Endothelial cell tropism

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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.

Contents

Cellular features and mechanisms

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.

Cell surface receptors

Virus Life Cycle (Simplified for RNA Viruses). Upon attaching to the cell surface, virus entry occurs via binding cell surface receptor and via endocytosis. The virus utilizes host proteins and other cell machinery to replicate. Once the viral genome has been replicated, the progeny virions are assembled and released out of the cell. Viral Replication Cycle.svg
Virus Life Cycle (Simplified for RNA Viruses). Upon attaching to the cell surface, virus entry occurs via binding cell surface receptor and via endocytosis. The virus utilizes host proteins and other cell machinery to replicate. Once the viral genome has been replicated, the progeny virions are assembled and released out of the cell.

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.

Comparison of Healthy vs. Dysfunctional Vascular Endothelium. Characteristics of endothelium at (1) homestasis and (2) damaged upon infection. Viruses-13-00029-g001.webp
Comparison of Healthy vs. Dysfunctional Vascular Endothelium. Characteristics of endothelium at (1) homestasis and (2) damaged upon infection.

Transcription Factors & Viral Replication

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. [7] 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. [8] These virulence factors can counter the host defense mechanisms that attempt eliminate the infection via the host's immune system.

Host defense mechanisms

Endothelial cells also possess intrinsic antiviral responses which leverage the host's immune system to battle the infection or restrict viral replication. [9] [10] 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). [11] 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.

Examples and effects on viral pathogenesis

Coronaviruses

Transmission and Virus Replication Cycle of SARS-CoV-2. ACE2 is the notable entry point of SARS-CoV-2 into cells. Fphar-11-00937-g001.jpg
Transmission and Virus Replication Cycle of SARS-CoV-2. ACE2 is the notable entry point of SARS-CoV-2 into cells.

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. [12] 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. [13]

Flaviviruses

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. [14] 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. [15]

Filoviruses

Influenza Virus Replication Life Cycle. Anti-influenza drugs target various stages of this cycle. Viruses-12-00504-g002.webp
Influenza Virus Replication Life Cycle. Anti-influenza drugs target various stages of this cycle.

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. [16] [17] Other alterations from homeostasis include the widespread expression of viral antigens in endothelial cells. [18] The glycoprotein of the virus, which serves as the virus's "key" into the cell, has been indicated to majorly damage the endothelium. [16] 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. [19] 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.

Orthomyxoviridae

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. [20] 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.

Applications

ACE2 Staining in HeLa Cells. Image adapted from: Zhou, P., Yang, XL., Wang, XG. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Credit: Nature 579, 270-273 (2020). https://doi.org/10.1038/s41586-020-2012-7 ACE2 SARS-COV-2 in HeLa CELLS.png
ACE2 Staining in HeLa Cells. Image adapted from: Zhou, P., Yang, XL., Wang, XG. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Credit: Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7

Technologies of study

Virus Pseudotyping. Viral vectors can be inserted into the genome of surrogate viruses such as Vesicular Stomatitis Virus (VSV) and Lentiviruses (LV). Pseudotyped viruses are used in in vitro or in vivo studies. Pseudotyping.jpg
Virus Pseudotyping. Viral vectors can be inserted into the genome of surrogate viruses such as Vesicular Stomatitis Virus (VSV) and Lentiviruses (LV). Pseudotyped viruses are used in in vitro or in vivo studies.

Depending on the biosafety level (BSL) also known as the pathogen or protection level, there are different levels of biocontainment and approvals required to study the pathogen; this protection level affects how and where the pathogen is studied. [21] While these summarizes focus on endothelial cell tropism, these techniques also apply broadly to various methods in virology. These summaries do not provide comprehensive list but are representative of common platforms to study emerging infectious diseases.

