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Translation of Pre-clinical Francisella tularensis Research
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Translation of Pre-clinical Francisella tularensis Research

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (25 November 2021) | Viewed by 22483

Special Issue Editors

Dr. Douglas S. Reed

E-Mail Website
Guest Editor
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA
Interests: respiratory infection; vaccines; immune correlates; tularemia; encephalitic viruses; avian influenza
Dr. Karsten Hazlett

E-Mail Website
Co-Guest Editor
Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
Interests: tularemia; pathogenesis; vaccines; gram negative bacteria; gene expression; protein expression
Prof. Dr. Eileen Barry

E-Mail Website
Co-Guest Editor
University of Maryland-Baltimore
Interests: tularemia, pathogenesis, vaccines, gram negative bacteria, enteric bacteria

Special Issue Information

Dear colleagues,

Francisella tularensis is the causative agent of tularemia, a zoonotic disease that can cause considerable morbidity and mortality in humans. Natural transmission is predominantly by direct contact with infected animals and tissues or arthropod vectors. If the bacterium is aerosolized, inhalation can lead to rapid, severe bacterial pneumonia and sepsis. Because of the potential for disease caused by inhalation exposure, there has long been concern that F. tularensis could be used as a biological weapon. Licensed vaccines and therapeutics for tularemia are needed to combat this potential misuse. Several promising vaccine candidates have been developed and there are urgent efforts to understand mechanisms and correlates of protection. The number of natural disease cases has declined since the 1950s, so there is a lack of knowledge regarding the pathogenesis of the disease in humans. The majority of studies with F. tularensis research has been done infecting inbred mice with attenuated strains passaged in vitro. It is unclear how well these results translate to humans. Animal models that can bridge the gap between inbred mice and outbred humans include rats, rabbits, and cynomolgus macaques. We are seeking manuscripts that explore the pathogenesis of tularemia or protective immune responses with an emphasis on translating these results to human clinical trials, particularly studies using outbred animals and/or aerosol challenge with virulent, pathogenic strains of F. tularensis.

Manuscripts that bridge some portion(s) of the inbred mouse–outbred human spectrum. By collecting multiple “bridging” reports, we seek to clarify areas of discontinuity that, ultimately, should inform and guide efforts towards human-relevant tularemia research.

Dr. Douglas S. Reed
Guest Editor
Dr. Karsten Hazlett
Prof. Dr. Eileen Barry
Co-Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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Research

