Early innate immunity against mycobacterial infection
|dc.contributor.author||Ryder, Brinsley Marcus|
|dc.identifier.citation||Ryder, B. M. (2021). Early innate immunity against mycobacterial infection (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/12118||en|
|dc.description.abstract||Infection by Mycobacterium tuberculosis is not consistently prevented by the only licensed vaccine, bacillus Calmette-Guérin (BCG). It is widely believed that adaptive immune memory confers protection against tuberculosis (TB). Although that particular immunological correlate has led to development of a wide range of new vaccine candidates, none have enhanced protection against TB. To improve vaccination, the essential events of immune responses which progress either to disease or control of bacilli must be identified. Phagocytes populating the lungs include not only macrophages, but granulocytes and dendritic cells as well. Given this breadth, the central dogma that alveolar macrophages dominate early mycobacterial infection begs better experimental evidence. I measured the early lung immune response to infection in naturally resistant mice to compare the involvement of distinct phagocyte subsets. Fluorescent M. bovis BCG tdTomato and cytometry were used to quantify the lung phagocyte compartment and which cells took up mycobacteria 1-14 days post-infection. Contrary to popular belief, granulocytes were the predominant infected cell on the first day of infection, before alveolar macrophages. Granulocytes accumulated early but did not persist – an important contrast against animal genotypes which are more susceptible to mycobacterial disease. Besides stimulating adaptive immunity, it is likely that BCG immunisation provides protection by altering innate aspects of the secondary response to mycobacteria. In immunised mice, lung innate immune cells differed both prior and in response to re-challenge infection. Before re-challenge, immunised lungs contained twice as many alveolar macrophages compared with unimmunised mice, and the majority expressed the surface integrin CD11b. Interstitial macrophages and dendritic cells were also more abundant in immunised mice than in unimmunised mice. Alveolar macrophages expressing CD11b were enriched for transcripts encoding products involved in activation, intracellular pathogen response, cytokine and chemokine signalling, opsonisation of microbes, and phagocytosis of mycobacteria. In immunised mice, CD11b-high macrophages were more rapidly recruited early after challenge, and comprised the majority of infected macrophages. These alterations indicate a macrophage compartment which is poised to respond more rapidly and effectively to microbial invasion of the lungs. The canonical cytokines associated with protection against mycobacterial infection are not restricted to antigen-specific adaptive lymphocytes. The response of innate lymphoid cells (ILCs) to infection was distinct in BCG-immunised mice, producing cytokines more frequently 1 day post-challenge, and featuring expansion of group 3 ILCs (ILC3s) associated with supplementing alveolar macrophage responses. In particular, a population of ILC3s expressing both RORγt and T-bet transcription factors emerged after challenge in immunised mice, which produced interleukin-17 twice as frequently as T-bet-neg ILC3s by 14 days post-challenge. These modifications to the lung ILC compartment may contribute to the enhanced responsiveness of phagocytes during early infection. In sum, these findings provide additional context to the early immune response to mycobacterial infection, and offer examples of how it is modulated by BCG immunisation beyond adaptive immunity. Early predominance of granulocytes in taking up mycobacteria provides explanation as to why host immune responses and disease outcomes vary so dramatically in different disease models. In immunised mice, the changes to lung macrophages after mucosal BCG immunisation may represent elements of trained innate immunity underlying protection against infection. In future, these aspects of the early immune response may serve as more useful correlates of protection in the development and assessment of candidate vaccines against TB.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Early innate immunity against mycobacterial infection|
|thesis.degree.discipline||Microbiology and Immunology|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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