Mycobacterium tuberculosis curli pili reduces oxygen consumption rate of THP-1 macrophages during early infection

Abstract

The development of improved anti-tuberculosis (TB) strategies to address drug-resistance and ineffectual TB treatment regimens should focus on interrupting the initial host-pathogen interaction. This study aimed to elucidate the effect of surface-located adhesin, Mycobacterium tuberculosis (Mtb) curli pili (MTP), on the bioenergetic and metabolomic profiles of THP-1 macrophages during initial stages of infection. Differentiated THP-1 macrophages were infected with wildtype (WT), ∆mtp, or mtp-complemented strains of Mtb. Bioenergetic profiles and metabolic flux were determined and statistical analysis highlighted differences/similarities amongst the THP-1 macrophage groups. The ∆mtp infected THP-1 macrophages mimicked the higher oxygen consumption rate (OCR) for basal respiration, ATP production, maximal respiration and spare respiratory capacity of the uninfected THP-1 macrophages, relative to the WT and mtp-complement infected THP-1 macrophages. The ∆mtp infected THP-1 macrophages displayed the highest compensatory glycolytic rate. Mtb infection caused the redirection of carbon from the tricarboxylic acid cycle to glycolysis, in addition to an increased flux through the pentose phosphate pathway. However, in the ∆mtp infected THP-1 macrophages, the total metabolite abundance was lower, similar to the uninfected THP-1 macrophages. Data indicates that the absence of MTP facilitates prompt clearance of the intracellular pathogen before it establishes a successful infection. This implies that the presence of MTP facilitates the survival of the pathogen during the early stages until infection is established. These findings support the growing evidence that the MTP adhesin is an important virulence factor and interruption of the interaction between pathogen and host, will facilitate swift clearance of the infection by the host.

Keywords: Adhesin; Bioenergetics; LC-MS/MS; Mycobacterium tuberculosis; THP-1 macrophages.