Biology subjects

Doolan, D. L.

Publications and source records attributed to Doolan, D. L..

3 recordsLinked to original sources

bioRxiv2024

Lung epithelial progenitor-mediated release of TGF-β regulates induction and persistence of lung CD8+ TRM cells following mucosal BCG vaccination

A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guerin (BCG), as parenteral BCG does not induce local pulmonary immune memory. Animal studies have shown that mucosal BCG vaccination provides superior protection against TB due to generation of lung resident memory T cells (TRM). Here, we demonstrated that following mucosal vaccination with the genetically modified virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their migration-mediated activation of latent TGF-{beta}, lung CD8+ TRM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of migration-mediated activation of TGF-{beta}, resulted in significantly lower numbers of lung CD8+ TRM. In addition, we discovered CD8+ cells with ex-lung and stem-like TRM phenotypes that persisted in the lung-draining mediastinal lymph nodes for up to four months following mucosal BCG vaccination. These results link airway epithelial progenitor-mediated repair of injured lung tissue with induction of resident T cell memory and delineate why persistence of TRM in the lung is short-lived. These findings may explain why mucosal vaccination with virulent BCG strains is more protective against TB and thus have notable implications for future TB vaccine development. One Sentence SummaryFollowing lung damage due to inhalation of virulent BCG, distal airway epithelial progenitor cells interact with lung CD8+ T cells to induce their differentiation into resident memory T cells via migration-mediated activation of TGF-{beta}.

immunology↗

bioRxiv2018

Development and validation of serological markers for detecting recent exposure to Plasmodium vivax infection

In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of individuals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, individuals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria.\n\nOne Sentence SummaryThe manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.

microbiology↗

bioRxiv2018

Protective immunity against severe malaria is associated with antibodies to a conserved repertoire of PfEMP1 variants

Extreme diversity of the major surface antigen and virulence determinant of the malaria parasite Plasmodium falciparum, Erythrocyte Membrane Protein-1 (PfEMP1), poses a major barrier to identifying targets of protective immunity. To overcome this problem, we developed a PfEMP1 protein microarray containing 456 DBL domains, which was used to characterize the immunome of a cohort of semi-immune children and to identify variants associated with protective immune responses. Children with high mean antibody levels to DBL group 2 had a 26-36% reduced risk of uncomplicated (clinical) malaria, however only 8 diverse DBL variants were weakly associated with protection from clinical malaria and had low predictive accuracy. On the other hand, children with high mean antibodies to DBL groups 1 and 2 (which are markers for pathogenic \"Type A\" PfEMP1) and elevated antibodies to 85 (18.6%) of individual DBL variants had a 70 -100% reduced risk of severe malaria. Of the top 20 predictive variants for severe disease protection, 17 were strongly associated with protection (86 - 100% reduction in risk of severe malaria) and had high predictive accuracy for severe disease risk. Many variants were conserved and had highly correlated antibody responses, including the three highest-ranking variants, which were linked to EPCR-binding CIDR domains. The results suggest that while immunity to uncomplicated malaria is characterised by antibodies to a diverse repertoire of PfEMP1, immunity to severe malaria requires antibodies to a limited subset of antigenically conserved variants. These findings provide new insights into antimalarial immunity and potential biomarkers for tracking disease risk.

microbiology↗