Correction: Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis

ABSTRACT Francisella tularensis is a gram-negative intracellular bacterium and the causative agent of the zoonotic disease tularemia. F. tularensis is a category A select agent and thus a potential agent of bioterrorism. Whereas an F. tularensis live, attenuated vaccine strain (LVS) is the basis of an investigational vaccine, this vaccine is not licensed for human use because of efficacy and safety concerns. In the present study, we immunized mice with isolated native outer membrane proteins (OMPs), ethanol-inactivated LVS (iLVS), or purified LVS lipopolysaccharide (LPS) and assessed the ability of each vaccine preparation to protect mice against pulmonary challenge with the virulent type A F. tularensis strain SchuS4. Antibody isotyping indicated that both Th1 and Th2 antibody responses were generated in mice after immunization with OMPs or iLVS, whereas LPS immunization resulted in only immunoglobulin A production. In survival studies, OMP immunization provided the greatest level of protection (50% survival at 20 days after infection with SchuS4), and there were associated 3-log reductions in the spleen and liver bacterial burdens (compared to nonvaccinated mice). Cytokine quantitation for the sera of SchuS4-challenged mice indicated that OMP and iLVS immunizations induced high levels of tumor necrosis factor alpha and interleukin-2 (IL-2) production, whereas only OMP immunization induced high levels of IL-10 production. By comparison, high levels of proinflammatory cytokines, including RANTES, granulocyte colony-stimulating factor, IL-6, IL-1α, IL-12p40, and KC, in nonvaccinated mice indicated that these cytokines may facilitate disease progression. Taken together, the results of this study demonstrate the potential utility of an OMP subunit (acellular) vaccine for protecting mammals against type A F. tularensis.

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Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2014.00045 ◽

2014 ◽

Vol 4 ◽

Cited By ~ 11

Author(s):

Devyn D. Gillette ◽

Heather M. Curry ◽

Thomas Cremer ◽

David Ravneberg ◽

Kavin Fatehchand ◽

...

Keyword(s):

Francisella Tularensis ◽

Type A ◽

Human Monocytes ◽

Cytokine Responses ◽

Virulent Type

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Prior Inoculation with Type B Strains of Francisella tularensis Provides Partial Protection against Virulent Type A Strains in Cottontail Rabbits

PLoS ONE ◽

10.1371/journal.pone.0140723 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0140723 ◽

Cited By ~ 1

Author(s):

Vienna R. Brown ◽

Danielle R. Adney ◽

Francisco Olea-Popelka ◽

Richard A. Bowen

Keyword(s):

Francisella Tularensis ◽

Type A ◽

Type B ◽

Partial Protection ◽

Virulent Type

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Toll-like receptor 4 (TLR4) does not confer a resistance advantage on mice against low-dose aerosol infection with virulent type A Francisella tularensis

Microbial Pathogenesis ◽

10.1016/j.micpath.2004.06.010 ◽

2004 ◽

Vol 37 (4) ◽

pp. 185-191 ◽

Cited By ~ 39

Author(s):

Wangxue Chen ◽

Rhonda KuoLee ◽

Hua Shen ◽

Maria Bùsa ◽

J. Wayne Conlan

Keyword(s):

Francisella Tularensis ◽

Low Dose ◽

Type A ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Virulent Type ◽

Aerosol Infection

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Live Attenuated Mutants of Francisella tularensis Protect Rabbits against Aerosol Challenge with a Virulent Type A Strain

Infection and Immunity ◽

10.1128/iai.01498-14 ◽

2014 ◽

Vol 82 (5) ◽

pp. 2098-2105 ◽

Cited By ~ 19

Author(s):

Douglas S. Reed ◽

Le'Kneitah P. Smith ◽

Kelly Stefano Cole ◽

Araceli E. Santiago ◽

Barbara J. Mann ◽

...

Keyword(s):

Weight Loss ◽

Francisella Tularensis ◽

Type A ◽

Content Type ◽

Time To Death ◽

Virulent Type ◽

No Weight Loss ◽

The 1960S ◽

Schu S4 ◽

Derivatives Of

ABSTRACTFrancisella tularensis, a Gram-negative bacterium, is the causative agent of tularemia. No licensed vaccine is currently available for protection against tularemia, although an attenuated strain, dubbed the live vaccine strain (LVS), is given to at-risk laboratory personnel as an investigational new drug (IND). In an effort to develop a vaccine that offers better protection, recombinant attenuated derivatives of a virulent type A strain, SCHU S4, were evaluated in New Zealand White (NZW) rabbits. Rabbits vaccinated via scarification with the three attenuated derivatives (SCHU S4 ΔguaBA, ΔaroD, and ΔfipBstrains) or with LVS developed a mild fever, but no weight loss was detected. Twenty-one days after vaccination, all vaccinated rabbits were seropositive for IgG toF. tularensislipopolysaccharide (LPS). Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4 at doses ranging from 50 to 500 50% lethal doses (LD50). All rabbits developed fevers and weight loss after challenge, but the severity was greater for mock-vaccinated rabbits. The ΔguaBAand ΔaroDSCHU S4 derivatives provided partial protection against death (27 to 36%) and a prolonged time to death compared to results for the mock-vaccinated group. In contrast, LVS and the ΔfipBstrain both prolonged the time to death, but there were no survivors from the challenge. This is the first demonstration of vaccine efficacy against aerosol challenge with virulent type AF. tularensisin a species other than a rodent since the original work with LVS in the 1960s. The ΔguaBAand ΔaroDSCHU S4 derivatives warrant further evaluation and consideration as potential vaccines for tularemia and for identification of immunological correlates of protection.

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Mouse Model of Oral Infection with Virulent Type A Francisella tularensis

Infection and Immunity ◽

10.1128/iai.01834-06 ◽

2007 ◽

Vol 75 (4) ◽

pp. 1651-1660 ◽

Cited By ~ 21

Author(s):

R. KuoLee ◽

X. Zhao ◽

J. Austin ◽

G. Harris ◽

J. W. Conlan ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Francisella Tularensis ◽

Tumor Necrosis ◽

Type A ◽

Oral Infection ◽

Gamma Interferon ◽

Health Concern ◽

High Dose ◽

Virulent Type ◽

Necrosis Factor

ABSTRACT Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Little is known about the immunopathogenesis of oral infection with this pathogen. Here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type A F. tularensis and characterized the course of infection and the associated host responses. Both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inoculation of type A F. tularensis with a 50% lethal dose (LD50) of 106 organisms, which was 100,000-fold higher than the LD100 for intradermal or respiratory routes of infection. Mice deficient in gamma interferon or tumor necrosis factor receptors 1 and 2 were more susceptible than wild-type controls to oral infection with a high dose of the pathogen. After oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the livers and spleens, where the organism multiplied to high numbers and induced marked neutrophilic infiltration and severe tissue necrosis. Infected mice showed rapid increases in tissue cytokine mRNA expression, which peaked in the MLN at 2 days postinfection (dpi) and in the liver and spleen at 3 dpi. The levels of gamma interferon, interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1α, KC, interferon-inducible protein 10, and monocyte chemotactic protein 1 were elevated from day 2 postinoculation onward. Moreover, mice intradermally immunized with the live vaccine strain of F. tularensis showed little survival advantage over naive mice after oral challenge with type A F. tularensis. These results suggest that type A F. tularensis is an effective oral pathogen that can cause fatal systemic infection and could pose a public health concern, particularly to immunocompromised individuals, if ingested in contaminated water and food.

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