Lipid Mediators of Inflammation in TB and TB-Diabetes

This study was terminated August 1, 2019. It was funded and conducted under the U.S. National Institutes of Health and is nested within Impact of Diabetes on TB Treatment Outcomes. Dr. Jonathan Golub was the PI.

 

Studies have shown that individuals with Tuberculosis (TB) and diabetes (TB-DM) have a distinct immune profile compared to individuals with TB alone. Individuals with TB-DM have higher inflammation, a higher bacillary load, increased Th1 immune responses and a defective neutrophil and macrophage function including impaired phagocytosis. This profile in TB-DM individual correlates with adverse clinical outcomes including worse treatment responses. 

 

However, the role of lipid mediators of inflammation have not been well-characterized in either TB or TB-DM patients. Recent studies have shown the significant role that host lipids play in modulating immunity and disease outcomes. Prostaglandins and leukotrienes are lipids that have a pro-inflammatory role in the fight against infectious agents while Specialized Pro-resolving lipid Mediators (SPMs) including resolvins, protectins and maresins, are important for the effective resolution of inflammation. 

 

In studies of TB alone (without diabetes), there is evidence of a delicate balance where an excess of either the pro-inflammatory LTB4 or pro-resolving LXA4 can result in impaired host response to Mycobacterium tuberculosis (Mtb). But the role of the other lipid mediators in TB have not been studied. Importantly, in studies of diabetes (without TB), it has been shown that SPMs can reduce inflammation, improve phagocytosis and reduce bacterial burden (sepsis). Thus, studying the profile of the lipid mediators of inflammation could be important from an intervention perspective for both TB and especially TB-DM patients (who have higher inflammation): SPMs are particularly attractive therapeutic candidates for inflammation resolution (and improved clinical outcomes) because synthetic SPMs have already been developed and other more sustainable approaches also hold promise (e.g.: fish oil as most of these SPMs are derivatives of omega-3 fatty acids).

 

In this study, we will address this research gap by a) comparing baseline (pre-treatment) levels of these lipid mediators of inflammation between individuals with TB and TB-DM (aim 1) and b) by studying the association of these mediators with TB treatment outcomes (recurrence and death as primary outcomes) in individuals with TB and TB-DM (aim 2). To assess these mediators, we will utilize bio-banked serum samples collected from individuals in the TB and TB-DM cohorts at BJ Medical College from the “the impact of diabetes on TB treatment outcomes” study.   

 

Knowledge to be gained and Future Directions: This study will identify lipid mediators, with a specific focus on pro-inflammatory and pro-resolving lipids that are associated with adverse TB outcomes in individuals with TB and TB-DM. Identifying relevant mediators could drive treatment strategies. For example, individuals with high levels of pro-inflammatory lipids could benefit from administration of aspirin or fish oil which triggers production of pro-resolving mediators. On the other hand, an individual with high levels of pro-resolving mediator could benefit from administration of an inhibitor as done in studies with zebrafish models(6). Based on our results, future studies will be designed to determine appropriate interventions.