MODULATING LOCAL IMMUNE ENVIRONMENT TO DETER TUBERCULOSIS PROGRESSION
Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host environment at the site of infection. In this dissertation, we have taken two different approaches to target immune environment, with the hope to perturb Mtb infection. First, we report that inhibition of matrix metalloproteinases (MMPs) enhances the in vivo potency of the frontline TB drugs isoniazid and rifampicin. MMPs expression is markedly upregulated in human tuberculosis (TB) granulomas and murine infection models. Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of Evans Blue dye and frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens. Second, we show that synthetic mRNA encoding CCL2 or CCL3 are able to recruit certain populations of monocyte in a non-inflammatory manner. These recruited monocytes stay in a neutral, non-programmed state, exhibiting neither bactericidal nor tissue-repairing phenotypes. Additional Ifn- mRNA or Il-4 mRNA can polarize these cells to different phenotypes. Furthermore, the monocytes recruited by Ccl3 and Ifn- mRNA were able to launch the most rapid and strongest superoxide burst compared to other mRNA combinations. These findings demonstrate a synthetic mRNA based immune-modulation scheme that allows recruitment and modification of specific immune cell populations in vivo, which can impact tuberculosis progression.
Biology; Enhanced TB drug efficacy; Immune cell modulation; Immune cell recruitment; Matrix metalloproteinase inhibitor; Mycobacterium tuberculosis; Synthetic mRNA; Bioengineering
Soloway, Paul; Russell, David G.
Biological and Environmental Engineering
Ph. D., Biological and Environmental Engineering
Doctor of Philosophy
dissertation or thesis