Using freshly resected lung tissue from 21 patients and two distinct mouse models, tuberculosis researchers have identified a protein that plays an essential role in host defense against this deadly disease.
The researchers were able to separate different types of cells found in distinct niches of human freshly resected TB lungs and characterize those cells for production of the protein heme oxygenase-1. Heme oxygenase-1, or HO-1, is an enzyme that protects cells from harmful reactive oxygen or nitrogen intermediates; HO-1 also is able to control inflammatory responses.
The researchers found that HO-1 in human TB lungs was expressed primarily by myeloid immune cells, including neutrophils and macrophages, and that HO-1 levels in these cells were directly proportional to protection against TB pathophysiology.
Specifically, there was a greater percentage of HO-1-producing neutrophils and macrophages in uninfected areas of the lung than in diseased areas, and those cells in uninfected areas produced more HO-1 than the cells in diseased areas. As a consequence, the lack of HO-1 protection in diseased areas allowed myeloid cell-production of destructive reactive oxygen and nitrogen species. What makes these findings clinically relevant is that HO-1 is essential in humans but not in mice, which points to the importance of examining human TB lung tissue to complement animal models for TB.
This finding in humans was supported by two HO-1 deficient mouse models that showed HO-1 is necessary to control myeloid cell infiltration and inflammation to protect against TB progression. One mouse model was a global knockout of the HO-1 gene; the other model was an HO-1 knockout in myeloid cells only. In both models, knockout mice had more susceptibility to Mtb infection -- the knockout mice died sooner and had higher loads of Mtb in their lungs and spleens. The knockout mice also had increased infiltration of immune cells and levels of cytokines, the cell-signaling proteins that regulate or stimulate immune responses.
Overall, the findings from human lungs and the mouse models showed that expression of HO-1, especially within myeloid cells, appears to be essential for host defense against Mtb disease progression. For human TB patients, the senior author says, the research suggests that finding a way to upregulate HO-1 activity might limit immunopathology during active TB disease. This research was published in the journal Cell Reports.
An immune cell enzyme in the defense against tuberculosis
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