Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections

Abstract

Summary Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

“…These regions of high proinflammatory signatures are required for an early control of bacterial replication and could lead to necrotic damage (caseation) and consequent cavity formation if not appropriately regulated. 30 Evidently, PKCd was more abundant in the caseous and cavitary regions in this study, colocalizing with antimicrobial signatures 21 and the regions of abundant lipids in granulomas. 31 However, it is not clear whether mediators of inflammation and antimicrobials are responsible for the overwhelming inflammation at the site of infection, or they are remnants of a robust immune response meant to eliminate the pathogen in the lung.…”

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

“…Increasing evidence from human and animal models of Mtb indicates excessive inflammation or highly activated populations of CD4 Th1 cells exacerbates TB disease and promotes immunopathology (33)(34)(35)(36), thus underscoring the critical need for a balanced regulatory and effector T-cell response for optimal control of bacterial replication while simultaneously limiting effector cell-mediated tissue damage. PD-1 was transiently expressed at high levels on M72-specific CD4 T cells 7 days after each vaccination, consistent with transient PD-1 expression on virus-specific CD8 T cells in previous studies in humans vaccinated with either YFV or smallpox vaccines (21,37).…”

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…Finally, since immune impairment is usually observed in patients with chronic infections, and given that the STAT3 activity grants a tolerance capacity to the myeloid compartment [36], we estimate that short-term blockade of STAT3 within the monocyte-to-macrophage differentiation program has the potential to modulate mechanisms of disease tolerance and restore the antimicrobial immunity. STAT3 inhibitors, currently assessed in phase I clinical trials for their antitumor effects [74,75], might be particularly useful in patients with TB meningitis, for example, who fail to control mycobacterial proliferation because of intrinsic exacerbation of immune suppression, and in which dexamethasone treatment has deleterious effects [76].…”