Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

Summary Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth factor limitation or ER stress. Combined metabolomics and RNA-seq linked this anomalous autophagy to defective mTOR signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

Chlamydia trachomatis is one of the most common bacterial pathogens and is the etiological agent of debilitating sexually transmitted and ocular diseases in humans. The organism is an obligate intracellular prokaryote characterized by a highly specialized biphasic developmental cycle. We have performed genomic transcriptional analysis of the chlamydial developmental cycle. This approach has led to the identification of a small subset of genes that control the primary (immediate-early genes) and secondary (late genes) differentiation stages of the cycle. Immediate-early gene products initiate bacterial metabolism and potentially modify the bacterial phagosome to escape fusion with lysosomes. One immediate early gene (CT147) is a homolog of the human early endosomal antigen-1 that is localized to the chlamydial phagosome; suggesting a functional role for CT147 in establishing the parasitophorous vacuole in a nonfusogenic pathway. Late gene products terminate bacterial cell division and constitute structural components and remodeling activities involved in the formation of the highly disulfide cross-linked outer-membrane complex that functions in attachment and invasion of new host cells. Many of the genes expressed during the immediate-early and late differentiation stages are Chlamydia-specific and have evolutionary origins in eukaryotic lineages.T he Chlamydia trachomatis bacterium is an obligate intracellular pathogen of humans that primarily infects columnar epithelial cells of the ocular and genital mucosae. Chlamydial infections of the eye and genital tract have a significant impact on human health worldwide, causing trachoma, the leading cause of preventable blindness, and sexually transmitted diseases (STD) that include pelvic inflammatory disease and tubal factor infertility (1, 2). Chlamydial STDs are also risk factors in cervical squamous cell carcinoma (3) and HIV infection (4, 5).C. trachomatis has a small genome of Ϸ1 Mb encoding 893 chromosomal and 8 plasmid ORFs that share significant homology in both gene structure and order among strains that infect human and animal hosts (6, 7). Two distinguishing characteristics of this pathogen are its developmental cycle and predilection for causing persistent infections (8). The developmental cycle consists of infectious and noninfectious stages that exhibit unique morphological, biochemical, and biological properties. The infectious elementary body (EB) is a metabolically inactive particle with a rigid, disulfide cross-linked outer membrane (OM) (9-12) that enables the EB to attach to and enter host cells (13-15). After host cell entry, the EB is localized to a phagosome, and the primary differentiation process is initiated. This developmental process involves the commencement of bacterial metabolism and the conversion of the EB to the intracellular replicating form of the organism, termed the reticulate body (RB).At the very early stage of infection (1-3 h) the parasite exerts profound effects on the host. Through an unknown mechanism, dependent on both ba...

Toxoplasma gondii strains differ dramatically in virulence despite being genetically very similar. Genetic mapping revealed two closely adjacent quantitative trait loci on parasite chromosome VIIa that control the extreme virulence of the type I lineage. Positional cloning identified the candidate virulence gene ROP18, a highly polymorphic serine-threonine kinase that was secreted into the host cell during parasite invasion. Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs. These attributes of ROP18 required kinase activity, which revealed that secretion of effectors is a major component of parasite virulence.