Mycobacterium tuberculosis Infection-Driven Foamy Macrophages and Their Implications in Tuberculosis Control as Targets for Host-Directed Therapy

Abstract

Tuberculosis (TB) is a leading cause of death worldwide following infection with Mycobacterium tuberculosis (Mtb), with 1.5 million deaths from this disease reported in 2018. Once the bacilli are inhaled, alveolar and interstitial macrophages become infected with Mtb and differentiate into lipid-laden foamy macrophages leading to lung inflammation. Thus, the presence of lipid-laden foamy macrophages is the hallmark of TB granuloma; these Mtb-infected foamy macrophages are the major niche for Mtb survival. The fate of TB pathogenesis is likely determined by the altered function of Mtb-infected macrophages, which initiate and mediate TB-related lung inflammation. As Mtb-infected foamy macrophages play central roles in the pathogenesis of Mtb, they may be important in the development of host-directed therapy against TB. Here, we summarize and discuss the current understanding of the alterations in alveolar and interstitial macrophages in the regulation of Mtb infection-induced immune responses. Metabolic reprogramming of lipid-laden foamy macrophages following Mtb infection or virulence factors are also summarized. Furthermore, we review the therapeutic interventions targeting immune responses and metabolic pathways, from in vitro, in vivo, and clinical studies. This review will further our understanding of the Mtb-infected foamy macrophages, which are both the major Mtb niche and therapeutic targets against TB.

PE_PGRS3 ensures provision of the vital phospholipids cardiolipin and phosphatidylinositols by promoting the interaction betweenM. tuberculosisand host cells

“…In the caseating debris of human TB granulomas, there is an enrichment of cholesterol, cholesteryl esters, and triacylglycerides (TAGs), with the latter being the main components of the large lipid droplets commonly found in foamy macrophages, another important niche for Mtb [ 36 , 37 ]. Phagosome-containing Mtb can be found tightly associated with lipid droplets [ 38 ] and Mtb can translocate to these droplets where it utilizes lipids as a carbon source for survival [ 39 , 40 ]. Interestingly, elevated levels of TAGs are found during rapid disease development caused by modern Mtb Beijing strains compared to ancient Mtb Beijing strains [ 41 ], highlighting the importance of lipid metabolism in TB pathogenesis.…”

Protective Immunity Against Neospora Caninum Infection Induced by 14-3-3 Protein in Mice

“…Increasing evidence has indicated that EVs are used by parasites to orchestrate bene cial changes in the host environment and to ensure successful infection or activate the innate immune response to control infection [25,26,27]. EVs and their cargo can participate in cell-to-cell communication via various functional biomolecules, including proteins, bioactive lipids, and RNA, which can alter recipient cell functions [28,29,30]; therefore, our previous study also selected NEVs as vaccine controls.…”

Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection

“…Macrophages infected with Mtb increase lipid metabolism, which results in lipid droplet (LD) formation and further differentiation into “foamy” macrophages within granulomas ( Hunter et al, 2007 ; Peyron et al, 2008 ; Shim et al, 2020 ). Mtb and other bacteria are believed to specifically induce LD formation as a pathogenic strategy for use as a carbon source to promote intracellular growth ( Saka and Valdivia, 2012 ; Nolan et al, 2017 ).…”

“…Since host cells and Mtb are extensively dependent on lipid and carbohydrate metabolic pathways, these metabolic pathways can be used as treatment targets ( Shim et al, 2020 ). Formation of host foamy macrophages can persist during bacterial infection and contribute to the cavitation and release of infectious bacilli in patients with active disease ( Pandey and Sassetti, 2008 ; Griffin et al, 2012 ).…”