ORCID Profile
0000-0003-1238-1552
Current Organisation
Malaghan Institute of Medical Research
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Publisher: Cold Spring Harbor Laboratory
Date: 17-07-2023
DOI: 10.1101/2023.07.15.549135
Abstract: Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses however, less is known about the role of IFNγ in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria Mycobacterium bovis BCG achieved though intravenous ( iv ) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed that iv BCG induces a robust IFNγ response and low levels of IFNβ. Here we examined the role of ongoing IFNγ responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFNγ receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of interferon-stimulated genes (ISGs) with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFNγ in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.
Publisher: Cold Spring Harbor Laboratory
Date: 06-01-2021
DOI: 10.1101/2021.01.05.425466
Abstract: The signals driving the adaptation of type-2 dendritic cells (DC2s) to erse peripheral environments are not well understood. We show that the development of CD11b low migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11b hi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ ROR γ t+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2021
DOI: 10.1038/S41590-021-01067-0
Abstract: The signals driving the adaptation of type 2 dendritic cells (DC2s) to erse peripheral environments remain mostly undefined. We show that differentiation of CD11b
Publisher: Rockefeller University Press
Date: 02-12-2016
DOI: 10.1084/JEM.20160470
Abstract: The dendritic cell signals required for the in vivo priming of IL-4–producing T cells are unknown. We used RNA sequencing to characterize DCs from skin LN of mice exposed to two different Th2 stimuli: the helminth parasite Nippostrongylus brasiliensis (Nb) and the contact sensitizer dibutyl phthalate (DBP)-FITC. Both Nb and DBP-FITC induced extensive transcriptional changes that involved multiple DC subsets. Surprisingly, these transcriptional changes were highly distinct in the two models, with only a small number of genes being similarly regulated in both conditions. Pathway analysis of expressed genes identified no shared pathways between Nb and DBP-FITC, but revealed a type-I IFN (IFN-I) signature unique to DCs from Nb-primed mice. Blocking the IFN-I receptor at the time of Nb treatment had little effect on DC migration and antigen transport to the LN, but inhibited the up-regulation of IFN-I–induced markers on DCs and effectively blunted Th2 development. In contrast, the response to DBP-FITC was not affected by IFN-I receptor blockade, a finding consistent with the known dependence of this response on the innate cytokine TSLP. Thus, the priming of Th2 responses is associated with distinct transcriptional signatures in DCs in vivo, reflecting the erse environments in which Th2 immune responses are initiated.
No related grants have been discovered for Kerry Hilligan.