Although infection by group A streptococc is a model of extracellular mucosal pathogenesis, these organisms can be associated with highly invasive infections resulting in sepsis and shock. Over the last 6 yr this species has renewed its reputation as a si nt cause of sepsis and has piqued interest in the m nim by which some strains are better able to breach mucosal barriers to gain access to the bloodstream than are others. An ite tion assay was developed on the basis of resistance of intacellular streptococci to penicillin and gentamicin. Experiments showed that stationary-phase, as opposed to logarithmic-phase, bacteria are efficiently internalized and can persist in cultured human cells. Electron microscopy confirmed that streptococci were contained within intraceflular vacuoles. Various strains of streptococci revealed signicant differences in their capacity to be intenalied. Two type Ml streptococci Isolated from blood infections were internalized at frequencies equal to those reported for Sabnonella and Listeria monocytogenes and greater than the frequency of a cional variant from a case of pharyngitis.Numerous mucosal pathogens that readily invade the bloodstream have the capacity to be internalized and to persist within human epithelial cells (1). Although the importance of intracellular invasion in pathogenesis is debated by some, there is general agreement that this process can lead to invasion of deeper tissue and blood. The capacity ofListeria (2), Shigella (3), Salmonella (4), and several Yersinia species (5) to invade epithelial cells is entirely consistent with the pathophysiology associated with their infections. Listeria monocytogenes has become the paradigm for Gram-positive intracellular infections (6). L. monocytogenes possesses the adhesin internalin that mediates internalization and shares structural similarities to streptococcal surface proteins (6). In addition, both group A streptococci and L. monocytogenes express highly related thiol-activated hemolysins (7). Until recently, streptococcal species were traditionally considered to be extracellular pathogens of the oral or vaginal mucosa, even though some species have long been recognized to cause deadly blood or meningeal infections. Group A streptococci are commonly associated with pharyngitis and impetigo, but the recent resurgence of blood infections caused by this species has reminded the public health community of their potential to invade deeper tissues and the bloodstream and to cause significant morbidity (8,9 RPMI-1640 (1 ml) containing gentamicin (100 Ag/ml) and penicillin (5 pg/ml) was then added to wells to eliminate extracellular bacteria. Neither antibiotic penetrates eukaryotic cells (16). Infected monolayers were incubated at 370C for various time periods depending on the experiment before they were washed and dispersed by addition of 100 A4 of 0.25% trypsin/l mM EDTA. Streptococci were released from disrupted monolayers by the addition of 400 pA of 0.025% Triton X-100 (10). In later experiments, monolayers were...
Group A streptococci express at least two surface-associated virulence factors, the antiphagocytic M protein and the antichemotactic streptococcal C5a peptidase (SCP). Preliminary evidence suggested that the biosynthesis of these two proteins is coordinately controlled and subject to simultaneous phase variation. To explore this possibility further, a series of phase-switching and phase-locked M-variants were assayed for SCP by enzyme-linked immunosorbent assay inhibition and for SCP-specific mRNA by dot blot hybridization. All Mcultures produced diminished amounts of SCP antigen and specific mRNA, whereas revertants produced quantities equivalent to those of the wild-type M' culture. A phase-locked strain that harbors a deletion in a region upstream of the M12 and SCP genes, termed the virR locus, failed to produce SCP antigen or SCP-specific transcripts. The SCP-specific transcript produced by M' bacteria was shown by Northern (RNA) blot hybridization to be 4 kilobases in size, distinguishing it from the transcript which encodes M protein. These data demonstrate that phase switching of both SCP and M12 proteins is at the transcriptional level and that expression is under the control of the upstream virR locus. We propose that the genetic determinants of these proteins and of colony morphology comprise a virulence regulon.The survival and multiplication of bacterial pathogens in a susceptible host depend on their abilities to acquire appropriate nutrients, interact with tissue receptors, and resist host defenses. A recent review (10) noted that the expression of multiple virulence determinants by gram-negative pathogens is a finely tuned process which is responsive to environmental changes and the general physiological state of the bacterial cell. It is now apparent that these virulence genes are globally controlled by a master gene which couples external stimuli to response pathways (10).The avoidance of human immunological defenses by group A streptococci is dependent on the following surface components: a diffuse hyaluronic capsule which mimics the ground substance of animal tissues (25); immunoglobulin G Fc receptors, which may disrupt recognition by antibodies (6b); a C5a peptidase which destroys chemotactic signals (23); and M protein, which interferes with the deposition of C3b opsonin to prevent phagocytic uptake (8, 9). M protein, thought to be the key determinant of virulence, has been the subject of intensive investigation. This dimeric coiled-coil molecule protrudes from the cell wall, where it both blocks the deposition of C3b opsonin and limits the interaction of bound C3b with receptors on polymorphonuclear leukocytes (8, 9). As a result, M+ streptococci are resistant to phagocytosis in the absence of type-specific M protein antibody and complement.Group A streptococcal cultures have long been recognized as genetically unstable (6,17,20). The expression of M protein on their surfaces, colony morphology, and virulence were reported to vary dramatically both in laboratory cultures (6, 17) and in st...
The M1inv+ subclone of M1 group A streptococci that spread globally in the late 1980s and early 1990s was previously identified by restriction fragment length polymorphism (RFLP), M protein, and SpeA exotoxin sequence analyses. Strains representing this subclone were characterized with regard to carriage of bacteriophage and capacity to invade cultured human epithelial cells. The M1inv+ subclone was found to harbor two entirely different prophages, phage T13 and phage T14, which together supplement its genome with nearly 70 kb of DNA. Phage T14 encodes the SpeA exotoxin and is closely related to the classic converting phage T12. Plaque-forming characteristics and RFLP analyses of phages T13 and T14 were compared to each other and to phage T12. Other subclones of M1, isolated in the 1970s to the early 1980s, lacked both prophages. The M1inv+ subclone was previously reported to be efficiently internalized by human epithelial cells. This potential was confirmed and expanded by comparing a variety of clinical isolates. The capacity for high-frequency invasion of epithelial cells was not transmitted to a laboratory strain of group A streptococci by the above-mentioned bacteriophages.
Se examinó una vacuna diseñada para inmunizar al hombre, preparada con extracto de fenol insoluble, para determinar si protegía a cobayos contra el desafío con la cepa virulenta B. abortus 2308. Se incluyeron en el experimento las vacunas vivas atenuadas B. abortus cepa 19 y B. melitensis Rev. 1, para comparar los resultados. Se vacunaron 93 animales en cada grupo, que fueron subdivididos en subgrupos de 31 y se los desafió con 10(4), 10³ y 10² unidades formadoras de colonias de la cepa B. abortus 2308 virulenta. El análisis global de los resultados demostró una protección del 11.9% en animales vacunados con el extracto de fenol insoluble, 65% en los vacunados con B. abortus cepa 19 y 95% en el grupo que recibió vacuna B. melitensis Rev. 1.
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