Date of Completion

1-27-2017

Embargo Period

1-26-2018

Keywords

macrophage, infection, bacteria, sepsis, CD169+ macrophage, Listeria monocytogenes, spleen

Major Advisor

Kamal Khanna, Ph.D.

Associate Advisor

Juan Salazar, M.D.

Associate Advisor

Anthony Vella, Ph.D.

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

The spleen is an important site for generating protective immune responses against pathogens. Immune cells in the spleen undergo rapid reorganization to initiate and maintain localized inflammatory responses against pathogens. However, the mechanisms regulating this complex cellular reorganization process remain unclear. Here we show that splenic marginal zone CD169+ macrophages utilize their strategic localization and unique gene expression profile to rapidly initiate antibacterial responses essential for host protection. In addition to controlling initial bacterial growth, CD169+ macrophages orchestrate a second phase of innate protection by mediating the transport of bacteria to splenic T cell zones by recruiting and trans-infecting CD8α DCs and driving the subsequent reorganization of innate immune cells into hierarchical clusters. The recruitment and clustering of CD8α+ DCs with infected CD169+ macrophages required bacterial escape from the phagosome. Although, CD8α+ DCs are known to be required for a productive Listeria monocytogenes (Lm) infection in the spleen, our results indicate that the protection provided by CD169+ macrophages to the host during Lm infection overrode the pathogen favorable CD8α+ DC niche. These new findings provide fundamental mechanistic insight into how the anatomical positioning of CD169+ macrophages regulate pathogen localization, which was critical for the subsequent reorganization of innate immune cells and the generation of protective innate immune responses in secondary lymphoid organs.

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