期刊
PATHOGENS
卷 10, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/pathogens10060638
关键词
Francisella tularensis; SCHU S4; attenuation; virulence; substrain; rats; rabbits
类别
资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201000037I-HHSN27200001]
- Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201400027C]
- National Institute of Allergy & Infectious Diseases at the National Institutes of Health [U01 AI077909-01, 1 R01 AI123129-01]
The study revealed variations in virulence and genetic differences among different SCHU S4 strains, with NR-643 and FTS-635 showing lower virulence compared to other strains. Therefore, it is recommended that NR-643/FTS-635 be clearly designated as a separate SCHU S4 substrain and no longer used in studies evaluating potential vaccines and therapeutics.
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.
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