In vitro approaches

Immortalized cells offer a renewable resource to study variety of pathogens. The characterization of the endothelial tropism allows researchers to modify either the cell to display the receptor that the virus's glycoprotein interacts with to attach to the cell. However, these 2D cell cultures are not necessarily intended to mimic viral propagation or host responses in vivo . These formats of bioassays allow for investigation of virus and potentially identification of cell surface receptors or other factors involved in cell tropism. Commonly, molecular biology methods such as, immunofluorescence or immunohistochemistry, enables researchers to visualize where receptor is present on the cell. Conversely, using a surrogate or pseudotyped virus, is also a method of understanding cell tropism. In brief, these approaches typically take a different and well-characterized pathogen such as Vesicular Stomatitis Virus (VSV) and modify it so that it displays the glycoprotein of another virus of interest. [22] As the glycoprotein serves as the "key" into the cell, this method allows study of entry into the cell independent of the other processes in the virus life cycle. The further growing or serial passaging of this recombinant virus can demonstrate how the virus evolves or mutates to support infection efficiency.

In vivo models of infection

Rhesus Macaque Monkey. The macaque monkeys come in various species. Model of infections include these captive nonhuman primates. Rhesus macaque monkey D72 16856k 01.jpg
Rhesus Macaque Monkey. The macaque monkeys come in various species. Model of infections include these captive nonhuman primates.

Nonhuman primates such as rhesus macaques serve as the "gold standard" approach for animal models for many BSL4 pathogens when the biological phenomenon cannot be studied in other species. [23] As many infectious diseases are zoonotic in nature, modeling these diseases in these macaque species which have some biological similarities to humans provide insight into disease understanding in circumstances which a virus is poorly understood and treatment options are limited or nonexistent. The readouts of these models can be evaluated through tissue samples or blood samples, for instance. However, these in vivo models of infection such as rodent and nonhuman primate models have presented ethical concerns and shortcomings as it involves laboratory confinement of an animal and introducing to it a disease insult. [24] The emergence of advanced in vivo including humanized or transgenic rodent models provide an alternative to the macaque series but also harbor concerns if these models recapitulate human physiology or are predictive of human-like responses to a disease or therapeutic. These models involve genetically modifying and/or transplanting human tissue into a rodent model. [25] In conjunction to in vitro cell-based assays, these in vivo models are critical to validate therapeutics during drug discovery and development.

Drug discovery and development

Endothelial cell tropism informs medical countermeasures in response to an emerging infectious diseases. These medical countermeasures include how therapeutics such as small molecules compounds and vaccines are developed.

Antivirals and other small molecule drugs

Antiviral drugs are therapeutics which aid the human body to eliminate an infection, mitigate symptoms of the infection, and/or decrease the clinical course of disease. The understanding of endothelial cell tropism introduces is used in discovery of antiviral drug targets. Many mechanisms of actions of these therapeutics first target the virus life cycle. [26] These drugs come in the form of small molecule compounds or other biotherapeutics (e.g., monoclonal antibody therapies). In cell-based, high-throughput drug screening, cell tropism is an important consideration during cell type selection. The cell type in these assays should display the targeted receptor to representatively validate the drug's proposed mechanism of action and determine its potency, safety, and efficacy in vitro. [27] Furthermore, other aspects of endothelial cell tropism lend themselves to therapeutic approaches. These aspects includes the diverse mechanisms of how endothelial cells detect viruses and respond to infection. For instance, the endothelial barrier serves as both as a protective barrier and mediator for immune responses against foreign bodies. However, the endothelial barrier is subjected to damage as a result of viral infection. Therapeutics that enhance or regain the integrity endothelial barrier after it has been damaged have been considered as potential targets for emerging infectious diseases like COVID-19, Ebola, Dengue fever, and more. [1] [28] Altogether, the investigation of endothelial cells tropism can provide insight into appropriate therapeutic interventions.

