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Regulation of toll-like receptor 9 trafficking and signaling in host-fungal interactions
Başlık:
Regulation of toll-like receptor 9 trafficking and signaling in host-fungal interactions
Yazar:
Khan, Nida Shafiq, author.
ISBN:
9780438006577
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (182 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Jatin M. Vyas.
Özet:
Candida albicans and Aspergillus fumigatus are the major causes of invasive fungal infections (IFI) in patients. Despite the widespread use of potent anti-fungal medications, the morbidity and mortality associated with IFI remain significantly high, suggesting that the immune system plays a critical and non-redundant role in determining the outcome of the infection. Advances in the treatment of IFI require elucidation of the molecular mechanisms that govern the host immune response.
Pathogen recognition receptors expressed by phagocytes recognize fungal pathogen-associated molecular patterns and initiate phagocytic uptake. Following uptake, a phagosome is formed and matures while recruiting specific host proteins including tetraspanin CD82 and other PRRs, TLR9 and Dectin-1, dependent on the cargo within the phagosomes. Phagosomal maturation is a highly regulated process that involves vesicular fusions for pathogen degradation and antigen presentation. Dectin-1 is required for the maturation of fungal containing phagosomes. However, the regulation of molecular signaling pathways in recognition of fungi remains unknown. This thesis identifies the regulatory mechanism of TLR9 recruitment to fungal-containing phagosomes. We discover CD82 as a specific regulator of TLR9 signaling. In addition to TLR9, we reveal a novel role of STING in C. albicans infection.
In the first chapter, we provide overall introduction and relevance of the topics discussed in this dissertation. In the second chapter, we asked whether Dectin-1 modulates TLR9 trafficking to fungal-containing phagosomes. To interrogate the cell biology of phagosomes we engineered synthetic fungal-like particles (FLPs) using fungal-derived beta-1,3 glucan or mannan covalently bound to polystyrene beads and characterized proteins specifically recruited to the phagosomes. We show that Dectin-1 controls TLR9 recruitment to fungal phagosomes and beta-1,3 glucan is sufficient to trigger and retain proteolytically-cleaved TLR9. Using chemical inhibition and genetic approaches, we show that acidification and Dectin-1 mediated Syk activation are critical for the trafficking of proteolytically-cleaved TLR9 to fungal- or beta-1,3 glucan-containing phagosomes. To establish if this recruitment is functionally relevant, we performed transcriptomics analysis and demonstrated that Dectin-1 controls TLR9-dependent gene expression.
In the third chapter, we determined whether tetraspanin CD82 affects TLR9 signaling. CD82 is primarily known for its role in cancer metastasis. In the context of fungal pathogens, CD82 recruits to A. fumigatus and C. albicans phagosomes independent of TLRs. However, the mechanisms by which CD82 participates in innate immunity are unknown. Using CD82-deficient mice, we report that CD82 is a key regulator of TLR9 signaling. We demonstrate that TLR9 and CD82 associate in macrophages and CD82 controls TLR9-dependent myddosome formation. Finally, CD82 modulates TLR9-dependent NF&kgr;B nuclear translocation and subsequent TNFalpha production. Collectively, our study demonstrates that CD82 is a specific regulator of TLR9 signaling, which may be critical in cancer immunotherapy approaches and coordinating the innate immune response to pathogens.
Similar to TLR9, STING recognizes endosomal DNA and triggers type I IFNs production in the host defense during viral infections. In the fourth chapter, our proteomics data revealed STING on beta-1,3 glucan bead-containing phagosomes. Using STING-KO mice, we identified that STING deficiency confers resistance to C. albicans infection.
The overall goal of this thesis was to interrogate and advance our understanding of the host innate immune defense mechanisms in signal transduction to invasive fungal pathogens. Given the important role of Dectin-1 in phagosomal maturation which is crucial for cytokine production and fungal killing, we explored Dectin-1 mediated regulation of TLR9 signaling, identified CD82 as a key regulator of TLR9 signaling, and assign a novel role for STING in C. albicans infection. Our findings advance the current understanding of key molecular pathways critical in fungal infections that will also aid in the development of therapeutic strategies.
Notlar:
School code: 0111
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(683995.1) | 683995-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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