Author ORCID Identifier

0000-0002-8272-5819

Date of Graduation

8-2021

Document Type

Thesis (MS)

Program Affiliation

Immunology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Jeffrey K. Actor, Ph.D.

Committee Member

Marian L. Kruzel, Ph.D.

Committee Member

Robert L. Hunter, M.D. Ph.D.

Committee Member

Pamela L.Wenzel, Ph.D.

Committee Member

Scott E. Evans, M.D.

Abstract

Despite extensive research and worldwide eradication efforts, Mycobacterium tuberculosis (Mtb) remains a major infectious pathogen to the human population with about 10 million cases of infection per year globally. The host-pathogen interaction, pulmonary granuloma formation, and Mtb adaptions result in increased complexity of the disease. Granulomas are formed by active immune responses generated during Mtb infection, and serve to contain and limit bacterial dissemination. The major mycobacterial surface mycolic acid, trehalose 6,6'-dimycolate (TDM), functions in multiple ways to enhance immune cell recruitment of sites of infection, to induce inflammation and granulomatous responses, and to initiate survival strategies for the organism inside macrophages. Mtb also benefits from establishment of a tightly formed granuloma, which both protects it from immune reactivity and serves as a physical boundary to limit penetration of drugs during therapeutic treatment. In order to demystify the complicated relationship between the host and pathogen, many studies have been performed around the primary Mtb-induced granuloma to combat the challenges that come with this specific immunopathology. We hypothesized that by altering the immunopathology of granulomas using lactoferrin, an immunomodulating agent, it will allow greater penetration of therapeutics into the site of focal inflammation. Our lab has reported that oral bovine lactoferrin treatments during the innate immune response leads to significant modulation of the primary Mtb granuloma response and lessen Mtb burden in mouse lungs. Here, we show that such modulation during granuloma development can also be achieved by using recombinant human lactoferrin oral treatments to increase granuloma permeability and promotes drug penetration in both TDM-induced granulomatous inflammation as well as during active Mtb-infection. Findings from this work show lactoferrin’s potential as a host-directed therapeutic that can be combined with current TB standard treatment to reduce pathological damage in the lungs post mycobacterial infection.

Keywords

Lactoferrin, Mycobacterium tuberculosis, Mtb, trehalose 6, 6'-dimycolate, TDM, granuloma, immunomodulating, drug penetration, inflammation, permeability, therapeutics.

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