Summary: The recent pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was first reported in China (December 2019) and now prevalent in ∼170 countries across the globe. Entry of SARS-CoV-2 into mammalian cells require the binding of viral Spike (S) proteins to the ACE2 (angiotensin converting enzyme 2) receptor. Once entered the S protein is primed by a specialised serine protease, TMPRSS2 (Transmembrane Serine Protease 2) in the host cell. Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection when patients become viraemic, a significant number of COVID-19 patients also develop liver comorbidities. We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms. Here we employed single-cell RNA-seq (scRNA-seq) to survey the human liver and identified potentially implicated liver cell-type for viral ingress. We report the co-expression of ACE2 and TMPRSS2 in a TROP2 ⁺ liver progenitor population. Importantly, we fail to detect the expression of ACE2 in hepatocyte or any other liver (immune and stromal) cell types. These results indicated that in COVID-19 associated liver dysfunction and cell death, viral infection of TROP2 ⁺ progenitors in liver may significantly impaired liver regeneration and could lead to pathology. Highlights: - EPCAM ⁺ Liver progenitors co-express ACE2 and TMPRSS2 - ACE2 and TMPRSS2 expression is highest in TROP2 ^high progenitors - ACE2 and TMPRSS2 cells express cholangiocyte biased fate markers - ACE2 and TMPRSS2 positive cells are absent in human fetal liver

Mycobacterium tuberculosis has been infecting millions of people worldwide over the years, causing tuberculosis. Drugs targeting distinct cellular mechanisms including synthesis of the cell wall, lipids, proteins, and nucleic acids in Mtb are currently being used for the treatment of TB. Although extensive research is being carried out at the molecular level in the infected host and pathogen, the identification of suitable drug targets and drugs remains under explored. Pranlukast, an allosteric inhibitor of MtArgJ (Mtb ornithine acetyltransferase) has previously been shown to inhibit the survival and virulence of Mtb. The main objective of this study was to identify the altered metabolic pathways and biological processes associated with the differentially expressed metabolites by PRK in Mtb. Here in this study, metabolomics was carried out using an LC-MS/MS-based approach. Collectively, 50 metabolites were identified to be differentially expressed with a significant p-value through a global metabolomic approach using a high-resolution mass spectrometer. Metabolites downstream of argJ were downregulated in the arginine biosynthetic pathway following pranlukast treatment. Predicted human protein interactors of pranlukast-treated Mtb metabolome were identified in association with autophagy, inflammation, DNA repair, and other immune-related processes. Further metabolites including N-acetylglutamate, argininosuccinate, L-arginine, succinate, ergothioneine, and L-phenylalanine were validated by multiple reaction monitoring, a targeted mass spectrometry-based metabolomic approach. This study facilitates the understanding of pranlukast-mediated metabolic changes in Mtb and holds the potential to identify novel therapeutic approaches using metabolic pathways in Mtb.

Mycobacterium tuberculosis (Mtb) is considered to be a devastating pathogen worldwide, affecting millions of people globally. Several drugs targeting distinct pathways are utilized for the treatment of tuberculosis. Despite the monumental efforts being directed at the discovery of drugs for Mtb, the pathogen has also developed mechanisms to evade the drug action and host processes. Rifampicin was an early anti-tuberculosis drug, and is still being used as the first line of treatment. This study was carried out in order to characterize the in-depth rifampicin-mediated metabolic changes in Mtb, facilitating a better understanding of the physiological processes based on the metabolic pathways and predicted protein interactors associated with the dysregulated metabolome. Although there are various metabolomic studies that have been carried out on rifampicin mutants, this is the first study that reports a large number of significantly altered metabolites in wild type Mtb upon rifampicin treatment. In this study, a total of 173 metabolites, associated with pyrimidine, purine, arginine, phenylalanine, tyrosine, and tryptophan metabolic pathways, were significantly altered by rifampicin. The predicted host protein interactors of the rifampicin-dysregulated Mtb metabolome were implicated in transcription, inflammation, apoptosis, proteolysis, and DNA replication. Further, tricarboxylic acidcycle metabolites, arginine, and phosphoenolpyruvate were validated by multiple-reaction monitoring. This study provides a comprehensive list of altered metabolites that serves as a basis for understanding the rifampicin-mediated metabolic changes, and associated functional processes, in Mtb, which holds therapeutic potential for the treatment of Mtb.