Lipids and fatty acids feature extensively in the life cycle of Mtb. Mtb has evolved from saprophytic actinomycetes, and its free living relatives have genomes that are 50% larger (M. smegmatis; 6.3K genes, Mtb; 4.3K genes). Clearly genome downsizing has been significant, likely due to Mtb’s “simpler” life style involving one major host species and no free-living stage. Therefore, logically, what it keeps is important to its success and upon sequencing the Mtb genome it was noted that lipid metabolism, synthesis and catabolism, was the most common single theme1. I’d like to discuss 3 areas where lipids play a critical role in the biology of this pathogen.
Cell wall lipids: Mtb cell wall is rich in lipidoglycans that have marked immunomodulatory activities. The activation of the innate immune sensing pathways of the host has major impact on both infection at the cell level and disease progression at the tissue level.
Bacterial nutrition: Atypically for a pathogen, Mtb exploits host fatty acids and cholesterol as its primary carbon sources in vivo. Limiting access to these nutrients by either genetic or pharmacological intervention suppresses bacterial growth within its host cell in culture and in vivo.
Host macrophage metabolism: While it was originally thought that all macrophages originated from blood monocytes this is now known not to be true. Tissues, such as the lung, are populated by self-renewing resident lineages, including alveolar macrophages, during embryogenesis. These macrophages are differentially-programmed epigenetically, and this is reflected in their metabolic bias towards OXPHOS and FAO. The metabolic states of these macrophage lineages is central to disease outcome in vivo.
This presentation will explore the biology of these host and bacterial lipid pathways and discuss their potential significance to therapeutic approaches to combat this disease, which, following COVID, is back as the most frequent cause of death by a single infectious agent.
1. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537-544, doi:10.1038/31159 (1998).