Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

Marohn, Mark E.; Santiago, Araceli E.; Shirey, Kari Ann; Lipsky, Michael; Vogel, Stefanie N.; Barry, Eileen M.

doi:10.1128/iai.00144-12

Cited by 18 publications

(33 citation statements)

References 43 publications

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“…For example, deletion of phtA in Legionella pneumophila (32) and three phtA orthologues in Francisella tularensis resulted in reduced intracellular growth and attenuation (33). However, while deletion of icgA did not affect growth in broth, it significantly enhanced intracellular growth compared to that of the wild-type strain.…”

Section: Figmentioning

confidence: 97%

IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth

et al. 2014

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bVirulence of the intracellular pathogen Rhodococcus equi depends on a 21.3-kb pathogenicity island located on a conjugative plasmid. To date, the only nonregulatory pathogenicity island-encoded virulence factor identified is the cell envelope-associated VapA protein. Although the pathogenicity islands from porcine and equine R. equi isolates have undergone major rearrangements, the virR operon (virR-icgA-vapH-orf7-virS) is highly conserved in both, suggesting these genes play an important role in pathogenicity. VirR and VirS are transcriptional regulators controlling expression of pathogenicity island genes, including vapA. Here, we show that while vapH and orf7 are dispensable for intracellular growth of R. equi, deletion of icgA, formerly known as orf5, encoding a major facilitator superfamily transport protein, elicited an enhanced growth phenotype in macrophages and a significant reduction in macrophage viability, while extracellular growth in broth remained unaffected. Transcription of virS, located downstream of icgA, and vapA was not affected by the icgA deletion during growth in broth or in macrophages, showing that the enhanced growth phenotype caused by deletion of icgA was not mediated through abnormal transcription of these genes. Transcription of icgA increased 6-fold within 2 h following infection of macrophages and remained significantly higher 48 h postinfection compared to levels at the start of the infection. The major facilitator superfamily transport protein IcgA is the first factor identified in R. equi that negatively affects intracellular replication. Aside from VapA, it is only the second pathogenicity island-encoded structural protein shown to play a direct role in intracellular growth of this pathogenic actinomycete.

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Section: Figmentioning

confidence: 97%

IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth

et al. 2014

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“…One of the more recent reports demonstrated the attenuation of three LVS mutants of a family of genes predicted to encode transporter proteins of the MFS family [26]. LVSΔ fptB , LVSΔ fptE , and LVSΔ fptG were all found to display altered intracellular replication kinetics in either J774.1 cells and/or HepG2 cells.…”

Section: Summary Of Recent Live Attenuated Lvs Mutantsmentioning

confidence: 99%

Live attenuated tularemia vaccines: Recent developments and future goals

Marohn

Barry

2013

Vaccine

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In the aftermath of the 2001 anthrax attacks in the U.S., numerous efforts were made to increase the level of preparedness against a biological attack both in the US and worldwide. As a result, there has been an increase in research interest in the development of vaccines and other countermeasures against a number of agents with the potential to be used as biological weapons. One such agent, Francisella tularensis, has been the subject of a surge in the level of research being performed, leading to a substantial increase in knowledge of the pathogenic mechanisms of the organism and the induced immune responses. This information has facilitated the development of multiple new Francisella vaccine candidates. Herein we review the latest live attenuated F. tularensis vaccine efforts. Historically, live attenuated vaccines have demonstrated the greatest degree of success in protection against tularemia and the greatest promise in recent efforts to develop of a fully protective vaccine. This review summarizes recent live attenuated Francisella vaccine candidates and the lessons learned from those studies, with the goal of collating known characteristics associated with successful attenuation, immunogenicity, and protection.

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“…F. tularensis is predicted to encode 31 MFS transporters. Characterization of a subset of MFS transporters revealed their role in pathogenesis and virulence of F. tularensis (Marohn et al, 2012). Bina et al (2008) identified and characterized AcrAB RND multidrug transporter.…”

Section: Introductionmentioning

confidence: 99%

EmrA1 membrane fusion protein of Francisella tularensis LVS is required for resistance to oxidative stress, intramacrophage survival and virulence in mice

Banik

Rane

et al. 2014

Molecular Microbiology

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Francisella tularensis is a Category A Biodefense agent that causes a fatal human disease known as tularemia. The pathogenicity of F. tularensis depends on its ability to persist inside host immune cells primarily by resisting an attack from host-generated reactive oxygen and nitrogen species (ROS/RNS). Based on the ability of F. tularensis to resist high ROS/RNS levels, we have hypothesized that additional unknown factors act in conjunction with known antioxidant defenses to render ROS resistance. By screening a transposon insertion library of F. tularensis LVS in the presence of hydrogen peroxide, we have identified an oxidant sensitive mutant in putative EmrA1 (FTL_0687) secretion protein. The results demonstrate that the emrA1 mutant is highly sensitive to oxidants and several antimicrobial agents, and exhibits diminished intramacrophage growth that can be restored to wild type F. tularensis LVS levels either by transcomplementation, inhibition of ROS generation, or infection in NADPH oxidase deficient (gp91Phox−/−) macrophages. The emrA1 mutant is attenuated for virulence, which is restored by infection in gp91Phox−/− mice. Further, EmrA1 contributes to oxidative stress resistance by affecting secretion of Francisella antioxidant enzymes SodB and KatG. This study exposes unique links between transporter activity and the antioxidant defense mechanisms of F. tularensis.

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Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

Abstract: ABSTRACTFrancisella tularensisis the causative agent of tularemia. Due to its aerosolizable nature and low infectious dose,F. tularensisis classified as a category A select agent and, therefore, is a priority for vac… Show more

Cited by 18 publications

References 43 publications

IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth

IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth

Live attenuated tularemia vaccines: Recent developments and future goals

EmrA1 membrane fusion protein of Francisella tularensis LVS is required for resistance to oxidative stress, intramacrophage survival and virulence in mice

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