Biology subjects

Ozberk, V.

Publications and source records attributed to Ozberk, V..

3 recordsLinked to original sources

bioRxiv2025

Sub-clinical exposure to Streptococcus pyogenes drives the development of immunity

Age-related decline in Streptococcus pyogenes infection rates suggests that immunity develops progressively through repeated exposure during early life. However, the intensity or duration of exposure required is unknown, as to why some individuals appear to develop immunity, despite having few or no previously detected infections. Here, drawing on samples from a human challenge model of pharyngeal S. pyogenes infection, we investigate whether symptomatic disease is required for induction of humoral and cellular immunity. Challenge with M75 S. pyogenes induced M75-specific serum IgG and IgA antibodies and memory B cell in both symptomatic and asymptomatic participants, with responses persisting for at least 6 months. Purified IgG from asymptomatic participants exhibited significantly enhanced binding to M75 S. pyogenes and were bactericidal when transferred into a murine model of pharyngeal infection. M75-specific IgG from these participants had an altered Fc glycosylation signature, indicative of enhanced effector function and ability to limit inflammation. However, S. pyogenes challenge had no impact on cellular or humoral immune responses to a conserved cryptic epitope, p*17. These findings show that asymptomatic (or sub-clinical) exposure to M75 S. pyogenes generates functional immune responses and contributes to the streptococcal immunity that emerges by adulthood.

microbiology↗

bioRxiv2023

Disruption of IL-17 signaling in the respiratory mucosa results in invasive streptococcal infection

Streptococcus pyogenes infection of the upper respiratory tract and skin can lead to severe invasive streptococcal disease (ISD). Previous studies have demonstrated that the deficiency of IL-17 in mice (IL-17-/-) reduces mucosal immunity against S. pyogenes. However, the impact of IL-17 deficiency on the development of ISD is unknown. Here, we model single or repeated non-lethal, intranasal (IN) S. pyogenes M1 strain infections in immunocompetent and IL-17-/-mice to assess bacterial dissemination following a final IN or skin challenge. Immunocompetent mice that received a single S. pyogenes IN infection displayed long-lasting mucosal immunity and no systemic infection. However, in the absence of IL-17, a single IN infection resulted in the dissemination of S. pyogenes to the spleens, which was further exacerbated by repeated IN infections. Interestingly, immunity following skin challenge did not show a correlation with IL-17 and was instead associated with the activation of germinal center responses and the accumulation of neutrophils in the spleen. Our results highlight the critical role of IL-17 in preventing ISD following S. pyogenes infection of the respiratory mucosa.

immunology↗

bioRxiv2022

A phasevarion controls multiple virulence traits, including expression of vaccine candidates, in Streptococcus pneumoniae

Streptococcus pneumoniae is the most common cause of bacterial illness worldwide. Current vaccines based on the polysaccharide capsule (PCV-13 and PPSV-23) are only effective against a limited number of the >100 capsular serotypes. A universal vaccine based on conserved protein antigens requires a thorough understanding of gene expression in S. pneumoniae. Restriction-Modification (R-M) systems, classically described as a defence against bacteriophage, are almost ubiquitous in the bacterial domain, and roles other than phage defence. All S. pneumoniae strains encode the SpnIII R-M system. This system contains a phase-variable methyltransferase that randomly switches specificity, and controls expression of multiple genes; a phasevarion. We aimed to determine the role of the SpnIII phasevarion during pneumococcal pathobiology and determine if phase-variation resulted in differences in expression of protein antigens that are being investigated as vaccine candidates. Using locked S. pneumoniae strains that express a single SpnIII methyltransferase specificity, we found significant differences in clinically relevant traits, including survival in blood, and adherence to and invasion of human cells. Crucially, we also observed differences in expression of numerous proteinaceous vaccine candidates, which complicates selection of protein antigens for inclusion in a universal protein-based pneumococcal vaccine. This study will inform future vaccine design against S. pneumoniae by ensuring only stably expressed candidates are included in a rationally designed vaccine. Significance StatementS. pneumoniae is the worlds foremost bacterial pathogen. S. pneumoniae encodes a randomly expressed epigenetic regulator, a phasevarion (phase-variable regulon), that results in random expression of multiple genes. Previous work demonstrated that the pneumococcal SpnIII phasevarion switches between six different expression states, generating six unique phenotypic variants in a pneumococcal population. Here, we show that this phasevarion generates multiple phenotypic differences relevant to pathobiology. Importantly, expression of conserved protein antigens varies with phasevarion switching. As capsule expression, a major pneumococcal virulence factor, is also controlled by the phasevarion, our work will inform the selection of the best candidates to include in a rationally designed, universal pneumococcal vaccine.

microbiology↗