14 pages, 2753 KiB  
Article
The O-Ag Antibody Response to Francisella Is Distinct in Rodents and Higher Animals and Can Serve as a Correlate of Protection
by Lauren E. Shoudy, Prachi Namjoshi, Gabriela Giordano, Sudeep Kumar, Jennifer D. Bowling, Carl Gelhaus, Eileen M. Barry, Allan J. Hazlett, Brian A. Hazlett, Kristine L. Cooper, Phillip R. Pittman, Douglas S. Reed and Karsten R. O. Hazlett
Pathogens 2021, 10(12), 1646; https://doi.org/10.3390/pathogens10121646 - 20 Dec 2021
Cited by 4 | Viewed by 3784
Abstract
Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live [...] Read more.
Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live vaccine strain (LVS) demonstrated ~80% vaccine efficacy against low dose (~50 CFU) challenge; however, protection deteriorated with higher challenge doses (~2000 CFU of SchuS4) and no COPs were established. Here, we describe our efforts to develop clinically relevant, humoral COPs applicable to high-dose, aerosol challenge with S4. First, our serosurvey of LVS-vaccinated Hu and animals revealed that rabbits (Rbs), but not rodents, recapitulate the Hu O-Ag dependent Ab response to Ft. Next, we assayed Rbs immunized with distinct S4-based vaccine candidates (S4ΔclpB, S4ΔguaBA, and S4ΔaroD) and found that, across multiple vaccines, the %O-Ag dep Ab trended with vaccine efficacy. Among S4ΔguaBA-vaccinated Rbs, the %O-Ag dep Ab in pre-challenge plasma was significantly higher in survivors than in non-survivors; a cut-off of >70% O-Ag dep Ab predicted survival with high sensitivity and specificity. Finally, we found this COP in 80% of LVS-vaccinated Hu plasma samples as expected for a vaccine with 80% Hu efficacy. Collectively, the %O-Ag dep Ab response is a bona fide COP for S4ΔguaBA-vaccinated Rb and holds significant promise for guiding vaccine trials with higher animals. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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16 pages, 1788 KiB  
Article
Development of Immunoassays for Detection of Francisella tularensis Lipopolysaccharide in Tularemia Patient Samples
by Emily E. Hannah, Sujata G. Pandit, Derrick Hau, Haley L. DeMers, Kayleigh Robichaux, Teerapat Nualnoi, Anjana Dissanayaka, Jose Arias-Umana, Heather R. Green, Peter Thorkildson, Kathryn J. Pflughoeft, Marcellene A. Gates-Hollingsworth, Yasemin Ozsurekci and David P. AuCoin
Pathogens 2021, 10(8), 924; https://doi.org/10.3390/pathogens10080924 - 22 Jul 2021
Cited by 8 | Viewed by 4166
Abstract
Francisella tularensis is the causative agent of tularemia, a zoonotic bacterial infection that is often fatal if not diagnosed and treated promptly. Natural infection in humans is relatively rare, yet persistence in animal reservoirs, arthropod vectors, and water sources combined with a low [...] Read more.
Francisella tularensis is the causative agent of tularemia, a zoonotic bacterial infection that is often fatal if not diagnosed and treated promptly. Natural infection in humans is relatively rare, yet persistence in animal reservoirs, arthropod vectors, and water sources combined with a low level of clinical recognition make tularemia a serious potential threat to public health in endemic areas. F. tularensis has also garnered attention as a potential bioterror threat, as widespread dissemination could have devastating consequences on a population. A low infectious dose combined with a wide range of symptoms and a short incubation period makes timely diagnosis of tularemia difficult. Current diagnostic techniques include bacterial culture of patient samples, PCR and serological assays; however, these techniques are time consuming and require technical expertise that may not be available at the point of care. In the event of an outbreak or exposure a more efficient diagnostic platform is needed. The lipopolysaccharide (LPS) component of the bacterial outer leaflet has been identified previously by our group as a potential diagnostic target. For this study, a library of ten monoclonal antibodies specific to F. tularensis LPS were produced and confirmed to be reactive with LPS from type A and type B strains. Antibody pairs were tested in an antigen-capture enzyme-linked immunosorbent assay (ELISA) and lateral flow immunoassay format to select the most sensitive pairings. The antigen-capture ELISA was then used to detect and quantify LPS in serum samples from tularemia patients for the first time to determine the viability of this molecule as a diagnostic target. In parallel, prototype lateral flow immunoassays were developed, and reactivity was assessed, demonstrating the potential utility of this assay as a rapid point-of-care test for diagnosis of tularemia. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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24 pages, 3472 KiB  
Article
Deletion Mutants of Francisella Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal Francisella LVS Challenge in a Murine Model of Respiratory Tularemia
by Brandi E. Hobbs, Courtney A. Matson, Vasileios I. Theofilou, Tonya J. Webb, Rania H. Younis and Eileen M. Barry
Pathogens 2021, 10(7), 799; https://doi.org/10.3390/pathogens10070799 - 24 Jun 2021
Cited by 2 | Viewed by 3488
Abstract
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 Francisella phagosomal transporter (fpt) genes belonging to the [...] Read more.
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 Francisella phagosomal transporter (fpt) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the fptA and fptF genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔfptA and LVSΔfptF were highly attenuated with LD50 values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the fpt mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔfptA and LVSΔfptF were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of Ft and the modulation of the host immune response. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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20 pages, 2112 KiB  
