Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces Soluble Tumor Necrosis Factor Receptor Production through Tumor Necrosis Factor Alpha-Converting Enzyme Activation

Abstract

c Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-␣) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-␣-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosisinfected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNF-RII/sTNFRI ratio as an indicator of tuberculosis disease.

Lipoarabinomannan‐specific TNF‐α and IFN‐γ as markers of protective immunity against tuberculosis: a cohort study in an endemic setting

“…One possible explanation is that LAM suppresses the production of TNF-a during Mtb infection through production of TNF-receptor as a mechanism to reduce circulating TNF-a level (30). TNF-a is a potent inducer of apoptosis of infected macrophages, thereby facilitating cell-mediated immunity (31).…”

Immunological recovery in patients with pulmonary tuberculosis after intensive phase treatment

“… 33 Previous studies have shown that excessive TNF-α levels cause damage to the immune pathological response in cells and to protection of the body’s defense. 34 – 36 TNF-α levels may be related to the severity of the disease process and may serve as a parameter for predicting the prognosis of pulmonary TB.…”

Manipulation of the endocytic pathway and phagocyte functions by Mycobacterium tuberculosis lipoarabinomannan

“…More recently, one report indicates that ManLAM can promote extracellular release of soluble TNF-α receptor. Thus, ManLAM might also interfere with the extrinsic apoptosis pathway by neutralizing TNF-α (Richmond et al, 2012 ).…”