A new paradigm for leprosy diagnosis based on host gene expression
Fig 7
Hypothetical hourglass model contextualizing the observed findings for leprosy clinical outcomes.
The host-pathogen interaction in the skin leads to opposing leprosy clinical forms. Upon infection, M. leprae induces baseline metabolic alterations such as an increase in glucose uptake, modulation of lipid biosynthesis, reduction of mitochondrial metabolism, and upregulation of IDO-1 and type I IFN. Eventually, progression towards an unspecified inflammatory state can be observed where three ways could be anticipated: I) self-healing; II) progression towards the tuberculoid pole; or III) progression to lepromatous pole. These outcomes are driven by specific environmental and host genetic factors. It is expected that lower (or shorter) M. leprae exposure, food shortage, BCG vaccination, and polymorphisms in genes controlling autophagy/granuloma formation (NOD2, LRRK2, PRKN) all contribute to developing leprosy per se. Excessive inflammation is one phenotype observed, that is also seen in other granulomatous diseases (e.g., cutaneous sarcoidosis, granuloma annulare), especially in paucibacillary lesions. On the other pole, epithelial-mesenchymal transition and local immunosuppression are present due to a probably higher (and/or longer) M. leprae exposure, combined with host single-nucleotide polymorphisms (SNPs) at key genes, like lipid biogenesis (APOE) and central metabolism (HIF1A, LACC1/FAMIN), culminating in disease progression.