A Non-Human Primate Model of Acute Group A Streptococcus Pharyngitis

Sumby, Paul; Tart, Anne H.; Musser, James M.

doi:10.1007/978-1-60327-032-8_20

Cited by 20 publications

(25 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a consequence, we have extensively used non-human primates, the most human-relevant animal model possible, as the preferred host for testing hypotheses bearing on GAS molecular pathogenesis. 13,14,34,[37][38][39] However, high cost and substantial…”

Section: Discussionmentioning

confidence: 99%

Virulence of serotype M3 Group AStreptococcusstrains in wax worms (Galleria mellonellalarvae)

et al. 2011

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Virulence of serotype M3 Group AStreptococcusstrains in wax worms (Galleria mellonellalarvae)

et al. 2011

Self Cite

View full text Add to dashboard Cite

“…This infection model has been used extensively and recapitulates human disease (14,23,24). Strain MGAS2221 was used because its genome has been sequenced to high quality, it has been used in many previous studies of necrotizing fasciitis, and it lacks mutations in major regulatory genes (25)(26)(27)(28).…”

Section: Identification Of Acquired Polymorphisms In Serotype M1 Stramentioning

confidence: 99%

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

et al. 2016

Self Cite

View full text Add to dashboard Cite

dTo obtain new information about Streptococcus pyogenes intrahost genetic variation during invasive infection, we sequenced the genomes of 2,954 serotype M1 strains recovered from a nonhuman primate experimental model of necrotizing fasciitis. A total of 644 strains (21.8%) acquired polymorphisms relative to the input parental strain. The fabT gene, encoding a transcriptional regulator of fatty acid biosynthesis genes, contained 54.5% of these changes. The great majority of polymorphisms were predicted to deleteriously alter FabT function. Transcriptome-sequencing (RNA-seq) analysis of a wild-type strain and an isogenic fabT deletion mutant strain found that between 3.7 and 28.5% of the S. pyogenes transcripts were differentially expressed, depending on the growth temperature (35°C or 40°C) and growth phase (mid-exponential or stationary phase). Genes implicated in fatty acid synthesis and lipid metabolism were significantly upregulated in the fabT deletion mutant strain. FabT also directly or indirectly regulated central carbon metabolism genes, including pyruvate hub enzymes and fermentation pathways and virulence genes. Deletion of fabT decreased virulence in a nonhuman primate model of necrotizing fasciitis. In addition, the fabT deletion strain had significantly decreased survival in human whole blood and during phagocytic interaction with polymorphonuclear leukocytes ex vivo. We conclude that FabT mutant progeny arise during infection, constitute a metabolically distinct subpopulation, and are less virulent in the experimental models used here. Streptococcus pyogenes is a Gram-positive bacterium that causes a range of diseases in humans, including pharyngitis, superficial and deep skin infections, acute rheumatic fever, poststreptococcal glomerulonephritis, bacteremia, and necrotizing fasciitis ("flesh-eating disease") (1, 2). Globally, there are over 700 million group A streptococcus (GAS) infections annually (3). It has been estimated that 9,000 to 11,500 cases of invasive GAS disease occur each year in the United States, resulting in 1,000 to 1,800 deaths annually (4; http://www.cdc.gov). Rheumatic fever, necrotizing fasciitis, and toxic shock syndrome are responsible for the high morbidity and mortality rates due to GAS infections (5).Advances in DNA sequencing and related technologies have facilitated genome-wide dissection of genetic events involved in colonization (6), immune evasion (7), virulence (8-10), and the evolution and spread of highly virulent S. pyogenes clones (11-13). To advance our understanding of S. pyogenes molecular-pathogenesis events occurring during invasive infection, we performed whole-genome sequencing of 2,954 isolates recovered from a nonhuman primate model of necrotizing fasciitis. The resulting genome sequence data stimulated us to construct an isogenic fabT deletion mutant strain and to compare its global transcriptome and virulence attributes with those of the wild-type parental strain. MATERIALS AND METHODSBacterial strains and growth conditions. Escherichia coli strai...

show abstract

“…Several known and putative GAS virulence factors have modest or no activity against mouse molecules (10,11), which means that a full understanding of molecular pathogenesis based exclusively on mouse infection models cannot be achieved. The cynomolgus macaque is an excellent model of human GAS pharyngitis, and this model has been successfully employed in several studies to provide new information about GAS pathogenesis (12). Inasmuch as necrotizing fasciitis is a devastating disease with high rates of morbidity and mortality, with little known about pathogenesis, we sought to unambiguously demonstrate that mtsR is involved (8,9,13,14).…”

Section: Wild-type Strain Mgas315 Causes Significantly More Extensivementioning

confidence: 99%

Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis

Olsen

Sitkiewicz

Ayeras

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

View full text Add to dashboard Cite

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the ΔmtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.group A streptococcus | invasive infection | molecular epidemiology of strain genotype patient phenotype relationships | nonhuman primate S ingle-nucleotide mutations are the most abundant cause of genetic variation among members of the same species (1, 2). However, in striking contrast to humans, who have been studied extensively, our understanding of how naturally occurring singlenucleotide mutations alter bacterial phenotypes is rudimentary. Most prokaryotic pathogenesis research efforts have focused intensively on large regions of genetic difference, such as pathogenicity islands and prophages. Thus, there is little information that directly bears on the relationship between particular singlenucleotide changes, their direct or indirect effect on virulence factor expression, and the manifestation of medically important traits such as strain virulence and infection specificity.Recently, we have investigated the molecular genomic landscape of infection phenotype-strain genotype relationships in human patients at the nucleotide level in group A Streptococcus (GAS), a bacterial pathogen that is a major cause of human morbidity and mortality worldwide (1, 3-5). These studies were made possible by the availability of the 1.9-Mb genome sequences of 12 GAS strains cultured from patients with welldefined clinical syndromes such as pharyngitis, acute rheumatic fever, and necrotizing fasciitis (also known as "flesh-eating" disease) (1, 5). The core genome of strains of distinct M protein serotype differed, on average, by 14,475 SNPs (1, 3). In contrast, strains with the same M protein serotype were far less variable, differing overall by less...

show abstract

A Non-Human Primate Model of Acute Group A Streptococcus Pharyngitis

Cited by 20 publications

References 25 publications

Virulence of serotype M3 Group AStreptococcusstrains in wax worms (Galleria mellonellalarvae)

Virulence of serotype M3 Group AStreptococcusstrains in wax worms (Galleria mellonellalarvae)

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis

Contact Info

Product

Resources

About