Endothelial cell tropism or endotheliotropism is a type of tissue tropism or host tropism that characterizes an pathogen's ability to recognize and infect an endothelial cell. Pathogens, such as viruses, can target a specific tissue type or multiple tissue types. Like other cells, the endothelial cell possesses several features that supports a productive viral infection a cell including, cell surface receptors, immune responses, and other virulence factors.[1] Endothelial cells are found in various tissue types such as in the capillaries, veins, and arteries in the human body. As endothelial cells line these blood vessels and critical networks that extend access to various human organ systems, the virus entry into these cells can be detrimental to virus spread across the host system and affect clinical course of disease. Understanding the mechanisms of how viruses attach, enter, and control endothelial functions and host responses inform infectious disease understanding and medical countermeasures.
There are a multitude of endothelial cell features that influence cell tropism and ultimately, contribute to endothelial cell activation and dysfunction as well as the continuation of the virus life cycle.
Viral pathogens capitalize on cell surface receptors that are ubiquitous and can recognize many diverse ligands for attachment and ultimately, entry into the cell. These ligands not only consist of endogenous proteins but also bacterial and viral products. Once the virus is anchored to the cell surface, virus uptake typically occurs using host mechanisms such as endocytosis.[2] [3] One method of viral uptake is through clathrin-mediated endocytosis (CME).[4] The cell surface receptors provide a binding pocket for attachment and entry into the cell, and therefore, affects a cell's susceptibility to infection. In addition, the receptor density on the surface of the endothelial cell also affects how efficiently the virus enters the host cell. For instance, a lower cell surface receptor density may render an endothelial cell less susceptible for virus infection than an endothelial with a higher cell surface receptor density. The endothelium contains a myriad of cell surface receptors associated with functions such as immune cell adherence and trafficking, blood clotting, vasodilation, and barrier permeability.[5] Given these vital functions, virus interactions with these receptors offers insight into the symptoms that present during viral pathogenesis such as inflammation, increased vascular permeability, and thrombosis.
After entry into the cell, these intracellular parasites require factors in the host cell to support viral replication and release of progeny virions. Specifically, the host factors include proteins, such as transcription factors and polymerases, which aid in replicating the viral genome. Therefore, the sole entry into a live host does not necessarily result in propagation for viral progeny as the cell may not contain the critical transcription factors or polymerases for virus replication. Furthermore, within the viral genome, there are not only instructions to synthesize viral proteins but also other virulence factors such as genes, cellular structures, and other regulatory processes that enable a pathogen to control the host's antiviral responses.[6] These virulence factors can counter the host defense mechanisms that attempt eliminate the infection via the host's immune system.
Endothelial cells also possess intrinsic antiviral responses which leverage the host's immune system to battle the infection or restrict viral replication.[7] [8] In response to the virus production in the cell, the host cell can release a protein such as cytokine like interferon (IFN) that will signal for an immune response. IFN "intereferes" with virus replication by signaling to other cells in our immune system stop the infection. Other cell mechanisms are also at the different subcellular levels. Specifically, there are cellular pattern recognition receptors such as TLR7 and TLR8 (detecting RNA) and TLR9 (detecting DNA).[9] These toll-like receptors which can distinguish if there are viral nucleic acids in the host cell and likewise, will trigger an immune response to flag the cell and attempt to eliminate the pathogen. The combination of these mechanisms that support successful virus entry, virus replication, and blocking of the host immune response contribute to a productive virus infection and replication.
SARS-CoV-2 is the virus that causes the disease COVID-19 and infects different cell types, but also has shown multi-organ vascular involvement. In severe cases, SARS-CoV-2 can cause endothelial dysfunction or injury. This virus-induced endothelial responses can lead to thrombosis, congestion, and microangiopathy.[10] The cell surface receptors associated with viral entry include ACE2 and co-receptor TMPRSS2. TMPRSS2 is needed to cleave the spike protein for viral fusion to cell membrane. However, a recent study has demonstrated that low expression of ACE2 in endothelial cells has been associated with poor ability for viral propagation due the lack of the entry points on the cell surface.[11]
Dengue is an example of a mosquito-borne flavivirus that causes Dengue fever. While endothelial cells are not the major cell type Dengue targets, the virus binds to various cell surface receptors on endothelial cells with particular productive infection via heparan sulfate-containing cell surface receptors.[12] The infection of the endothelium via these receptors have been indicated to impair critical immune responses and alter capillary permeability which in turn support the clinical course of the disease.[13]
Ebola is one viral hemorrhagic fever virus that causes Ebola Virus Disease (EVD). Analysis of human samples of nonsurvivors of the disease have shown that the endothelium is significantly changed from the healthy state.[14] [15] Other alterations from homeostasis include the widespread expression of viral antigens in endothelial cells.[16] The glycoprotein of the virus, which serves as the virus's "key" into the cell, has been indicated to majorly damage the endothelium. For instance, the liver has been highly implicated as an area of damage upon infection. Liver sinusoidal endothelial cells (LSEC) express a variety of scavenger receptors including FcγRIIb2 and mannose receptor which are critical in eliminating waste molecules in the liver but also engulf ligands via the CME pathway.[17] In addition to supporting entry of virus, the interactions to these receptors also may also hinder the clearance of pharmaceuticals given to mitigate the infection.
Influenza A H1N1 is a subtype of flu virus that targets and infects endothelial cells of the respiratory system, such as in the lung. The virus can also target the epithelium of the mucus membranes of these organ systems.[18] Virus particles tend to exit from the lumen of the endothelium, leading to viral antigens found in the blood and lymphatic endothelial cells. However, as this virus spreads, it will be targeted to endothelial cells in lung but not in the brain, for instance.