Biology subjects

Pyle, C. J.

Publications and source records attributed to Pyle, C. J..

4 recordsLinked to original sources

bioRxiv2026

A rhinovirus vaccine evokes T cell mediated cross-reactive immunity in a preclinical model of rhinovirus infection

Rhinovirus (RV) infection is the most common cause of acute exacerbations of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Vaccines are available for two less common respiratory viruses (influenza and respiratory syncytial viruses), but development of a RV vaccine to protect patients with chronic respiratory disease has been hampered by the large number of serologically distinct RV strains ([~]180, grouped genetically into [~]80 A, [~]30 B and [~]70 C strains). We have explored the potential of the RV-A16 VP0 subunit vaccine in both CpG-adjuvanted protein subunit and mRNA formats. We demonstrate that both vaccine formats induce strong effector CD4 and CD8 T cell responses in the airways and lungs of immunized mice that rapidly expand following infection with a heterotypic RV strain and are associated with enhanced virus clearance. Adjuvanted VP0 protein subunit vaccination evoked strong germinal center reactions in the lymph nodes and markedly accelerated the production of neutralizing antibodies following heterotypic RV infection. In contrast, VP0 mRNA vaccination evoked limited germinal center responses and neutralizing antibody production. Th1 polarized immune responses were induced against a large panel of 20 heterologous RV strains representative of all RV-A, -B and -C strains. This study confirms the potential of RV VP0 vaccination as an approach to overcome the serological diversity of RV and describes the immune response evoked, including cross-strain cellular immunity and protection against heterotypic RV infection.

immunology↗

bioRxiv2025

CCR6 is essential for effective immunity against Mycobacterium tuberculosis infection in mice

Tuberculosis (TB) is a global epidemic that has threatened human health throughout recorded history. TB disease, caused by infection with Mycobacterium tuberculosis (M.tb), is heterogeneous between individuals, and clinical TB outcomes are impacted by genetic and environmental risk factors. Infected individuals must maintain a careful balance of cytokines and chemokines following M.tb infection to eliminate or contain the bacteria without causing excessive inflammation and lung damage. The CC chemokine receptor 6 (CCR6) is expressed by several immune cell populations that are classically involved in the pathogenesis of M.tb infection. However, the precise functions of CCR6 in the context of TB disease remain underexplored. Here, we show that mice lacking the CCR6 receptor (CCR6 KO) fail to restrict bacterial burden in the lungs, leading to increased disseminated infection at 4-weeks post-infection compared to wild-type C57BL/6J (B6) mice, with a more pronounced effect in females. CCR6 KO mice also developed necrotic pulmonary lesions, phenotypically distinct from B6 mice, and produced elevated levels of pro-inflammatory cytokines and chemokines at the onset of adaptive immunity, particularly IL-17. Long-term infection experiments revealed that the absence of CCR6 enhances risk for mortality following M.tb infection, particularly in females. This study provides insights into the role of CCR6 during TB pathogenesis and establishes its importance in maintaining protective immunity against M.tb within the context of a genetically tractable mouse model that forms necrotic pulmonary granulomas.

microbiology↗

bioRxiv2025

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, CXCL1 overproduction, and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of CXCL1, a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

genetics↗

bioRxiv2018

Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease

Allergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (TFH) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of TFH in established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, TFH were first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of TFH, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted TFH without adversely affecting the differentiation of other CD4+ T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. TFH did not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that TFH play a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.

immunology↗