Control of Mycobacterial Replication in Human Macrophages: Roles of Extracellular Signal-Regulated Kinases 1 and 2 and p38 Mitogen-Activated Protein Kinase Pathways

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Abstract
Intracellular persistence of mycobacteria may result from an intricate balance between bacterial replication and signaling events leading to antimicrobial macrophage activities. Using human monocyte-derived macrophages, we investigated the relevance of mitogen-activated protein kinase activation for the growth control ofMycobacterium aviumisolates differing in their abilities to multiply intracellularly. The highly replicative smooth transparent morphotype ofM. aviumstrain 2151 induced significantly less p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation than the smooth opaque morphotype of the same strain, which was gradually eliminated from macrophage cultures. Inhibition of the p38 pathway by highly specific inhibitors did not significantly affect mycobacterial replication within macrophages, regardless of the in vitro virulence of theM. aviumstrain. However, repression of the ERK1/2 pathway further enhanced intracellular growth of highly replicativeM. aviumstrains, although it did not increase survival of the poorly replicatingM. aviumisolate. Inhibition of the ERK1/2 pathway resulted in decreased tumor necrosis alpha (TNF-α) secretion irrespective of the virulence of theM. aviumisolate used for infection, revealing that TNF-α could have been only partially responsible for the control of intracellularM. aviumgrowth. In conclusion, ERK1/2- and TNF-α-independent pathways are sufficient to limit intramacrophage growth of less-virulentM. aviumstrains, but early ERK1/2 activation in infected macrophages is critically involved in controlling the growth of highly replicativeM. aviumstrains.