The Toll-like and IL-1 family receptors play critical roles in innate and adaptive immunity against intracellular pathogens. Although previous data demonstrated the importance of TLRs and IL-1R signaling events for the establishment of an effective immune response to mycobacteria, the possible function of the adaptor molecule IL-1R–associated kinase (IRAK)-4 against this pathogen has not been addressed. In this study, we determined the role of IRAK-4 in signaling pathways responsible for controlling mycobacterial infections. This kinase is important for the production of IL-12 and TNF-α by macrophages and dendritic cells exposed to mycobacteria. Moreover, Mycobacterium bovis–infected IRAK-4–knockout macrophages displayed impaired MAPK and NF-κB activation. IL-1β secretion and caspase-1 activation were also dependent on IRAK-4 signaling. Mice lacking IRAK-4 showed increased M. bovis burden in spleen, liver, and lungs and smaller liver granulomas during 60 d of infection compared with wild-type mice. Furthermore, 80% of IRAK-4−/− mice succumbed to virulent M. tuberculosis within 100 d following low-dose infection. This increased susceptibility to mycobacteria correlated with reduced IFN-γ/TNF-α recall responses by splenocytes, as well as fewer IL-12p70–producing APCs. Additionally, we observed that IRAK-4 is also important for the production of IFN-γ by CD4+ T cells from infected mice. Finally, THP-1 cells treated with an IRAK-4 inhibitor and exposed to M. bovis showed reduced TNF-α and IL-12, suggesting that the results found in mice can be extended to humans. In summary, these data demonstrate that IRAK-4 is essential for innate and adaptive immunity and necessary for efficient control of mycobacterial infections.
Surface and secreted mycobacterial proteins play a major role on the infection process by mediating macrophage-bacteria interactions as well as the fate of cell’s death. We have previously described a secreted 13-kDa lectin (sMTL-13) in Mycobacterium tuberculosis (Mtb), encoded by Rv1419 gene, and although a possible importance for this protein as a major mycobacterial antigen was shown in tuberculosis patients, the importance of such lectin during infection has not been formally addressed. We have generated an Rv1419 knockout Mtb (ΔRv1419) to investigate a possible role of this gene during infection. In silico analysis of the protein as well as its detection on Mtb surface suggest that sMTL-13 may participate during bacteria entry in the host macrophage. This was confirmed by binding experiments performed in either murine or human derived macrophages. In addition, lower levels of TNF were detected in ΔRv1419-infected cells, indicating that this lectin may be important for pathogen recognition. Importantly, ΔRv1419 displays higher intracellular growth than the WT bacteria. Thus, although binding of Mtb to macrophages is decreased in the absence of Rv1419 gene, cells exposed to the knockout Mtb display higher bacterial replication rate and cell death. These data suggest that sMTL-13 expressed on Mtb regulates macrophage entry and perhaps cell fate, which could serve as a pathogen survival strategy, allowing bacterial growth without leading host cells to a premature death.
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