Table 1. Examples of Antiviral Therapeutics Targeting Endothelial Functions & the Virus Life Cycle
GroupDrug(s)Mechanism of ActionReferences
Viral Entry Inhibitors Maraviroc

Inmazeb

Blocks receptor engagement, endocytosis/macropinocytosis, attachment, fusion or signaling involved uptake of the virus [26] [29] [30]
Viral Protein Synthesis Inhibitors Lopinavir/ritonavir Suppresses or slows virus replication by disrupting processes involved in translation or generation of protein [31]
Viral Polymerase Inhibitors Molnupiravir Interferes with regulation of transcription of viral proteins during viral replication [32]
Immunomodulators Nitazoxanide Interfere and counter with host regulated pathways during viral replication (e.g., IFN pathways and mechanism of viral RNA sensing) [26] [33]

Vaccines

Vaccines are therapeutics that are preventative measure to infectious diseases. These therapeutics offer the body adaptive immunity to a specific pathogen. Fundamentally, vaccines provide patients protection by eliciting an immune response so that they develop antibodies that will help protect against the invading pathogen. The development, production, and global distribution of these vaccines is imperative to prevent, control, and eradicate pandemic potential pathogens. Specifically, cell cultured-based vaccine technologies utilize cell lines that have a wide range of viral tropism to adapt virus strains used in the development of vaccines to new cells. [34] This application of cell tropism evaluates the diverse viral entry pathways and host receptors to accomplish this goal. Moreover, the aspects endothelial cell activation and dysfunction become important readouts during vaccine development as they are part the hallmarks of many clinical courses of infectious diseases. One of the most promising vaccine candidates for Ebola is Merck's recombinant VSV-EBOV vaccine, Ervebo. The vaccine was critical during the end of 2014/2015 Ebola outbreak in Guinea. Ervebo was shown to be effective in nonhuman primate and later in Guinea during the authorized human efficacy trial which showed that Ervebo was also highly protective in humans. The vaccine employs VSV as the surrogate to display the Ebola glycoprotein. [35] VSV does not cause disease in humans which renders it a useful backbone to hold an important protein of Zaire Ebola virus. When the vaccine is administered, the recombinant VSV introduces a functional Ebola virus glycoprotein which interacts with endothelial cell barrier and elicit a rapid immune response without causing disease in patients. Therefore, the development and scaling of vaccines involves important considerations to endothelial cell tropism.

Related Research Articles

<i>Henipavirus</i> Genus of RNA viruses

Henipavirus is a genus of negative-strand RNA viruses in the family Paramyxoviridae, order Mononegavirales containing six established species, and numerous others still under study. Henipaviruses are naturally harboured by several species of small mammals, notably pteropid fruit bats, microbats of several species, and shrews. Henipaviruses are characterised by long genomes and a wide host range. Their recent emergence as zoonotic pathogens capable of causing illness and death in domestic animals and humans is a cause of concern.

<i>Indiana vesiculovirus</i> Species of virus

Indiana vesiculovirus, formerly Vesicular stomatitis Indiana virus is a virus in the family Rhabdoviridae; the well-known Rabies lyssavirus belongs to the same family. VSIV can infect insects, cattle, horses and pigs. It has particular importance to farmers in certain regions of the world where it infects cattle. This is because its clinical presentation is identical to the very important foot and mouth disease virus.

<i>Lassa mammarenavirus</i> Type of viral hemorrhagic fever

Lassa mammarenavirus (LASV) is an arenavirus that causes Lassa hemorrhagic fever, a type of viral hemorrhagic fever (VHF), in humans and other primates. Lassa mammarenavirus is an emerging virus and a select agent, requiring Biosafety Level 4-equivalent containment. It is endemic in West African countries, especially Sierra Leone, the Republic of Guinea, Nigeria, and Liberia, where the annual incidence of infection is between 300,000 and 500,000 cases, resulting in 5,000 deaths per year.

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

<span class="mw-page-title-main">DC-SIGN</span> Protein-coding gene in the species Homo sapiens

DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene.

<i>Herpesviridae</i> Family of DNA viruses

Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν, referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.

<i>Pestivirus</i> Genus of viruses

Pestivirus is a genus of viruses, in the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae and the family Suidae. There are 11 species in this genus. Diseases associated with this genus include: hemorrhagic syndromes, abortion, and fatal mucosal disease.

