자료유형  

 학위논문

Control Number  

0016933850

International Standard Book Number  

9798380622936

Dewey Decimal Classification Number  

576

Main Entry-Personal Name  

Ching, Krystal L.

Publication, Distribution, etc. (Imprint  

[S.l.] : New York University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(182 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-04, Section: B.

General Note  

Advisor: Cadwell, Ken;Torres, Victor J.

Dissertation Note  

Thesis (Ph.D.)--New York University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Autophagy controls cellular fitness during perturbations such as nutrient deprivation and hypoxia by facilitating the formation of vesicles called autophagosomes which engulf cytosolic material and fuse with the lysosome for degradation. While the homeostatic function of autophagy is well characterized, its contribution to immunity is less defined. Our labs recently found a novel non-degradative role for the autophagy protein ATG16L1 in mediating protection against pore forming toxins produced by Staphylococcus aureus through the release of exosomes harboring the cognate receptor, ADAM10. Exosomes are small extracellular vesicles (EVs) secreted by all cell types that carry various substrates with pleiotropic functions in cell growth and communication. We defined this subset of exosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins (ATGs) as 'defensosomes'. However, to what extent defensosomes are used as a defense mechanism against other pathogens remains unknown. Given defects in autophagy have been linked to increased susceptibility to viral infections, we investigated the role of defensosomes against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consistent with a protective function, higher levels of exosomes containing the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients were associated with reduced hospitalization times. We show that ACE2+ defensosomes can directly bind virions and block viral entry, and that induction requires activation of viral sensors and the presence of ATG16L1. Finally, we investigated the cell biological mechanisms regulating defensosome production following recognition of microbial ligands through TLR9. Using genetic screens and ultrastructural microscopy, we uncovered that TLR9 signaling inhibits lysosomal fusion with multivesicular bodies (MVBs) by inducing the dissociation of Rab7. We further demonstrate that ATG16L1 has a role in promoting intraluminal budding upstream of TLR9 activation. Altogether, our findings support a mechanism where TLR9 signaling and ATG16L1 work in parallel to promote defensosome production during infection.

Subject Added Entry-Topical Term  

Pathology.

Subject Added Entry-Topical Term  

Microbiology.

Subject Added Entry-Topical Term  

Biology.

Index Term-Uncontrolled  

Autophagy proteins

Index Term-Uncontrolled  

Exosomes

Index Term-Uncontrolled  

Innate immunity

Index Term-Uncontrolled  

Vesicles

Index Term-Uncontrolled  

Bronchoalveolar lavage fluid

Added Entry-Corporate Name  

New York University Basic Medical Science

Host Item Entry  

Dissertations Abstracts International. 85-04B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642001