Biology subjects

Frost, H.

Publications and source records attributed to Frost, H..

3 recordsLinked to original sources

bioRxiv2026

Attenuated interferon signalling in alveolar epithelium limits resistance to Streptococcus pyogenes

The upper respiratory tract is a primary niche for Streptococcus pyogenes colonisation and disease. Lower respiratory tract infection (pneumonia) is the most common invasive S. pyogenes syndrome. Studies have not previously examined how epithelial cells, from the airway to the alveolus, respond to S. pyogenes infection. Here, we established a scalable human in vitro model by differentiating induced pluripotent stem cells (iPSCs) into mature pseudostratified airway epithelium or alveolar type 2 epithelial cells, cultured at air-liquid interface and infected with S. pyogenes (M1UK and M75 strains). Both strains attached to iPSC-derived lung epithelial cells, with significantly greater adherence to the airway epithelium by M75 compared to M1UK. Moreover, invasion by both S. pyogenes strains of alveolar epithelial cells was greater than for the airway epithelium. Dynamic S. pyogenes gene expression changes were evident between 6 and 24 hours after infection, which was influenced by the infected cell type; however, virulence genes were not significantly altered. While infection of the airway epithelium induced rapid and dynamic inflammatory signalling, the alveolar epithelium demonstrated augmented cell death and mounted a transcriptional pro-inflammatory and proliferative response that was uncoupled from cytokine secretion. The airway epithelium model exhibited consistently higher baseline type I interferon (IFN) signalling than the alveolar epithelium. Invasion by S. pyogenes and inflammation was significantly reduced in IFN-{beta}-treated alveolar epithelial cells. In summary, we have established the first model of S. pyogenes infection in physiologically relevant airway and alveolar epithelial cells. Our findings suggest that host responses to infection are influenced by lung compartment, the S. pyogenes strain type, and infection timepoint, highlighting context-specific pathways that could be leveraged therapeutically.

microbiology↗

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↗

bioRxiv2021

Does the evolution of division of labour require accelerating returns from individual specialisation?

Recent theory has overturned the assumption that accelerating returns from individual specialisation are required to favour the evolution of division of labour. Yanni et al. (2020) showed that topologically constrained groups, where cells cooperate with only direct neighbours such as for filaments or branching growths, can evolve a reproductive division of labour even with diminishing returns from individual specialisation. We developed a conceptual framework and specific models to investigate the factors that can favour the initial evolution of reproductive division of labour. We found that selection for division of labour in topologically constrained groups: (1) is not a single mechanism to favour division of labour - depending upon details of the group structure, division of labour can be favoured for different reasons; (2) always involves an efficiency benefit at the level of group fitness; and (3) requires a mechanism of coordination to determine which individuals perform which tasks. Given that such coordination is unlikely to evolve before division of labour, this limits the extent to which topological constraints could have favoured the initial evolution of division of labour. We conclude by suggesting experimental designs that could determine why division of labour is favoured in the natural world.

evolutionary biology↗