Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis

Abstract

The fate of infected macrophages has an essential role in protection against Mycobacterium tuberculosis by regulating innate and adaptive immunity. M. tuberculosis exploits cell necrosis to exit from macrophages and spread. In contrast, apoptosis, which is characterized by an intact plasma membrane, is an innate mechanism that results in lower bacterial viability. Virulent M. tuberculosis inhibits apoptosis and promotes necrotic cell death by inhibiting production of prostaglandin E2. Here we show that by activating the 5-lipoxygenase pathway, M. tuberculosis not only inhibited apoptosis but also prevented cross-presentation of its antigens by dendritic cells, which impeded the initiation of T cell immunity. Our results explain why T cell priming in response to M. tuberculosis is delayed and emphasize the importance of early immunity.

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

“…This notion is based on the observation that while the cells infected with attenuated M.tbH37Ra undergo apoptotic cell death pathways, virulent M.tbH37Rv infection tends to promote necrotic cell death, thus preventing the efficient generation of mycobacterial antigen and subsequently, delaying T-cell priming [15,16,32]. Our current findings support the notion that delayed Th1-type immunity is rather a trait of infection by the slow-growing mycobacterial species including M.tbH37Rv, M.tbH37Ra, and M. bovis BCG, independent of the relative virulence.…”

“…However, despite some recent progress [15][16][17], the immune mechanisms behind delayed Th1 immunity still remain poorly understood, and this has recently been identified as an important outstanding issue in the field of anti-mycobacterial immunity and TB vaccine research [7,13,14]. The relative virulence of M.tb has long been believed to play a role in delayed Th1-cell priming [7,[13][14][15][16]. It is less clear whether delayed Th1-cell priming also results from pulmonary NTM infection.…”

A Simple and Highly Sensitive Quantitation of Eicosanoids in Biological Samples Using Nano-flow Liquid Chromatography/ Mass Spectrometry

“…The variety of molecular species contributes to exerting diverse biological functions and regulating various body responses, such as inflammation, immune system regulation, muscle contraction, pain, and body temperature control. [1][2][3][4][5][6][7] These functions are mostly derived from structural differences of the eicosanoids. Therefore, the simultaneous measurement of eicosanoids is valuable for understanding their physiological and pathophysiological roles.…”

Eicosanoids, Prostaglandins, and the Progression of Tuberculosis

“…In contrast, the BCG vaccine strain and avirulent strains of M. tuberculosis preferentially induce the expression of PGE2, which protects against plasma membrane damage, leading to efficient apoptosis. In the absence of PGE2, extensive plasma membrane damage occurs, causing necrosis in lieu of apoptosis [6,7].…”

“…Recent reports indicate that M. tuberculosis can also modulate the host eicosanoid metabolism as a survival strategy [6]. Eicosanoids and prostaglandins are lipid molecules that have long been of interest in metabolic biology.…”