Biology subjects

Good, M. F.

Publications and source records attributed to Good, M. F..

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↗

bioRxiv2024

Immunotherapeutic strategy to prevent progression and complications of acute rheumatic fever

Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T-cells targeting the Group A streptococcal (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD). Long-term antibiotic therapy is recognized as a cornerstone of public health programs to prevent reinfection and progression of ARF. However, better tools to slow disease progression, and mitigate its lifelong consequences are required. Evidence obtained in a preclinical model suggests that this can be achieved. Using the rat autoimmune valvulitis model, we explored the potential of low-dose interleukin 2 (LD-IL-2) as an immunotherapeutic intervention. In this model injection of recombinant Strep A M5 protein (rM5) to Lewis rats induce autoimmune complications, cardiac tissue inflammation and conduction abnormalities. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes were observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies against cardiac tissue and induced a significant increase in classical regulatory T-cells (Treg) and CD8+ Tregs in the mediastinal (heart-draining) lymph nodes. These novel findings suggest LD-IL-2 will be an effective immunotherapeutic agent for treating ARF/RHD.

immunology↗

bioRxiv2024

Streptococcus pyogenes pharyngitis elicits diverse antibody responses to key vaccine antigens influenced by the imprint of past infections.

Knowledge gaps regarding human immunity to Streptococcus pyogenes have impeded vaccine development. To address these gaps and evaluate vaccine candidates, we established a human challenge model of S. pyogenes pharyngitis. Here, we analysed antibody responses in serum and saliva against 19 antigens to identify characteristics distinguishing 19 participants who developed pharyngitis and 6 who did not. Pharyngitis elicited serum IgG responses to key vaccine antigens and a muted mucosal IgA response, whereas the 6 participants without pharyngitis had more pronounced IgA responses and minimal IgG responses. Serum IgG responses to pharyngitis in adult participants resembled those observed in children and were inversely correlated with the magnitude of pre-existing responses. While a straightforward correlate of protection was not evident, baseline antibody signatures distinguished clinical and immunological outcomes following experimental challenge. This highlights the influence of a complex humoral imprint from previous exposure, relevant for interpreting immunogenicity in forthcoming vaccine trials.

immunology↗