Date of Award

January 2020

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biomedical Sciences

First Advisor

Nadeem Khan

Abstract

Influenza viruses (IV) have caused untold morbidity and mortality throughout the previous centuries. These viruses have caused several pandemics that have witnessed the loss of millions of lives. Today, IVs continue to circulate annually, and the efficacy of influenza virus vaccines are limited. As IV pandemics in 1918, 1957, and 2009 have shown the world, the push for a universal influenza vaccine has never been more relevant. While much research has been devoted to understanding the virology around IVs, the immunopathology of the host-pathogen axis has been less studied. Recently, there has been much attention on the role of the immune response during IV infections as they pertain to damage to the host’s lungs. Therefore, pathological immune mechanisms implicated in lung damage represent targets of therapeutic interventions aimed at mitigating the lung inflammation and at increasing resistance to influenza-associated bacterial pneumonia.

In the current study, we identified an interferon (IFN)-γ-regulated subset of monocytes, CCR2+ monocytes, as a critical component facilitating the crosstalk between leukocytes and barrier cells, and a driver of lung damage in a mouse influenza model. IFN-γ regulated the infiltration and inflammatory phenotype of CCR2+ monocytes in influenza-infected lungs. At the transcriptional level, IFN-γ deficiency attenuated the inflammatory phenotype of monocytes. Effector CD8 T cells were identified as the dominant cell type associated with pathogenic IFN-γ response in our influenza model. These previously unappreciated immune mechanisms highlight the immunoregulatory roles of IFN-γ response in regulating the monocyte inflammation and a molecule of therapeutic target in the future.

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