65
Recent significant contributions have been made to the
understanding of Group A Streptococcus (GAS)
pathogenesis. New regulatory pathways have been discovered,
insight into the molecular basis of epidemics of serotype M1
disease has been obtained, the crystal structures of four toxins
have been reported and a genome sequence of one GAS
strain has been determined. Genome-scale approaches to the
study of GAS pathogenesis are now rapidly emerging and will
advance our fundamental understanding of the molecular basis
of host–pathogen interactions.
Addresses
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain
Laboratories, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, 903 South 4th Street, Hamilton,
MT 59840, USA;
*e-mail: jmusser@niaid.nih.gov
Current Opinion in Microbiology 2001, 4:65–70
1369-5274/01/$ — see front matter
Published by Elsevier Science Ltd.
Abbreviations
GAS Group A Streptococcus
Introduction
Group A Streptococcus (GAS) is an important human
pathogen that causes infections ranging in severity from
mild pharyngitis and skin infections to severe invasive dis-
eases such as necrotizing fasciitis, streptococcal toxic shock
and myositis (for a comprehensive review, see [1]). Primary
infection with GAS can also lead to debilitating nonsuppu-
rative sequelae, such as rheumatic heart disease and
glomerulonephritis. GAS infections have increased in fre-
quency and severity in the last decade in the United States
and Europe [1]. This resurgence has heightened public
concern, largely because no vaccine is available, resistance
to certain antibiotics has recently emerged, and GAS
infections cause high morbidity and mortality.
Many studies have focused on elucidating the regulatory
mechanisms involved in the coordinate expression of
genes encoding putative extracellular virulence
determinants, such as M and M-related proteins,
fibronectin-binding proteins, the hyaluronic acid capsule,
the cysteine protease SpeB, streptokinase, streptolysins
O and S, and several phage-encoded exotoxins [2
••
].
Significant recent achievements in GAS research have
contributed to our understanding of infection pathogene-
sis and the basic biology of virulence factors. The crystal
structure has been solved for the zymogen form of the
integrin-binding virulence determinant SpeB, a cysteine
protease that influences host–pathogen interactions by
many mechanisms [3
••
]. GAS internalization by epithelial
cells was shown to result in host cytoskeletal rearrange-
ments and to be mediated by M1 protein [4
•
]. In
addition, new insights have been obtained into the mol-
ecular basis of epidemics of serotype M1 infections [5,6],
and new regulatory pathways have been described
[7–12]. Important contributions to GAS vaccine research
have also been reported [13,14].
Despite these scientific advances, the molecular basis of
many GAS infections remains largely unknown (Figure 1).
An understanding of the functional genomics of GAS is
essential for elucidating the molecular mechanisms of
pathogenesis of this complex bacterial pathogen. Classical
approaches, such as the generation and characterization of
isogenic mutants, are difficult to apply to an in-depth
analysis of the vast number of bacterial gene products
potentially involved in virulence. Therefore, an integrated
approach consisting of both classical and genome-scale
methods is essential. The aim of this review is to demon-
strate how integrated genomics strategies will significantly
contribute to an understanding of GAS virulence
mechanisms and host interactions.
Comparative genome sequencing of group A
Streptococcus
Genome sequence data are currently available for a strain
of serotype M1 GAS [15]. In addition, a serotype M5 GAS
isolate is being sequenced [16] and genome sequencing
projects for strains of two other M serotypes are underway
in our laboratory. Together, these genome datasets have
provided an extensive catalog of open reading frames
(ORFs) required for bacterial survival and pathogenesis.
Features such as allelic diversity, genetic rearrangements,
insertion elements and lysogenic bacteriophages that may
play important roles in GAS virulence mechanisms have
been identified ([17
•
]; SD Reid, NP Hoe, LM Smoot,
JM Musser, unpublished data). Comparative genome
analysis has yielded population genetics data that may
benefit our understanding of certain diseases, such as
rheumatic fever and invasive disease or pathogenic mech-
anisms unique to specific clones. For example, large-scale
comparative sequencing of the gene encoding the strepto-
coccal inhibitor of complement protein (sic) has identified
SIC variants emerging in pharyngeal isolates in the general
population prior to the onset of an epidemic [6]. Some of
these variants are apparently selected in vivo by host
immunological pressure [5].
Numerous putative transcriptional regulators and two-
component regulatory systems are present in the available
GAS genome data, suggesting that this pathogen senses
Toward a genome-scale understanding of group A
Streptococcus pathogenesis
Morag R Graham, Laura M Smoot, BenFang Lei and James M Musser*