Pathogen interactions with endothelial cells and the induction of innate and adaptive immunity

Abstract

There are over 10 trillion endothelial cells (EC) that line the vasculature of the human body. These cells not only have specialized functions in the maintenance of homeostasis within the circulation and various tissues but they also have a major role in immune function. EC also represent an important replicative niche for a subset of viral, bacterial, and parasitic organisms that are present in the blood or lymph; however, there are major gaps in our knowledge regarding how pathogens interact with EC and how this influences disease outcome. In this article, we review the literature on EC-pathogen interactions and their role in innate and adaptive mechanisms of resistance to infection and highlight opportunities to address prominent knowledge gaps.

Keywords: Endothelial cells; Host/pathogens interactions; Immune responses; Infectious diseases.

Figure 1:. EC functions associated with homeostasis and resistance to infection.

(A) In steady state EC have mechanisms that act to prevent inflammation through their ability to produce prostaglandin I₂, which together with the constitutive expression of endothelial nitric oxide synthase (eNOS), antagonizes cytokine mediated upregulation of adhesion molecules. Basal expression of tissue factor pathway inhibitors (TFPIs) block the initiation of the coagulation cascade and inhibit platelet adhesion and aggregation. (B) EC contain Weibel–Palade bodies (WPB), which are cytoplasmic storage vesicles that contain von Willebrand factor (vWF) and P-selectin, in response to vascular injury, complement activation via the C1qRs and C5aR, EC release von Willebrand factor that supports the local recruitment of platelets and coagulation to prevent blood loss. EC damage can also promotes expression of adhesion molecules. (C) EC express cytokine receptors (eg IFN-γR and TNFR) and many classes of PRRs (e.g. TLR2, TLR4, TLR9, RIG-1, and STING) relevant to bacterial and viral infection, which allow EC to respond to infection by the activation of NF-κB and MAPK. Further, EC activation by pathogen leads to the up-regulation of adhesion molecules such as ICAM1, VCAM1, Selectins and CX3CL1, and the release of chemokines and pro-inflammatory cytokines such as IL-1/6/8, MCP, and CXCL9/10/11. (D) EC activation by IFN-γ, TNF-α or Type I IFNs induce a number of mechanisms that can restrict the growth of micro-organisms. IFN-γ and TNF-α activate EC to upregulate indoleamine 2,3-dioxygenase (IDO) leading to tryptophan degradation and starvation of T. gondii, S. aureus and Rickettsia. Moreover, EC production of nitric oxide (NO) inhibits microbial growth of Rickettsia and M. tuberculosis. Further, Type I IFNs induced expression of interferon-stimulated genes (ISG) inhibit viral replication during HCMV infection.

Figure 2:. EC-pathogen interactions that lead to disease.

(A) Infection of the endothelium by Bartonella sp. and Kaposi sarcoma–associated herpesvirus (KSHV) are associated with the influx of monocytes/lymphocytes that secrete pro-angiogenic factors that can lead to vaso-proliferation and the formation of vascular tumors. (B) For N. meningitidis, the adhesion of the meningococci to EC is accompanied by host cell cytoskeletal modifications and the formation of microvilli-like protrusions; these changes are associated with increased coagulation in small blood vessels. Plasmodium matures in erythrocytes and within these cells can adhere to EC. These events provoke localized inflammation within the capillaries and can lead to cerebral malaria. (C) For Human cytomegalovirus (HCMV), Dengue virus (DV), Nipah, Ebola and West Nile Virus there may be a viral tropism for EC and this viral presence is associated with a number of pathological symptoms; for some of these pathogens, this might allow their access to the CNS. (D) EC can serve as an important replicative niche for a subset of bacterial, parasitic and fungal pathogens. The infection of, replication in and lysis of EC can be critical for pathogen access to tissues like the CNS.