Foam Cells Control Mycobacterium tuberculosis Infection

Abstract

Mycobacterium tuberculosis (Mtb) infects macrophages and macrophage-derived foam cells, a hallmark of granulomata in tuberculous lesions. We analyzed the effects of lipid accumulation in human primary macrophages and quantified strong triglyceride and phospholipid remodeling which depended on the dietary fatty acid used for the assay. The enrichment of >70% in triglyceride and phospholipids can alter cell membrane properties, signaling and phagocytosis in macrophages. In conventional macrophage cultures, cells are heterogeneous, small or large macrophages. In foam cells, a third population of 30% of cells with increased granularity can be detected. We found that foam cell formation is heterogenous and that lipid accumulation and foam cell formation reduces the phagocytosis of Mtb. Under the conditions tested, cell death was highly prevalent in macrophages, whereas foam cells were largely protected from this effect. Foam cells also supported slower Mtb replication, yet this had no discernible impact on the intracellular efficacy of four different antitubercular drugs. Foam cell formation had a significant impact in the inflammatory potential of the cells. TNF-α, IL-1β, and prototypical chemokines were increased. The ratio of inflammatory IL-1β, TNF-α, and IL-6 vs. anti-inflammatory IL-10 was significantly higher in response to Mtb vs. LPS, and was increased in foam cells compared to macrophages, suggestive of increased pro-inflammatory properties. Cytokine production correlated with NF-κB activation in our models. We conclude that foam cell formation reduces the host cell avidity for, and phagocytosis of, Mtb while protecting the cells from death. This protective effect is associated with enhanced inflammatory potential of foam cells and restricted intracellular growth of Mtb.

Higher Serum Cholesterol Levels Are Associated With Reduced Systemic Inflammation and Mortality During Tuberculosis Treatment Independent of Body Mass Index

“…Preclinical studies have found that Mtb can manipulate host lipids in several ways. Mtb induces host lipid accumulation, primarily TG and cholesterol esters, to promote its intra-macrophage survival, leading to the formation of lipid-laden foam cells ( 19 , 20 ). In addition to serving as a nutrient reservoir for dormant Mtb ( 21 ), these host lipids impair the ability of macrophages to kill intracellular bacilli.…”

The role of lipid droplets in microbial pathogenesis

“…Several macrophage functions are downregulated by prostaglandins, resulting in decreased pro-inflammatory cytokine secretion, reduced antigen presentation and lowered production of free radicals in macrophages and other leukocytes. In vitro induction of foamy macrophages can be performed by exposing macrophages to exogenous polyunsaturated fatty acids [117]. Interestingly it was found that these foam cells, with increased LD formation, were less a phagocytic towards M. tuberculosis and, compared to control macrophages, were not dying to the same extend.…”

Rickettsia conorii survival in THP ‐1 macrophages involves host lipid droplet alterations and active rickettsial protein production

“…The development and contribution of foam cell development to pathogen intracellular survival have been well characterised for pathogens such as M. tuberculosis and C. pneumoniae (Cheng et al, 2014;Genoula et al, 2020;Mei et al, 2009;Reza et al, 2009). Similarly, oleic acid-albumin was used at a concentration of 400 μM as carried out previously during M. tuberculosis infection (Agarwal et al, 2020). To confirm a significant increase in LDs present during foam cell induction and to define the LD modulation initiated during infection in foam-like cells, LD visualisation and quantification were conducted as performed previously.…”

“…THP-1 macrophages were seeded in a 24-well plate with coverslips or a 96-well plate at 5 Â 10 5 -1 Â 10 6 cells/ml with 1 ml/well or 200 μl/well, respectively. After 24 hr, oleic acidalbumin or BSA (Thermo-Scientific) was added to the corresponding cells at a concentration of 400 μM as used previously to induce a foam cell-like phenotype in THP-1 macrophages (Agarwal et al, 2020). Oleic acid-albumin was incubated with THP-1 cells for 3 hrs before infection with R. conorii at an MOI of 2.…”

“…Interestingly, studies investigating the alteration of PPARα and PPARɣ during intracellular macrophage infection with various pathogens, including M. tuberculosis and Chlamydia pneumoniae, determined that the creation of a metabolically favorable niche for sustainable infection requires regulation of expression and function of PPARα and PPARɣ (Arnett et al, 2018;Cheng et al, 2014;Crane, Ireland, Alinger, Small, & Bosio, 2013;Kim et al, 2017;Mei et al, 2009;Reza et al, 2009). For M. tuberculosis and C. pneumoniae, modulation of these signalling molecules promotes development of a foam cell required for bacterial persistence within the infected cell (Agarwal et al, 2020;Cheng et al, 2014;Mei et al, 2009;Reza et al, 2009). S. typhimurium and M. tuberculosis have also been shown to regulate LDs directly during active bacterial infection suggesting a multitude of mechanisms are potentially involved in modulating lipid metabolism and the M2 macrophage response observed during R. conorii infection of macrophages (Arena et al, 2011;Ouimet et al, 2016).…”