The dynamics of infection

Researchers uncover the mechanism by which cytokine controls replication of bacteria in the Mycobacterium avium complex inside host cells

By Fábio de Castro

Agência FAPESP – Transforming growth factor beta (TGF-β) has been implicated in the pathogenesis of several illnesses including opportunistic infections caused by the Mycobacterium avium complex (MAC), which affect people with compromised immunological systems, like AIDS patients.

The mechanism by which TGF-β controls replication of MAC bacteria is more intricate, however, than originally thought, according to a study conducted by group of researchers at the Universidade Federal de São Paulo (Unifesp).

The study published by PLoS One is part of Carolina L’Abbate’s doctoral research, under the orientation of Joel Machado Junior and Celia Regina Whitaker Carneiro, respectively professors at Unifesp’s Biological Sciences Department, and the Microbiology, Immunobiology and Parasitology Department.

The study was conducted under the auspices of the FAPESP-funded Thematic Project “Mycobacteria of medical significance in Brazil: molecular characterization, interaction with the environment and with macrophages,” coordinated by Sylvia Luisa Pincherle Cardoso Leão and boasting Carneiro among the principal investigators. The article also had contributions from Elizabeth Cristina Pérez-Hurtado and Ivone Cipriano.

By uncovering the TGF-β’s significant control mechanism for replication of Mycobacterium avium Complex bacteria, the study helps “to understand how the enemy’s weapons work,” according to Machado Junior. 

“The study offers new prospects for comprehension of TGF-β influence on the host’s response. The better we understand the mechanisms by which these bacteria subvert host response, the greater the prospects for designing more efficient therapeutic interventions for treatment of these infections,” Machado commented to Agência FAPESP.

According to him, several pathogens that infect macrophages, including Toxoplasma gondii, Leishmania amazonensis, Trypanossoma cruzi and MAC bacteria, develop mechanisms capable of inducing TGF-β production, which is a cytokine – a group of molecules involved in intercellular communication during the triggering of immune response.

“It was believed that TGF-β function was only related to its immunosuppressive capacity on macrophage activity, allowing for proliferation of pathogens within the cell. This study shows, however, that the mechanism is more complex and the effects of this cytokine are not so direct,” he said.  

The study showed that TGF-β’s effect is largely dependent on the amplitude of the action. Cytokine coordinates the magnitude and the duration of the activation of kinase – enzymes that catalyze protein phosphorylation reactions – the ERK ½, and in this manner control replication of the bacteria. “The effects depend on the quantity of cytokine present in the infected macrophage and which signaling paths it is coordinating in the infected cell,” explained Machado.  

According to him, the literature had already indicated that infected macrophages produced a greater quantity of cytokine and with this favored the growth of bacteria within the cell. Unifesp scientists utilized a differentiated macrophage differentiation process induced by IL-4 overlap, which produce larger amounts of TGF-β, maintaining high levels of ERK ½ levels.

“But in the model, the effect was opposite:  TGF-β action on ERK ½ inhibited replication of bacteria inside cells. This suggests that this mechanism could be a strategy to keep intercellular replication of pathogens under control,” he explains.


The intercellular signaling pathways are significant parts of biological systems, which allow cells to modify their behavior in response to environmental changes like infection. “These pathways convert external signals and generate the appropriate response for changes in the external environment. This response includes changes in the regulation of metabolic processes and gene expression. All this is determined by the amplitude and type of signal that is generated by stimulation. The TGF-β  would therefore function as a dynamic arsenal for additional control of pathogens,” says Machado.

The article “TGF-β-Mediated Sustained ERK1/2 Activity Promotes the Inhibition of Intracellular Growth of Mycobacterium avium in Epithelioid Cells Surrogates” (doi:10.1371/journal.pone.0021465), by Carolina L’Abbate et al., can be read at www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0021465.