M tuberculosis Disrupts Regulatory Macrophage Pathways Driving Immunopathology

A recent study published in PLoS Pathogens found that Mycobacterium tuberculosis disrupts negative regulatory pathways in human macrophages, facilitating tissue destruction.1 The study also demonstrated, for the first time, the role of the mitogen-activated protein kinase-interacting protein kinase pathway in matrix metalloproteinase-1 secretion.

Investigators from Australia and the United Kingdom hypothesized that M tuberculosis specifically targets the negative regulatory pathways in macrophages to exacerbate tissue destruction and facilitate transmission. 

“We found that specific pathways limit the expression of matrix metalloproteinases in macrophages that cause lung destruction in tuberculosis,” said Paul Elkington, MA, BM, BCh, FRCP, PhD, professor of respiratory medicine at the Faculty of Medicine, University of Southampton, United Kingdom, in an email interview with Infectious Disease Advisor. 

“Surprisingly, we were unable to identify expression of the signaling molecules in patient samples, and went on to show that the infection reduced expression of negative regulatory pathways in macrophages via induction of microRNAs,” he added.

Specifically, the investigators found that M tuberculosis infection upregulated multiple microRNAs, including miR27a, miR125b, and miR199, that target the negative regulatory pathways. This, in turn, led to excessive production of proteases and tissue destruction. 

With death rates higher than any other infectious disease and high transmission rates in high-incidence regions, tuberculosis remains a serious public health problem.2 Thus, gaining a better understanding of the mechanisms involved in the immunopathology of M tuberculosis is one of the goals of the medical research community studying this pathogen.

“Our findings demonstrate another mechanism whereby M tuberculosis subverts host cellular signaling to increase its chances of transmission,” emphasized Dr Elkington. “This may help identify signaling targets that may be manipulated to reduce lung destruction in patients, but equally importantly, we need to ensure we do not inadvertently suppress the regulatory pathways and thereby increase pathology.”

Dr Elkington further noted that his team’s latest findings may be useful in informing “host-directed therapies that aim to limit immune-mediated tissue damage.” The question that remains to be answered is “whether this is a specific phenomenon to tuberculosis or a more generic inflammatory response to infection, and therefore relevant to other conditions such as sepsis.”

Human samples used in the study were obtained from the Southampton Research Biorepository, University Hospital Southampton NHS Foundation Trust and University of Southampton, United Kingdom. Blood samples used for isolation of peripheral blood mononuclear cells were obtained from healthy donors or from single donor leukocyte cones; lung biopsy tissue was collected during routine clinical exams. 

References

1. Bruce PT, Tezera LB, Bielecka MK, et al. Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology. PLoS Pathog. 2017;13(6):e1006367. do: 10.1371/journal.ppat.1006367
2. Wallis RS, Maeurer M, Mwaba P, et al. Tuberculosis – advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers. Lancet Infect Dis. 2016;16(4):e34-46.