Article
Modern Development and Production of a New Live Attenuated Bacterial Vaccine, SCHU S4 ΔclpB, to Prevent Tularemia
by J. Wayne Conlan, Anders Sjöstedt, H. Carl Gelhaus, Perry Fleming, Kevan McRae, Ronald R. Cobb, Roberto De Pascalis and Karen L. Elkins
Pathogens 2021, 10(7), 795; https://doi.org/10.3390/pathogens10070795 - 23 Jun 2021
Cited by 8 | Viewed by 3183
Abstract
Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by [...] Read more.
Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including Ftt. Between 2005–2009, we pursued a novel live vaccine against Ftt by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of Ftt. We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 ΔclpB, that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 ΔclpB has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 ΔclpB to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 ΔclpB to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 ΔclpB vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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15 pages, 2062 KiB  
Article
Identification of an Attenuated Substrain of Francisella tularensis SCHU S4 by Phenotypic and Genotypic Analyses
by Julie A. Lovchik, Douglas S. Reed, Julie A. Hutt, Fangfang Xia, Rick L. Stevens, Thero Modise, Eileen M. Barry and Terry H. Wu
Pathogens 2021, 10(6), 638; https://doi.org/10.3390/pathogens10060638 - 22 May 2021
Cited by 2 | Viewed by 3056
Abstract
Pneumonic tularemia is a highly debilitating and potentially fatal disease caused by inhalation of Francisella tularensis. Most of our current understanding of its pathogenesis is based on the highly virulent F. tularensis subsp. tularensis strain SCHU S4. However, multiple sources of SCHU S4 [...] Read more.
Pneumonic tularemia is a highly debilitating and potentially fatal disease caused by inhalation of Francisella tularensis. Most of our current understanding of its pathogenesis is based on the highly virulent F. tularensis subsp. tularensis strain SCHU S4. However, multiple sources of SCHU S4 have been maintained and propagated independently over the years, potentially generating genetic variants with altered virulence. In this study, the virulence of four SCHU S4 stocks (NR-10492, NR-28534, NR-643 from BEI Resources and FTS-635 from Battelle Memorial Institute) along with another virulent subsp. tularensis strain, MA00-2987, were assessed in parallel. In the Fischer 344 rat model of pneumonic tularemia, NR-643 and FTS-635 were found to be highly attenuated compared to NR-10492, NR-28534, and MA00-2987. In the NZW rabbit model of pneumonic tularemia, NR-643 caused morbidity but not mortality even at a dose equivalent to 500x the LD50 for NR-10492. Genetic analyses revealed that NR-10492 and NR-28534 were identical to each other, and nearly identical to the reference SCHU S4 sequence. NR-643 and FTS-635 were identical to each other but were found to have nine regions of difference in the genomic sequence when compared to the published reference SCHU S4 sequence. Given the genetic differences and decreased virulence, NR-643/FTS-635 should be clearly designated as a separate SCHU S4 substrain and no longer utilized in efficacy studies to evaluate potential vaccines and therapeutics against tularemia. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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17 pages, 13628 KiB  
Article
The Natural History of Aerosolized Francisella tularensis Infection in Cynomolgus Macaques
by Ondraya M. Frick, Virginia A. Livingston, Chris A. Whitehouse, Sarah L. Norris, Derron A. Alves, Paul R. Facemire, Douglas S. Reed and Aysegul Nalca
Pathogens 2021, 10(5), 597; https://doi.org/10.3390/pathogens10050597 - 13 May 2021
Cited by 5 | Viewed by 3679
Abstract
Tularemia is a severe, zoonotic infection caused by the Gram-negative bacterium Francisella tularensis. Inhalation results in a rapid, severe bacterial pneumonia and sepsis, which can be lethal. Because the cynomolgus macaque is the accepted nonhuman primate model for tularemia, we conducted a [...] Read more.
Tularemia is a severe, zoonotic infection caused by the Gram-negative bacterium Francisella tularensis. Inhalation results in a rapid, severe bacterial pneumonia and sepsis, which can be lethal. Because the cynomolgus macaque is the accepted nonhuman primate model for tularemia, we conducted a natural history study of pneumonic tularemia by exposing macaques to target inhaled doses of 50, 500, or 5000 colony forming units (CFU) of F. tularensis subsp. tularensis SCHU S4. Two animals within the 50 CFU group (calculated doses of 10 and 11 CFU) survived the challenge, while the remainder succumbed to infection. Exposure of cynomolgus macaques to aerosolized SCHU S4 resulted in fever, anorexia, increased white blood cell counts, lymphopenia, thrombocytopenia, increased liver enzymes, alterations in electrocardiogram (ECG), and pathological changes typical of infection with F. tularensis, regardless of the challenge dose. Blood pressure dropped during the febrile phase, particularly as temperature began to drop and macaques succumbed to the disease. ECG analysis indicated that in 33% of the macaques, heart rate was not elevated during the febrile phase (Faget’s sign; pulse-temperature disassociation), which has been reported in a similar percentage of human cases. These results indicated that infection of cynomolgus macaques with aerosolized F. tularensis results in similar disease progression and outcome as seen in humans, and that cynomolgus macaques are a reliable animal model to test medical countermeasures against aerosolized F. tularensis. Full article
(This article belongs to the Special Issue Translation of Pre-clinical Francisella tularensis Research)
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