<span class="mw-page-title-main">Viral envelope</span> Outermost layer of many types of the infectious agent

A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. A viral envelope protein or E protein is a protein in the envelope, which may be acquired by the capsid from an infected host cell.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

<span class="mw-page-title-main">Viral entry</span> Earliest stage of infection in the viral life cycle

Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, there are several shared generalities concerning viral entry.

Tissue tropism is the range of cells and tissues of a host that support growth of a particular pathogen, such as a virus, bacterium or parasite.

Host tropism is the infection specificity of certain pathogens to particular hosts and host tissues. This explains why most pathogens are only capable of infecting a limited range of host organisms.

<span class="mw-page-title-main">Antibody-dependent enhancement</span> Antibodies rarely making an infection worse instead of better

Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV virus and Dengue virus and is monitored for in vaccine development.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

Pseudotyping is the process of producing viruses or viral vectors in combination with foreign viral envelope proteins. The result is a pseudotyped virus particle, also called a pseudovirus. With this method, the foreign viral envelope proteins can be used to alter host tropism or increase or decrease the stability of the virus particles. Pseudotyped particles do not carry the genetic material to produce additional viral envelope proteins, so the phenotypic changes cannot be passed on to progeny viral particles. In some cases, the inability to produce viral envelope proteins renders the pseudovirus replication incompetent. In this way, the properties of dangerous viruses can be studied in a lower risk setting.

<i>Zaire ebolavirus</i> Species of virus affecting humans and animals

Zaire ebolavirus, more commonly known as Ebola virus, is one of six known species within the genus Ebolavirus. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD). Ebola virus has caused the majority of human deaths from EVD, and was the cause of the 2013–2016 epidemic in western Africa, which resulted in at least 28,646 suspected cases and 11,323 confirmed deaths.

Polioencephalitis is a viral infection of the brain, causing inflammation within the grey matter of the brain stem. The virus has an affinity for neuronal cell bodies and has been found to affect mostly the midbrain, pons, medulla and cerebellum of most infected patients. The infection can reach up through the thalamus and hypothalamus and possibly reach the cerebral hemispheres. The infection is caused by the poliomyelitis virus which is a single-stranded, positive sense RNA virus surrounded by a non-enveloped capsid. Humans are the only known natural hosts of this virus. The disease has been eliminated from the U.S. since the mid-twentieth century, but is still found in certain areas of the world such as Africa.

Ghanaian bat henipavirus (also known Kumasi virus belongs to the genus Henipavirus in the family Paramyxoviridae. Human infections are caused by zoonotic events where the virus crosses over from another animal species. Therefore, humans are not the innate host for this virus family but instead become infected by peripheral viral reservoirs such as bats and other carriers of the virus. When these virus are spread to humans through zoonotic events they have been found to be one of the most deadly viruses with the capability to infect humans, with mortality rates between 50 and 100%. Therefore, these viruses have been classified as a biosafety level four virus with regards to its pathogenesis when it infects humans.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

