Group A<i>Streptococcus</i>Gene Expression in Humans and Cynomolgus Macaques with Acute Pharyngitis

Virtaneva, Kimmo; Graham, Morag; Porcella, Stephen F.; Hoe, Nancy P.; Su, Hua; Graviss, Edward A.; Gardner, Tracie J.; Allison, James E.; Lemon, William J.; Bailey, John R.; Parnell, Michael J.; Musser, James M.

doi:10.1128/iai.71.4.2199-2207.2003

Cited by 66 publications

(74 citation statements)

References 59 publications

(64 reference statements)

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“…While nonhuman primates represent an alternative to study human GAS infections, 40,41 their use in immunogenetic population studies is expensive and impractical due to their slow breeding pattern and small progeny, high cost and ethical issues. Meanwhile, regular laboratory mice, which share B85% gene content with humans, 42 are not sensitive to invasive GAS infections 43,44 just as certain human populations are not good models for certain human diseases because of their genetic resistance.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

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Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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“…TaqMan primer and probe sequences are listed in Table S1. The constitutively transcribed housekeeping gene proS was used as an internal control, similar to previously published quantitative RT-PCR analyses (Shelburne et al, 2008;Virtaneva et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

The 4.5S RNA component of the signal recognition particle is required for group A Streptococcus virulence

2010

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The signal recognition particle (SRP) is a ribonucleoprotein complex that targets proteins for secretion in a co-translational manner. While originally thought to be essential in all bacteria, recent data show that the SRP is dispensable in at least some streptococcal species. The SRP from the human pathogen group A Streptococcus (GAS, Streptococcus pyogenes) is predicted to be composed of protein Ffh and 4.5S RNA. Deletion of ffh alters the secretion of several GAS proteins, and leads to a severe reduction in virulence. Here, we report that mutation of the gene encoding 4.5S RNA results in phenotypes both similar to and distinct from that observed following ffh mutation. Similarities include a reduction in secretion of the haemolysin streptolysin O, and attenuation of virulence as assessed by a murine soft tissue infection model. Differences include a reduction in transcript levels for the genes encoding streptolysin O and NADglycohydrolase, and the reduced secretion of the SpeB protease. Several differences in transcript abundance between the parental and mutant strain were shown to be dependent on the sensorkinase-encoding gene covS. Using growth in human saliva as an ex vivo model of upper respiratory tract infection we identified that 4.5S RNA mutation leads to a 10-fold reduction in colony-forming units over time, consistent with the 4.5S RNA contributing to GAS growth and persistence during upper respiratory tract infections. Finally, we determined that the 4.5S RNA was essential for GAS to cause lethal infections in a murine bacteraemia model of infection. The data presented extend our knowledge of the contribution of the SRP to the virulence of an important Gram-positive pathogen.

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“…However, these types of studies lack the ability to capture the complex host-pathogen interactions that take place during infection of an intact host. Therefore the use of a relevant animal infection model is critical to providing enhanced understanding of host-pathogen interactions (11,12).…”

mentioning

confidence: 99%

Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

Shea

Virtaneva

Kupko

et al. 2010

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

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Relatively little is understood about the dynamics of global hostpathogen transcriptome changes that occur during bacterial infection of mucosal surfaces. To test the hypothesis that group A Streptococcus (GAS) infection of the oropharynx provokes a distinct host transcriptome response, we performed genome-wide transcriptome analysis using a nonhuman primate model of experimental pharyngitis. We also identified host and pathogen biological processes and individual host and pathogen gene pairs with correlated patterns of expression, suggesting interaction. For this study, 509 host genes and seven biological pathways were differentially expressed throughout the entire 32-day infection cycle. GAS infection produced an initial widespread significant decrease in expression of many host genes, including those involved in cytokine production, vesicle formation, metabolism, and signal transduction. This repression lasted until day 4, at which time a large increase in expression of host genes was observed, including those involved in protein translation, antigen presentation, and GTP-mediated signaling. The interactome analysis identified 73 host and pathogen gene pairs with correlated expression levels. We discovered significant correlations between transcripts of GAS genes involved in hyaluronic capsule production and host endocytic vesicle formation, GAS GTPases and host fibrinolytic genes, and GAS response to interaction with neutrophils. We also identified a strong signal, suggesting interaction between host γδ T cells and genes in the GAS mevalonic acid synthesis pathway responsible for production of isopentenyl-pyrophosphate, a short-chain phospholipid that stimulates these T cells. Taken together, our results are unique in providing a comprehensive understanding of the host-pathogen interactome during mucosal infection by a bacterial pathogen.epithelial growth factor receptor | host pathogen | microarray | Streptococcus pyogenes | transcriptome

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Group AStreptococcusGene Expression in Humans and Cynomolgus Macaques with Acute Pharyngitis

Cited by 66 publications

References 59 publications

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

The 4.5S RNA component of the signal recognition particle is required for group A Streptococcus virulence

Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

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