precursor hypoxanthine or by introduction of purMCDN in trans. The F. tularensis LVS ΔpurMCD mutant escaped from the phagosome but failed to replicate in the cytosol or induce apoptotic and cytopathic responses in infected cells. Importantly, mice vaccinated with a low dose of the F. tularensis LVSΔ purMCD mutant were fully protected against subsequent lethal challenge with the LVS parental strain. Collectively, these results suggest that F. tularensis mutants deleted in the purMCD biosynthetic locus exhibit characteristics that may warrant further investigation of their use as potential live vaccine candidates.

scholarly journals Inactivated Francisella tularensis Live Vaccine Strain Protects against Respiratory Tularemia by Intranasal Vaccination in an Immunoglobulin A-Dependent Fashion

2007 ◽  
Vol 75 (5) ◽  
pp. 2152-2162 ◽  
Author(s):  
Shawn D. Baron ◽  
Rajendra Singh ◽  
Dennis W. Metzger
Keyword(s):  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Serum Antibody ◽  
Immunoglobulin A ◽  
Live Vaccine ◽  
Interleukin 12 ◽  
Live Vaccine Strain ◽  
Lethal Challenge ◽  
Mucosal Vaccination ◽  
Ifn Γ

ABSTRACT Francisella tularensis is a gram-negative intracellular bacterium that is considered to be a potential category A biological weapon due to its extreme virulence. Although vaccination with the attenuated live vaccine strain (LVS) of F. tularensis can protect against lethal challenge, use of inactivated or subunit forms as vaccine candidates for induction of protective antibody responses has not been fully evaluated. In the present study, we examined whether immune protection in the lung could be stimulated by intranasal administration of inactivated LVS together with interleukin-12 (IL-12) as an adjuvant. LVS was inactivated by heat, paraformaldehyde treatment, or exposure to UV, and inactivation of the preparations was confirmed by assessing bacterial growth and the survival of mice after direct inoculation. We found that mucosal vaccination with inactivated LVS provided 90 to 100% protection in mice after lethal intranasal challenge with 104 CFU of LVS, and this protection was dependent on inclusion of exogenous IL-12 during vaccine administration. Survival of vaccinated mice after live bacterial challenge was correlated with reduced bacterial burden, decreased pulmonary inflammation, increased serum antibody titers, and lower levels of gamma interferon (IFN-γ), tumor necrosis factor alpha, and IL-6 in the lungs, livers, and spleens. Whereas NK cells were primarily responsible for the production of IFN-γ in unvaccinated, challenged animals, vaccinated mice had increased levels of lung IFN-γ+ CD4+ T cells after challenge. Significantly, mice genetically deficient in immunoglobulin A (IgA) expression were unable to survive lethal challenge after vaccination. These results are the first results to demonstrate that IgA-mediated protection against lethal respiratory tularemia occurs after mucosal vaccination with inactivated F. tularensis LVS.

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