C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

Degradation process of Mycobacterium leprae cells in infected tissue examined by the freeze-substitution method in electron microscopy.

Mycobacterium leprae cells (strain Thai-53) harvested from infected mouse foot pads were examined by electron microscopy using the freeze-substitution technique. The population of M. leprae cells from the infected tissue consisted of a large number of degraded cells and a few normal cells. These thin sectioned cell profiles could be categorized into four groups depending on the alteration of the membrane structures, and the degradation process is considered to occur in stages, namely from stages 1 to 3. These are the normal cells with an asymmetrical membrane, a seemingly normal cell but with a symmetrical membrane (stage 1), a cell possessing contracted and highly concentrated cytoplasm with a membrane (stage 2), and a cell that has lost its membrane (stage 3). The peptidoglycan layer was found to remain intact in these cell groups.

Intracellular fate of Mycobacterium leprae in normal and activated mouse macrophages.

Mycobacterium leprae replicates within mononuclear phagocytes, reaching enormous numbers in the macrophage-rich granulomas of lepromatous leprosy. To examine the capability of macrophages to digest M. leprae, we studied the intracellular fate of M. leprae organisms in normal and activated mouse macrophages by using the electron-dense secondary lysosome tracer Thoria Sol. Intracellular M. leprae organisms, surrounded by a characteristic electron-transparent zone, were contained within phagosomal vacuoles of macrophages cultured in vitro for 1 to 6 days. In normal macrophages, a majority of phagosomes containing freshly isolated live M. leprae cells resisted fusion with Thoria Sol-labeled lysosomes. The extent of fusion was not significantly affected by pretreatment of M. leprae with human patient serum high in specific immunoglobulin G and M antibodies. In contrast, a majority of phagosomes containing gamma-irradiated M. leprae cells underwent lysosome fusion in normal macrophages. In addition, increased phagolysosome fusion was observed with live M. leprae-containing phagosomes in macrophages activated with gamma interferon. Increased fusion was associated with an increase in the number of fragmented and damaged bacilli, suggesting that increased digestion followed fusion. This study indicates that activated macrophages may have an increased capacity for clearance of normally resistant M. leprae.

Macrophage function in leprosy.

The macrophage function in patients with leprosy was assessed by estimating histochemically the acid phosphatase activity in skin biopsies and by assessment of phagocytic and lytic capability of in vitro cultured macrophages derived from peripheral blood monocytes, challenged with live M. leprae. Acid phosphatase was demonstrated in skin biopsies of different groups of leprosy patients classified according to the Ridley and Jopling scale. The degree of acid phosphatase positivity was correlated with clinical spectrum, Bacterial and Morphologic Indices and treatment status. Peripheral blood monocytes from patients with leprosy, either tuberculoid or lepromatous, were cultured in monolayers and challenged with M. leprae. The phagocytosis and lysis of mycobacteria by macrophages was observed at different time intervals from the 1st to the 28th day. The morphology of the macrophages in different types of leprosy was also studied. The results suggest that macrophages from patients with either tuberculoid or lepromatous leprosy are not by themselves capable of lysing live M. leprae. Live M. leprae injected into the foot pad of Wistar strain of rats evoked similar responses on the tenth day, in normal and protein deficient animals.