  1. 1 2 Fosse, Johanna Hol; Haraldsen, Guttorm; Falk, Knut; Edelmann, Reidunn (2021). "Endothelial Cells in Emerging Viral Infections". Frontiers in Cardiovascular Medicine. 8: 95. doi: 10.3389/fcvm.2021.619690 . ISSN   2297-055X. PMC   7943456 . PMID   33718448.
  2. ↑ McMahon, Harvey T.; Boucrot, Emmanuel (August 2011). "Molecular mechanism and physiological functions of clathrin-mediated endocytosis". Nature Reviews Molecular Cell Biology. 12 (8): 517–533. doi:10.1038/nrm3151. ISSN   1471-0080. PMID   21779028. S2CID   15235357.
  3. ↑ Kaksonen, Marko; Roux, Aurélien (May 2018). "Mechanisms of clathrin-mediated endocytosis". Nature Reviews Molecular Cell Biology. 19 (5): 313–326. doi:10.1038/nrm.2017.132. ISSN   1471-0080. PMID   29410531. S2CID   4380108.
  4. ↑ Cossart, Pascale; Helenius, Ari (2014-08-01). "Endocytosis of Viruses and Bacteria". Cold Spring Harbor Perspectives in Biology. 6 (8): a016972. doi:10.1101/cshperspect.a016972. ISSN   1943-0264. PMC   4107984 . PMID   25085912.
  5. ↑ Yuan, Sarah Y.; Rigor, Robert R. (2010). Signaling Mechanisms in the Regulation of Endothelial Permeability. Morgan & Claypool Life Sciences.
  6. ↑ Bernard, Isabelle; Limonta, Daniel; Mahal, Lara; Hobman, Tom (26 December 2020). "Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19". Viruses. 13 (1): 29. doi: 10.3390/v13010029 . PMC   7823949 . PMID   33375371.
  7. ↑ Fenner, Frank; Bachmann, Peter A.; Gibbs, E. Paul J.; Murphy, Frederick A.; Studdert, Michael J.; White, David O. (1987), Fenner, Frank; Bachmann, Peter A.; Gibbs, E. Paul J.; Murphy, Frederick A. (eds.), "Chapter 4 – Viral Replication", Veterinary Virology, Academic Press, pp. 55–88, ISBN   978-0122530555
  8. ↑ Baggen, Jim; Vanstreels, Els; Jansen, Sander; Daelemans, Dirk (October 2021). "Cellular host factors for SARS-CoV-2 infection". Nature Microbiology. 6 (10): 1219–1232. doi: 10.1038/s41564-021-00958-0 . ISSN   2058-5276. PMID   34471255. S2CID   237387636.
  9. ↑ McFadden, Grant; Mohamed, Mohamed R.; Rahman, Masmudur M.; Bartee, Eric (September 2009). "Cytokine determinants of viral tropism". Nature Reviews Immunology. 9 (9): 645–655. doi:10.1038/nri2623. ISSN   1474-1741. PMC   4373421 . PMID   19696766.
  10. ↑ Majdoul, Saliha; Compton, Alex A. (2021-10-13). "Lessons in self-defence: inhibition of virus entry by intrinsic immunity". Nature Reviews Immunology. 22 (6): 339–352. doi:10.1038/s41577-021-00626-8. ISSN   1474-1741. PMC   8511856 . PMID   34646033.
  11. ↑ Pandey, Surya; Kawai, Taro; Akira, Shizuo (2015-01-01). "Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors". Cold Spring Harbor Perspectives in Biology. 7 (1): a016246. doi:10.1101/cshperspect.a016246. ISSN   1943-0264. PMC   4292165 . PMID   25301932.
  12. ↑ Jin, Yuefei; Ji, Wangquan; Yang, Haiyan; Chen, Shuaiyin; Zhang, Weiguo; Duan, Guangcai (2020-12-24). "Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches". Signal Transduction and Targeted Therapy. 5 (1): 293. doi:10.1038/s41392-020-00454-7. ISSN   2059-3635. PMC   7758411 . PMID   33361764.
  13. ↑ Schimmel, Lilian; Chew, Keng Yih; Stocks, Claudia J.; Yordanov, Teodor E.; Essebier, Patricia; Kulasinghe, Arutha; Monkman, James; Miggiolaro, Anna Flavia Ribeiro dos Santos; Cooper, Caroline; Noronha, Lucia de; Schroder, Kate (2021). "Endothelial cells are not productively infected by SARS-CoV-2". Clinical & Translational Immunology. 10 (10): e1350. doi:10.1002/cti2.1350. ISSN   2050-0068. PMC   8542944 . PMID   34721846.
