Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis.
Highlights
Mycobacterium tuberculosis (MTB), the causative agent of human tuberculosis (TB), poses a still greater burden on human health globally [1, 2]
The pathophysiological and immunological role of MTB PE/PPE proteins have yet to be comprehensively understood, recent evidence has shown PE/PPE proteins serve as effectors for immune evasion during MTB infection [19, 53]
We found PPE32 increase IL-12p40 expression after 6 h stimulation (Figure 2A–2C), while the expression of IL-32 was induced 12 h after PPE32 stimulation (Figure 3)
Summary
Mycobacterium tuberculosis (MTB), the causative agent of human tuberculosis (TB), poses a still greater burden on human health globally (around 9.6 million people, including 5.4 million men, 3.2 million women and 1.0 million children) [1, 2]. During the initial stage of the disease, many mycobacterial cell wall-associated factors disturb the immune cells, including PE/PPE family protein antigens [3], crucial for the outcome of MTB infection [4]. The surface location or secreted characteristics of PE/PPE proteins suggest direct interaction with host [7]. Varied transcription level of several PE/PPE genes within macrophages or mouse during MTB infection [10] suggested roles in the interaction with host macrophage. Cell wall associated PE/PPE family proteins [11,12,13,14,15,16] might directly interact with host cell surface receptor, or even disrupts the host immunity [14, 17,18,19,20]
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