Importance of T Cells, Gamma Interferon, and Tumor Necrosis Factor in Immune Control of the Rapid GrowerMycobacterium abscessusin C57BL/6 Mice

Abstract

Mycobacterium abscessus is an emerging rapidly growing mycobacterium that causes tuberculous-like lesions in humans. We studied the immune control of this organism in C57BL/6 mice challenged intravenously with 10 7 CFU. Bacteria were eliminated from both the spleen and the liver within 90 days, and liver histology showed organized granulomatous lesions. A T-and B-cell requirement was investigated by challenging Rag2 ؊/؊ , Cd3 ؊/؊ , and MT ؊/؊ mice. Rag2 ؊/؊ and Cd3 ؊/؊ mice were significantly impaired in the ability to clear M. abscessus from the liver and spleen, and MT ؊/؊ mice were significantly impaired in the ability to clear M. abscessus from the liver, suggesting that infection control was primarily T cell dependent in the spleen and both T and B cell dependent in the liver. The liver granulomatous response was similar to that of wild-type controls in MT ؊/؊ mice but completely absent in Cd3 ؊/؊ and Rag2 ؊/؊ mice. We studied the involvement of gamma interferon (IFN-␥) and tumor necrosis factor (TNF) by challenging C57BL/6 mice deficient in the IFN-␥ receptor (Ifngr1 ؊/؊ ) and in TNF (Tnf ؊/؊ ). Ifngr1 ؊/؊ mice were significantly impaired in M. abscessus control both in the spleen and in the liver, and granulomas were profoundly altered. The effect was even more substantial in Tnf ؊/؊ mice; they failed to control M. abscessus infection in the liver and died within 20 to 25 days after infection with many hepatic inflammatory foci and major lesions of ischemic necrosis in the liver and kidney. These features were not observed with the closely related species M. chelonae. T-cell immunity, IFN-␥, and TNF are central factors for the control of M. abscessus in C57BL/6 mice, as they are for the control of pathogenic slowly growing mycobacteria.Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) that has emerged as a significant pathogen in humans (6, 21) following its recent recognition as a species distinct from M. chelonae (36). M. abscessus is now recognized as the causative agent of a wide spectrum of human infections, including skin and soft tissue infections (6,21,54,57), lung infections in individuals with or without underlying disorders (e.g., cystic fibrosis) (26, 50), and infections or pseudoinfections related to contaminated medical devices (3,25,57). Disseminated infections have also been reported (11) for immunocompromised patients (organ transplantation, autoimmune disorders, malignancies) (6,28,48) and for subjects with a genetic defect in the interleukin-12 (IL-12)-gamma interferon (IFN-␥) signaling circuit (9). These life-threatening infections are therapeutically problematic because M. abscessus strains are resistant to most antibiotics (6).In light of clinical data, M. abscessus is now considered by many authors to be one of the most pathogenic RGM species (6). However, clear experimental evidence for its pathogenicity is poor; various studies using strains identified as M. fortuitum and M. abscessus showed that both species were lethal for mice following intravenous injection (35,...

Acute Respiratory Failure Involving an R Variant of Mycobacterium abscessus

“…M. abscessus may grow on solid medium, with S and R morphotypes recognized by the appearances of the colonies (2, 10). The role of S-R variation in the pathogenesis of M. abscessus is unclear, but R forms have increased virulence in murine models compared to S forms (2,3,10,11,18). The data in this report and other recent on May 11, 2018 by guest http://jcm.asm.org/ studies strongly suggest that the most severe forms of lung infection may be linked to the involvement of R variants of the bacterium (12).…”

“…Aspergillus infection is a statistically significant predictor for nontuberculous mycobacterium infection (13) and may also have created favorable conditions for the development of the M. abscessus R variant in our patient. R variants, which appear spontaneously at very low frequencies in vitro (range of 1 R variant in 10 5 to 1 R variant in 10 6 S cells) (11), thus seem to be selected in vivo, probably through interactions between the host and the bacterium involving the immune system (18). Systemic steroids and nonsteroidal anti-inflammatory drugs may trigger this process, as they have been associated previously with the occurrence of severe M. abscessus infections (4,14).…”

Clinical relevance ofMycobacterium malmoenseisolation in the Netherlands

“…M. malmoense, however, lacks this element [17]. To date, immunological studies have focused on M. avium and M. abscessus [18,19], rather than M. malmoense. Studies of M. malmoense pathogenesis and virulence in murine models are warranted, as are studies on the role of host genetic factors in M. malmoense disease.…”

The Antioxidant Mimetic, MnTE-2-PyP, Reduces Intracellular Growth of Mycobacterium abscessus

“…Little is known about how the host controls M. abscessus infection. A recent study implies that having a healthy adaptive immune system, adequate T cell immunity in particular, is required for controlling M. abscessus infection (4). The adequate production of IFN-g and TNF-a also appears to be crucial in containing M. abscessus infections (4,5).…”