  14. ↑ Neufeldt, Christopher J.; Cortese, Mirko; Acosta, Eliana G.; Bartenschlager, Ralf (March 2018). "Rewiring cellular networks by members of the Flaviviridae family". Nature Reviews Microbiology. 16 (3): 125–142. doi:10.1038/nrmicro.2017.170. ISSN   1740-1534. PMC   7097628 . PMID   29430005.
  15. ↑ Basu, Atanu; Chaturvedi, Umesh C. (August 2008). "Vascular endothelium: the battlefield of dengue viruses". FEMS Immunology & Medical Microbiology. 53 (3): 287–299. doi:10.1111/j.1574-695x.2008.00420.x. ISSN   0928-8244. PMC   7110366 . PMID   18522648.
  16. 1 2 Falasca, L.; Agrati, C.; Petrosillo, N.; Di Caro, A.; Capobianchi, M. R.; Ippolito, G.; Piacentini, M. (August 2015). "Molecular mechanisms of Ebola virus pathogenesis: focus on cell death". Cell Death & Differentiation. 22 (8): 1250–1259. doi:10.1038/cdd.2015.67. ISSN   1476-5403. PMC   4495366 . PMID   26024394.
  17. ↑ Wahl-Jensen, Victoria M.; Afanasieva, Tatiana A.; Seebach, Jochen; Ströher, Ute; Feldmann, Heinz; Schnittler, Hans-Joachim (August 2005). "Effects of Ebola Virus Glycoproteins on Endothelial Cell Activation and Barrier Function". Journal of Virology. 79 (16): 10442–10450. doi:10.1128/JVI.79.16.10442-10450.2005. ISSN   0022-538X. PMC   1182673 . PMID   16051836.
  18. ↑ Jain, Sahil; Khaiboullina, Svetlana F.; Baranwal, Manoj (2020-10-17). "Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease". Pathogens (Basel, Switzerland). 9 (10): E850. doi: 10.3390/pathogens9100850 . ISSN   2076-0817. PMC   7603231 . PMID   33080902.
  19. ↑ Bhandari, Sabin; Larsen, Anett Kristin; McCourt, Peter; Smedsrød, Bård; Sørensen, Karen Kristine (2021). "The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease". Frontiers in Physiology. 12: 1711. doi: 10.3389/fphys.2021.757469 . ISSN   1664-042X. PMC   8542980 . PMID   34707514.
  20. ↑ Short, Kirsty R.; Veldhuis Kroeze, Edwin J. B.; Reperant, Leslie A.; Richard, Mathilde; Kuiken, Thijs (2014). "Influenza virus and endothelial cells: a species specific relationship". Frontiers in Microbiology. 5: 653. doi: 10.3389/fmicb.2014.00653 . ISSN   1664-302X. PMC   4251441 . PMID   25520707.
  21. ↑ Bayot, Marlon L.; King, Kevin C. (2021), "Biohazard Levels", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30570972 , retrieved 2021-11-01
  22. ↑ Joglekar, Alok V.; Sandoval, Salemiz (December 2017). "Pseudotyped Lentiviral Vectors: One Vector, Many Guises". Human Gene Therapy Methods. 28 (6): 291–301. doi:10.1089/hgtb.2017.084. ISSN   1946-6536. PMID   28870117.
  23. ↑ Bennett, Richard S.; Logue, James; Liu, David X.; Reeder, Rebecca J.; Janosko, Krisztina B.; Perry, Donna L.; Cooper, Timothy K.; Byrum, Russell; Ragland, Danny; St. Claire, Marisa; Adams, Ricky (2020-07-14). "Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model". Viruses. 12 (7): 753. doi: 10.3390/v12070753 . ISSN   1999-4915. PMC   7411891 . PMID   32674252.
  24. ↑ Carvalho, Constança; Gaspar, Augusta; Knight, Andrew; Vicente, Luís (2018-12-29). "Ethical and Scientific Pitfalls Concerning Laboratory Research with Non-Human Primates, and Possible Solutions". Animals. 9 (1): 12. doi: 10.3390/ani9010012 . ISSN   2076-2615. PMC   6356609 . PMID   30597951.
