Dataset Information

Strain-Dependent Effect of Capsule on Transmission and Persistence in an Infant Mouse Model of Group A Streptococcus Infection.

ABSTRACT: Streptococcus pyogenes (group A Streptococcus [GAS]) is a human pathogen responsible for a wide range of diseases. Asymptomatic carriage of GAS in the human pharynx is commonplace and a potential reservoir for GAS transmission. Early studies showed that GAS transmission correlated with high bacterial burdens during the acute symptomatic phase of the disease. Human studies and the nonhuman primate model are generally impractical for investigation of the bacterial mechanisms contributing to GAS transmission and persistence. To address this gap, we adapted an infant mouse model of pneumococcal colonization and transmission to investigate factors that influence GAS transmission and persistence. The model recapitulated the direct correlation between GAS burden and transmission during the acute phase of infection observed in humans and nonhuman primates. Furthermore, our results indicate that the ratio of colonized to uncolonized hosts influences the rates of GAS transmission and persistence. We used the model to test the hypothesis that capsule production influences GAS transmission and persistence in a strain-dependent manner. We detected significant differences in rates of transmission and persistence between capsule-positive (emm3) and capsule-negative (emm87) GAS strains. Capsule was associated with higher levels of GAS shedding, independent of the strain background. In contrast to the capsule-positive emm3 strain, restoring capsule production in emm87 GAS did not increase transmissibility, and the absence of capsule enhanced persistence only in the capsule-negative (emm87) strain background. These data suggest that strain background (capsule positive versus capsule negative) influences the effect of capsule in GAS transmission and persistence and that as-yet-undefined factors are required for the transmission of capsule-negative emm types.

SUBMITTER: Vega LA

PROVIDER: S-EPMC7093130 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Strain-Dependent Effect of Capsule on Transmission and Persistence in an Infant Mouse Model of Group A Streptococcus Infection.

Vega Luis Alberto LA Sanson Misu A MA Shah Brittany J BJ Flores Anthony R AR

Infection and immunity 20200323 4

<i>Streptococcus pyogenes</i> (group A <i>Streptococcus</i> [GAS]) is a human pathogen responsible for a wide range of diseases. Asymptomatic carriage of GAS in the human pharynx is commonplace and a potential reservoir for GAS transmission. Early studies showed that GAS transmission correlated with high bacterial burdens during the acute symptomatic phase of the disease. Human studies and the nonhuman primate model are generally impractical for investigation of the bacterial mechanisms contribu ...[more]

PMID: 32014891

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Project description:The capsular polysaccharide (CPS) of Streptococcus pneumoniae is characterized by its diversity, as it has over 95 known serotypes, and the variation in its thickness as it surrounds an organism. While within-host effects of CPS have been studied in detail, there is no information about its contribution to host-to-host transmission. In this study, we used an infant mouse model of intralitter transmission, together with isogenic capsule switch and cps promoter switch constructs, to explore the effects of CPS type and amount. The determining factor in the transmission rate in this model is the number of pneumococci shed in nasal secretions by colonized hosts. Two of seven capsule switch constructs showed reduced shedding. These constructs were unimpaired in colonization and expressed capsules similar in size to those of the wild-type strain. A cps promoter switch mutant expressing ~50% of wild-type amounts of CPS also displayed reduced shedding without a defect in colonization. Since shedding from the mucosal surface may require escape from mucus entrapment, a mucin-binding assay was used to compare capsule switch and cps promoter switch mutants. The CPS type or amount constructs that shed poorly were bound more robustly by immobilized mucin. These capsule switch and cps promoter switch constructs with increased mucin-binding affinity and reduced shedding also had lower rates of pup-to-pup transmission. Our results demonstrate that CPS type and amount affect transmission dynamics and may contribute to the marked differences in prevalence among pneumococcal types.IMPORTANCEStreptococcus pneumoniae, a leading cause of morbidity and mortality, is readily transmitted, especially among young children. Its structurally and antigenically diverse capsular polysaccharide is the target of currently licensed pneumococcal vaccines. Epidemiology studies show that only a subset of the >95 distinct serotypes are prevalent in the human population, suggesting that certain capsular polysaccharide types might be more likely to be transmitted within the community. Herein, we used an infant mouse model to show that both capsule type and amount are important determinants in the spread of pneumococci from host to host. Transmission rates correlate with those capsule types that are better at escaping mucus entrapment, a key step in exiting the host upper respiratory tract. Hence, our study provides a better mechanistic understanding of why certain pneumococcal serotypes are more common in the human population.

Project description:Group A Streptococcus (GAS) is a major cause of global infection-related morbidity and mortality. A modern controlled human infection model (CHIM) of GAS pharyngitis can accelerate vaccine development and pathogenesis research. A robust rationale for strain selection is central to meeting ethical, scientific, and regulatory requirements. Multifaceted characterization studies were done to compare a preferred candidate emm75 (M75) GAS strain to three other strains: an alternative candidate emm12 (M12) strain, an M1 strain used in 1970s pharyngitis CHIM studies (SS-496), and a representative (5448) of the globally disseminated M1T1 clone. A range of approaches were used to explore strain growth, adherence, invasion, delivery characteristics, short- and long-term viability, phylogeny, virulence factors, vaccine antigens, resistance to killing by human neutrophils, and lethality in a murine invasive model. The strains grew reliably in a medium without animal-derived components, were consistently transferred using a swab method simulating the CHIM protocol, remained viable at -80°C, and carried genes for most candidate vaccine antigens. Considering GAS molecular epidemiology, virulence factors, in vitro assays, and results from the murine model, the contemporary strains show a spectrum of virulence, with M75 appearing the least virulent and 5448 the most. The virulence profile of SS-496, used safely in 1970s CHIM studies, was similar to that of 5448 in the animal model and virulence gene carriage. The results of this multifaceted characterization confirm the M75 strain as an appropriate choice for initial deployment in the CHIM, with the aim of safely and successfully causing pharyngitis in healthy adult volunteers.IMPORTANCE GAS (Streptococcus pyogenes) is a leading global cause of infection-related morbidity and mortality. A modern CHIM of GAS pharyngitis could help to accelerate vaccine development and drive pathogenesis research. Challenge strain selection is critical to the safety and success of any CHIM and especially so for an organism such as GAS, with its wide strain diversity and potential to cause severe life-threatening acute infections (e.g., toxic shock syndrome and necrotizing fasciitis) and postinfectious complications (e.g., acute rheumatic fever, rheumatic heart disease, and acute poststreptococcal glomerulonephritis). In this paper, we outline the rationale for selecting an emm75 strain for initial use in a GAS pharyngitis CHIM in healthy adult volunteers, drawing on the findings of a broad characterization effort spanning molecular epidemiology, in vitro assays, whole-genome sequencing, and animal model studies.

Dataset Information

Strain-Dependent Effect of Capsule on Transmission and Persistence in an Infant Mouse Model of Group A Streptococcus Infection.

Publications

Strain-Dependent Effect of Capsule on Transmission and Persistence in an Infant Mouse Model of Group A Streptococcus Infection.

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