Abstract
Coxiella burnetii is a bacterium that thrives in an acidic parasitophorous vacuole (PV) derived from lysosomes. Leishmania mexicana, a eukaryote, has also independently evolved to live in a morphologically similar PV. As Coxiella and Leishmania are highly divergent organisms that cause different diseases, we reasoned that their respective infections would likely elicit distinct host responses despite producing phenotypically similar parasite-containing vacuoles. The objective of this study was to investigate, at the molecular level, the macrophage response to each pathogen. Infection of THP-1 (human monocyte/macrophage) cells with Coxiella and Leishmania elicited disparate host responses. At 5 days post-infection, when compared to uninfected cells, 1057 genes were differentially expressed (746 genes up-regulated and 311 genes down-regulated) in C. burnetii infected cells, whereas 698 genes (534 genes up-regulated and 164 genes down-regulated) were differentially expressed in L. mexicana infected cells. Interestingly, of the 1755 differentially expressed genes identified in this study, only 126 genes (~7%) are common to both infections. We also discovered that 1090 genes produced mRNA isoforms at significantly different levels under the two infection conditions, suggesting that alternate proteins encoded by the same gene might have important roles in host response to each infection. Additionally, we detected 257 micro RNAs (miRNAs) that were expressed in THP-1 cells, and identified miRNAs that were specifically expressed during Coxiella or Leishmania infections. Collectively, this study identified host mRNAs and miRNAs that were influenced by Coxiella and/or Leishmania infections, and our data indicate that although their PVs are morphologically similar, Coxiella and Leishmania have evolved different strategies that perturb distinct host processes to create and thrive within their respective intracellular niches.
Highlights
Macrophages that phagocytize pathogens and recruit other immune cells are critical for the elimination of potential infections
Cells were incubated in the presence of 200 nM phorbol 12-myristate 13-acetate (PMA; EMD Biosciences) for 24 h to induce differentiation into adherent, macrophage-like cells
Previous studies have investigated host responses during early stages (6–72 hpi) of infections by C. burnetii and by various Leishmania species (Ren et al, 2003; Mahapatra et al, 2010; De Muylder et al, 2011; Rabhi et al, 2012, 2013); because the transformation from the infective form (SCV and promastigote, respectively) to the replicative form (LCV and amastigote, respectively) occur at differing rates in the two pathogens, we analyzed a later point during infection (5 days pi) when both pathogens have generated large parasitophorous vacuole (PV) that fill most of the host cell volume
Summary
Macrophages that phagocytize pathogens and recruit other immune cells are critical for the elimination of potential infections. Within macrophages, engulfed pathogens are transported inside phagosomes that later fuse with lysosomes to generate the phagolysosome. Most pathogens are degraded within the phagolysosome, which has a very harsh environment (low pH, Coxiella and Leishmania elicit disparate reactions high concentration of lysosomal hydrolases, presence of cationic peptides etc.; Kinchen and Ravichandran, 2008; Flannagan et al, 2009). Coxiella (a bacterium) and Leishmania (an eukaryote) have independently evolved the ability to thrive in a parasitophorous vacuole (PV) that is derived from the fusion of phagosomes with lysosomes (Voth and Heinzen, 2007; Alix et al, 2011). SCV transforms into a metabolically active form called the large cell variant (LCV), and multiple Coxiella-containing vacuoles merge to form a single large vacuole that fuses with endolysosomal vesicles to give rise to the mature Coxiella PV (van Schaik et al, 2013)
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