عنوان

Characterizing Type I Interferon Mediated Inflammatory Responses During Acute and Chronic Infections

Number

TL769019n3

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

Characterizing Type I Interferon Mediated Inflammatory Responses During Acute and Chronic Infections

General Material Designation

[Thesis]

First Statement of Responsibility

Iyer, Shankar

Subsequent Statement of Responsibility

Cheng, Genhong

Date of Publication, Distribution, etc.

2013

Body granting the degree

Cheng, Genhong

Text preceding or following the note

2013

Text of Note

During the course of infectious disease, the immune system generates a robust inflammatory response in order to eradicate the invading pathogen and restore tissue homeostasis. An essential feature of this process is the ability of the host to provide an anti-microbial response while preventing unnecessary collateral tissue damage. Many pro-inflammatory pathways, which contribute to host defense against infectious disease have been identified; however, the pathways that regulate and resolve the pro-inflammatory response preventing tissue injury are not well understood. To study the mechanisms by which the acute inflammatory response is resolved, we studied the Type I Interferon (IFN) pathway, a hallmark feature of acute phase immune response to viral infection, where induction of interferon stimulatory genes (ISGs) is required for host defense. In contrast, a strong type I IFN response often correlates with higher bacterial virulence and absence of a type I IFN response can enhance host-mediated clearance of many bacterial species. Therefore, it remains unknown whether the type I IFN response to bacterial infection is of benefit to the host and what the functional role might be. To elucidate the key regulatory pathways involved, we utilized RNA sequencing to identify a network of pro-inflammatory molecules that are transiently up-regulated but rapidly down-regulated in Toll like receptor (TLR) 4 stimulated mouse macrophages. Further studies in transgenic knockout animals revealed that the resolution of this pro-inflammatory network was dependent on type I IFN signaling as well as signaling of two type I IFN downstream targets, interleukin 27 (IL-27) and interleukin 10 IIL-10). Importantly in a model of acute systemic bacterial infection, abrogating the function of these molecules enhanced the host anti-microbial response, but concomitantly augmented inflammation including immune mediated organ damage resulting in increased mortality. Thus we have defined a type I IFN, IL-27 and IL-10 gene program, which is required for resolving acute inflammatory response to protect against tissue injury. Conversely we hypothesized that prolonged signaling by this pathway could create an immunosuppressive state conducive to the establishment or persistence of chronic infection. Utilizing a murine model of herpesgammavirus we demonstrate that defects in IL-27 or IL-10 signaling had little effect on active, lytic viral replication but prevented the establishment of viral latency. Thus we demonstrate how a single pathway can provide both beneficial and detrimental features in response to infectious disease.

Pratt, Gabriel Asbury

Iyer, Shankar

UCLA

Electronic name

p

[Thesis]

276903

a

Y