Streptococcal adherence and colonization are complex multilevel processes that define the success or failure of the organism in human ecosystems. As such, streptococci devote considerable resources to ensuring the availability of an appropriate repertoire of effector molecules (Fig. ) with sufficient redundancy to be robust in situations where one particular activity is unavailable or impeded by host or other bacterial factors. Moreover, these are not passive events; rather, streptococci are continuously monitoring the local environment and fine-tuning the expression of adhesins, communication systems, and metabolic pathways to optimize fitness under the prevailing conditions. The universal presence of streptococci in humans (and in many other animal hosts) reflects the success of these strategies. Paradoxically, the strengths of the streptococcal colonization mechanisms may also turn out to be weaknesses that can be exploited to develop new ways to control colonization and infection.
Vaccination against pathogenic species is very much a preferred strategy because it reduces the usage of antibiotics. These may be harmful, as in the case of application to pregnant mothers to act against potential GBS infection of neonates, or simply add to the ongoing problem of antibiotic resistance development. However, the vaccine route is fraught with difficulties, a major one being that the best protective (opsonic) antibodies are directed against cell surface components that are highly antigenically variable. A strategy being adopted for GAS is to string together multiple A regions of M proteins representing the most invasive serotypes and then use this as a polyvalent vaccine. This avoids the conformational regions of M protein that may generate cross-reactive antibodies to heart, brain, kidney, or joint cartilage and includes the opsonic epitopes. A 26-valent vaccine of this type has been shown to be well tolerated in human adult volunteers (126
). However, the experience with pneumococcus conjugate vaccine comprised of seven or nine CPS serotypes is that the elimination of vaccine serotypes leads to serotype replacement and the emergence of new virulent strains. The careful construction of vaccine epitopes may go some way to reducing this, but nevertheless, the antigens to which protective antibodies have to be made are subject to immune selection. The many facets of GAS pathogenesis have been recently summarized in an excellent review (437
), and the reader is referred to that article for detailed information about virulence factors.
The sialic acid-containing CPS has been a focus of most vaccine strategies for GBS to date, and clinical trials with conjugate vaccines covering five CPS serotypes have shown them to be safe and immunogenic (24
). There are nine distinct CPS serotypes, but even a 9-valent vaccine would not protect against the increasing number of nontypeable isolates (24
). A protein-based vaccine could, on the other hand, provide antigenic targets that are conserved across all GBS serotypes. Major surface proteins include the Alp family of proteins, e.g., α, Rib, R28, and Alp2 (357
), that elicit protective immunity; ScpB C5a peptidase (96
); β protein that binds IgA and factor H (373
); Lmb (228
); FbsA fibrinogen-binding protein (535
); Sip (67
); LrrG (538
); and CspA protease (221
). Some of these proteins are promising vaccine candidates, but their potential for cross-protection is relatively unknown (279
). More recently, the components of GAS and GBS pili have been a focus of vaccine design. Backbone and ancillary subunits from each GBS PI have been shown to elicit protective immunity against GBS in a neonatal mouse model of immunization (376
). A vaccine comprising three selected pilus protein subunits could potentially confer protection against 94% GBS strains currently found in the United States and Italy (383
Anti-dental-caries vaccines have been under study since it was first shown that antigens from S. mutans
cells, such as Gtf, Gbp, and AgI/II, were protective against S. mutans
colonization and caries in animal models (557
). Clinical trails have tested the delivery of S. mutans
antigens via the nasal route to utilize the inductive characteristics of nasally associated lymphoid tissue for secretory IgA and IgG antibodies. Immunization with Gtf or GbpB consistently produces high levels of salivary antibodies and reductions in experimental dental caries. The oral health impact on children would be huge, especially for those who are at high risk, if an effective dental caries vaccine were to be developed that was stable and could be administered mucosally (560
). There are many interesting strategies under development that could affect longer-term colonization patterns of bacteria on mucosal surfaces or hard surfaces, e.g., teeth, to promote health. It is thought that the early retention of some organisms, e.g., S. salivarius
and S. sanguinis
, within the oral cavity of infants may be beneficial to their future oral health (88
). It is possible, then, that by supplementing the oropharynx or nasopharynx with selected streptococcal species shortly after birth and during infancy, less desirable bacterial species may be excluded. There is evidence that colonization of the tongue and throat by bacteriocin-producing S. salivarius
may assist in reducing the incidence of GAS pharyngitis in children (132
). Replacement therapy has been considered to have potential for controlling S. mutans
levels. By introducing an engineered nonpathogenic strain of S. mutans
with a selective advantage, it might be possible to replace pathogenic strains, but the efficacy when applied to human subjects remains to be established.
Biofilm formation occurs as a result of initial adherence, the growth of societies involving quorum sensing, and then community development associated with a range of intermicrobial communication reactions. In terms of preventing specific organisms from depositing onto surfaces or being incorporated into communities, promising results have been obtained by blocking the adherence of S. mutans
to salivary pellicles with peptides that mimic the streptococcal AgI/II surface protein adhesin (292
-chain antibodies to AgI/II expressed by lactobacilli have been shown to prevent S. mutans
colonization and caries development in rodent models of infection (321
). These observations suggest that there may be alternatives to vaccination and antibiotics for modulating Streptococcus
colonization. However, in removing a component of the natural microflora, there is a potential for exposing a niche that could be colonized by another less desirable organism.
Although not yet tried with complex biofilm communities, inhibitors of quorum sensing have been shown to effectively impair normal biofilm formation. Bromofuranone interferes with AI-2 signaling pathways and inhibits the formation of single-species biofilms of S. mutans
and S. intermedius
). However, halogenated furanones show toxic side effects on human cells and possible carcinogenic properties that make them unsuitable for use as pharmaceuticals for humans (56
). It is possible that nontoxic microbial signaling inhibitors (486
) or biomimetics (391
) that disrupt the interactions that occur between streptococci in establishing biofilms might be found.
It is clear that new approaches are required, informed by microbiology, immunology, and molecular biology, to control components of microbial communities that form on or in the human body. The increased use of DNA sequencing for the characterization of pathogens, commensals, and complex ecosystems such as the oral microbiome has led to new approaches in the study of host-bacterium interactions. The in silico prediction of streptococcal surface-exposed proteins (27
) is of interest for the rational development of vaccines or new inhibitors. The continuing use of broad-spectrum antibiotics to resolve problems associated with streptococcal infections might not be sustainable in the future, with the increasing incidence of antibiotic resistance. Since streptococci need to colonize mucosal surfaces, mainly in the upper respiratory tract, to be carried long-term or prior to causing infection, it seems crucial that nonantibiotic measures be developed in order to control colonization. The oropharynx and microflora therein provide an ideal system for experimental studies. The results of such studies might lead to an extension of methodologies to control the colonization of streptococci at other body sites.