  25. ↑ Masemann, Dörthe; Ludwig, Stephan; Boergeling, Yvonne (January 2020). "Advances in Transgenic Mouse Models to Study Infections by Human Pathogenic Viruses". International Journal of Molecular Sciences. 21 (23): 9289. doi: 10.3390/ijms21239289 . PMC   7730764 . PMID   33291453.
  26. 1 2 3 Kausar, Shamaila; Said Khan, Fahad; Ishaq Mujeeb Ur Rehman, Muhammad; Akram, Muhammad; Riaz, Muhammad; Rasool, Ghulam; Hamid Khan, Abdul; Saleem, Iqra; Shamim, Saba; Malik, Arif (2021-01-01). "A review: Mechanism of action of antiviral drugs". International Journal of Immunopathology and Pharmacology. 35: 20587384211002621. doi:10.1177/20587384211002621. ISSN   2058-7384. PMC   7975490 . PMID   33726557.
  27. ↑ Szymański, Paweł; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta (2011-12-29). "Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests". International Journal of Molecular Sciences. 13 (1): 427–452. doi: 10.3390/ijms13010427 . ISSN   1422-0067. PMC   3269696 . PMID   22312262.
  28. ↑ Mackow, Erich R.; Gorbunova, Elena E.; Gavrilovskaya, Irina N. (2015). "Endothelial cell dysfunction in viral hemorrhage and edema". Frontiers in Microbiology. 5: 733. doi: 10.3389/fmicb.2014.00733 . ISSN   1664-302X. PMC   4283606 . PMID   25601858.
  29. ↑ Zhou, Yanchen; Simmons, Graham (October 2012). "Development of novel entry inhibitors targeting emerging viruses". Expert Review of Anti-infective Therapy. 10 (10): 1129–1138. doi:10.1586/eri.12.104. ISSN   1478-7210. PMC   3587779 . PMID   23199399.
  30. ↑ Markham, Anthony (2021-01-01). "REGN-EB3: First Approval". Drugs. 81 (1): 175–178. doi:10.1007/s40265-020-01452-3. ISSN   1179-1950. PMC   7799152 . PMID   33432551.
  31. ↑ Lee, Bohae Rachel; Paing, May Hnin; Sharma-Walia, Neelam (2021). "Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation". Frontiers in Physiology. 12: 801. doi: 10.3389/fphys.2021.640374 . ISSN   1664-042X. PMC   8320392 . PMID   34335286.
  32. ↑ Singh, Awadhesh Kumar; Singh, Akriti; Singh, Ritu; Misra, Anoop (2021-11-01). "Molnupiravir in COVID-19: A systematic review of literature". Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 15 (6): 102329. doi:10.1016/j.dsx.2021.102329. ISSN   1871-4021. PMC   8556684 . PMID   34742052.
  33. ↑ Annunziata, Giuseppe; Sanduzzi Zamparelli, Marco; Santoro, Ciro; Ciampaglia, Roberto; Stornaiuolo, Mariano; Tenore, Gian Carlo; Sanduzzi, Alessandro; Novellino, Ettore (2020). "May Polyphenols Have a Role Against Coronavirus Infection? An Overview of in vitro Evidence". Frontiers in Medicine. 7: 240. doi: 10.3389/fmed.2020.00240 . ISSN   2296-858X. PMC   7243156 . PMID   32574331.
  34. ↑ Dai, Xiaofeng; Zhang, Xuanhao; Ostrikov, Kostya; Abrahamyan, Levon (2020-03-03). "Host receptors: the key to establishing cells with broad viral tropism for vaccine production". Critical Reviews in Microbiology. 46 (2): 147–168. doi:10.1080/1040841X.2020.1735992. ISSN   1040-841X. PMC   7113910 . PMID   32202955.
  35. ↑ Chappell, Keith J.; Watterson, Daniel (2017-01-12). "Fighting Ebola: A Window for Vaccine Re-evaluation?". PLOS Pathogens. 13 (1): e1006037. doi: 10.1371/journal.ppat.1006037 . ISSN   1553-7374. PMC   5230751 . PMID   28081225.
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