Trehalose 6,6-Dimycolate from Mycobacterium tuberculosis Induces Hypercoagulation

Abstract

Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 μg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 μg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM-IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB.

Oral recombinant human or mouse lactoferrin reducesMycobacterium tuberculosisTDM induced granulomatous lung pathology

“…(Guidry et al 2006, 2007; Welsh et al 2010; McMullen et al 2013; Donnachie et al 2016). All cytokines analyzed for controls were at or below the level of detection for the assays and were no different from naive controls.…”

“…C57BL/6 mice injected with the oil-water vehicle demonstrated a slight increase in macrophages by comparison with the naïve controls, albeit approximately 2-fold lower compared with mice injected with TDM. All of the immune data for the control mice have been previously published (Donnachie et al 2016). …”

Mycobacterial trehalose 6,6′-dimycolate induced vascular occlusion is accompanied by subendothelial inflammation

“…To replicate the hypercoagulation model, TDM was first administered IP at 10 μg/mouse in Drakeol, followed by IV administration at 10 μg/mouse TDM in oil/water emulsion 15 . Overall, the LWI was significantly elevated at day 7 post TDM administration, albeit with higher variability in individual mice, in the TDP-IPIV Hypercoagulation model [ Figure 1].…”

“…Recently, Donnachie, et al, was successful at repeating the pathology induced by the earlier methodologies of Block and Noll, using purified TDM 15 . They comparatively assessed the different formats of TDM administration, and identified unique cytokine and histological profiles present in the original cord factor model that were not present in the model adapted for direct granulomatous response.…”

Endothelial lineage-specific interaction of Mycobacterium tuberculosis with the blood and lymphatic systems

“…TDM is another major glycolipid that is shown to interact with host macrophage inducible c-type lectin (Mincle). Thereby, TDM induces the secretion of pro-inflammatory cytokines such as IL-6, IL-12, and TNF-α and triggers the granuloma formation identified in mouse and rabbit models (43)(44)(45). Among these PAMPs, LAM is the major component that modulates the host immune system and allows Mtb to infect macrophages, dendritic cells (DCs), and endothelial cells (ECs) (25,(46)(47)(48)(49).…”