The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis

Abstract

The protein C (PC) system is an important regulator of both coagulation and inflammation. Activated PC (APC), together with its receptor the endothelial protein C receptor (EPCR), has anticoagulant and anti-inflammatory properties. During tuberculosis (TB), a devastating chronic pulmonary disease caused by Mycobacterium (M.) tuberculosis, both a local inflammatory reaction characterised by the recruitment of mainly mononuclear cells and the formation of pulmonary granulomas as well as activation of coagulation occurs as part of the host immune response. We investigated the role of EPCR and APC in a mouse model of TBusing mice overexpressing EPCR (Tie2-EPCR), mice deficient for EPCR (EPCR-/-), mice treated with APC-inhibiting antibodies and mice overexpressing APC (APChigh) and compared them with wild-type (WT) mice. Blood and organs were harvested to quantify bacterial loads, cellular influxes, cytokines, histopathology and coagulation parameters. Additionally observation studies were performed. Lung EPCR expression was upregulated during experimental TB. No significant differences in bacterial growth were seen between WT and Tie2-EPCR mice. However, Tie2-EPCR mice had decreased pulmonary coagulation activation, displayed an increased influx of macrophages 2 and 6 weeks after infection, but no increase in other proinflammatory markers. On the other hand, in EPCR-/--mice coagulation activation was decreased 6 weeks post-infection, with little impact on other inflammation markers. APC-overexpression or treatment with anti-(A)PC antibodies displayed minimal effects during experimental TB. In conclusion, EPCR and APC play a limited role in the host response during experimental pulmonary TB.

Role of Tissue Factor in Mycobacterium tuberculosis-Induced Inflammation and Disease Pathogenesis

“…Our present data suggesting that TF may not play a significant role in host-defense during experimental TB is consistent with a recent report [55] where the role of blood coagulation in the host-defense in TB was investigated utilizing the mouse model. Kager et al [55] found that overexpression or deficiency of endothelial cell protein C receptor (EPCR), a critical regulator of the protein C anticoagulant system, had no significant effect on M.tb growth, dissemination or inflammatory parameters. Additionally, overexpression of activated protein C (APC) or treatment with anti-APC antibodies had no significant impact on the inflammatory response induced by M.tb [55] .…”

“…Kager et al [55] found that overexpression or deficiency of endothelial cell protein C receptor (EPCR), a critical regulator of the protein C anticoagulant system, had no significant effect on M.tb growth, dissemination or inflammatory parameters. Additionally, overexpression of activated protein C (APC) or treatment with anti-APC antibodies had no significant impact on the inflammatory response induced by M.tb [55] . In an earlier study, the same group of investigators reported that mice with a mutation in thrombomodulin (TM) gene (TM pro/pro ), which reduces APC generation, showed uncontrolled lung inflammation, elevated levels of pro-inflammatory cytokines, and higher bacterial dissemination to liver and spleen [56] .…”

A lung image reconstruction from computed radiography images as a tool to tuberculosis treatment control

“…Pulmonary infection with M. tuberculosis is also associated with increased neopterin levels [13]. C-reactive protein (CRP) levels are directly related to disease activity [14, 15]. Higher proteins levels that are caused by inflammation elevate the erythrocyte sedimentation rate (ESR) [16, 17].…”