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Covid-19 Glossary of Terms

COVID-19 Glossary Goal: In the various videos and referenced papers certain words and phrases are used as it applies to the pathophysiology that underlies certain aspects of COVID-19. A brief definition is given of these words and phrases presented alphabetically in order to ensure comprehension of terminology, acronyms and phrases as it applies to COVID-19.

ACE2: ACE2 stands for angiotensin converting enzyme 2. ACE2 is a transmembrane protein that is the functional receptor for the SARS CoV-2 virus and allows the virus to gain entry into the cell. The receptor is also very important for cardiovascular health because this enzyme results in the hydrolysis of angiotensin 1 which is a vasoconstrictor into angiotensin 7 which exhibits protective vasodilatory properties. Angiotensin7 has other protective effects on the blood lining cells i.e. endothelium. When the SARS CoV-2 glycoprotein binds to ACE-2, the ACE-2 becomes endocytosed and is no longer available to affectively achieve this hydrolytic conversion.

Alternative Pathway: The alternative pathway is one of the key complement pathways that like the other complement pathways generates the membranolytic attack complex also referred to as C5b-9 (i.e. the assembly of the components of complement activation C5a,C6, C7, C8 and multiple copies of C9), a molecule which damages cells and microbial pathogens. The pathway is triggered when C3b protein directly interacts with a microbial pathogen but can also be activated by damaged tissues and foreign material. When another complement pathway is activated and damages tissue the ensuing damage can activate the alternative pathway best exemplified by the amplification of the alternative pathway that occurs with mannan binding lectin pathway activation.

Capsid: The SARS CoV-2 is a single stranded RNA virus intertwined with nucleocapsid and surrounded by a capsule called a capsid that is composed of select proteins referred to as SARS CoV-2 membrane, envelope, and spike glycoprotein.

Clathrin vesicles: These are distinctive intracellular structures that are reflective of endocytosis. They have projections on the surface similar to spike glycoprotein and therefore these bodies could resemble SARS CoV-2 virions although are smaller and unlike a true endocytosed SARS CoV-2 virion, the vesicles sit freely in the cytoplasm of the cell and are not bound by a membrane. 

COVID-19: COVID-19 is an acronym for the Coronavirus(CO) Viral(VI) Disease(D) caused specifically by SARS CoV-2 and can range in disease severity; there are patients that are asymptomatic to mildly symptomatic defining the type of illness experienced by most while others have more substantial respiratory symptoms potentially requiring supplemental oxygen with or without other organ dysfunction.

Complement and specific components of the complement pathway (i.e. C3d, C4d, C5b-9 and MASP2):
The complement system is composed of proteins including C1q, C1r, C3, C3a, C3b, C3d, C4a,C4b, C4d, C5, C5a, C5b, C6, C7, C8, and C9. The noncleaved complement proteins such as C1q,C1r, C1s, C2, C3, C4, and C5 are produced by the liver and circulate in the blood as an inactive molecule but they have the ability to be stimulated by certain triggers that will result in the cleavage of a specific complement protein into another version of itself such as C2 into C2a, C3 into C3a and C3b, C4 into C4a and C4b and C5 into C5a and C5b and the assembly of the cleaved complement proteins to eventuate in the formation of and the fusion of C5b, C6, C7 C8 and C9 called C5b-9. The latter is also referred to as the membranolytic attack complex because of the ability C5b-9 to drill transmembrane pores into a cell or microbe and result in its cell death. While very protective against infections the complement pathway activation leading to the formation of C5b-9, can damage the host cells and if the target is the endothelium of small vessels, this complement activation can lead to microvascular injury and activation of the coagulation pathway resulting in both microvascular injury and clot formation. The triggers to the activation of the pathway are varied. The complement pathway is significantly activated in severe COVID-19 and is responsible for the multiorgan vascular injury and thrombosis (i.e the formation of blood clots) in patients with severe COVID-19.
There are three complement systems operational in the human body and they all generate the membranolytic attack complex C5b-9 even though the triggers vary and the nature of the C3 convertase being formed is different.
The three systems are:
1. the classical pathway triggered by antibody bound to antigen as a trigger to C1 complex activation to form C3 convertase
2. the alternative pathway where the C3 convertase is formed with spontaneous hydrolysis of C3 without involvement of C4 and is stimulated by cell death
3. finally the lectin pathway where glycoproteins rich on surfaces of organisms will interact with mannan binding lectin and generate a C3 convertase equivalent called MASP2.
C1 complex activation occurs in the classic pathway. An equivalent protein to C1q called C3bBb forms when there is spontaneous hydrolysis of C3 in the alternative pathway setting or formed with a C1 complex equivalent in the mannan binding lectin setting. In essence they have both points of difference and of commonality.

Cytokines: Cytokines are small proteins produced from cells including lymphocytes, where they are called lymphokines and monocytes where they are referred to as monokines. Chemokines work on attracting other cells and interleukins when they elaborate proteins that influence other cells. Among the earliest discovered cytokines are interferons and macrophage inhibitory factor.

D-Dimer: D-dimer is a fibrin degradation product following the dissolution of a blood clot by a process called fibrinolysis. The name is derived from the fact that the product that is being measured comprises two fragments of the fibrin protein joined by a cross link that forms with clot lysis. An elevated D-dimer indicates the presence of blood clots and hence reflective of an underlying procoagulant state characteristic of severe COVID-19.

Endocytosis: Endocytosis is a dynamic cellular process whereby material from the outside is brought into a cell. The internalization of the material is via a portion of the cell membrane surrounding the exogenous material. The structure composed of cell membrane and the foreign material is referred to as a vesicle. The clathrin vesicle which can be confused with a SARS CoV-2 virion is formed through endocytosis. 

Endothelium: Endothelium represents the cell that lines blood vessels. The endothelium is a critical target in COVID-19. When the endothelium is damaged the end result in vascular compromise and therefore an interference with critical oxygenation needed to maintain tissue viability.

Envelope: Envelope is in the context of SARS CoV-2 envelope and is part of the viral capsule. The SARS CoV-2 is a single stranded RNA virus intertwined with nucleocapsid and surrounded by a capsule called a capsid that is composed of certain proteins designated membrane, envelope, and spike glycoprotein

Interleukin 6: Interleukin-6 is elaborated by certain cells types including monocytes as a response to specific microbial molecules that are called pathogen associated molecular patterns but also under the influence of certain cytokines elaborated by T cells. Interleukin-6 has a proinflammatory effect especially in regards to neutrophil recruitment. However when interleukin-6 is produced by endothelial cells, it will promote the aggregation of platelets and therefore promotes the tendency to form blood clots which is a significant complication in severe COVID-19 and contributes to morbidity and mortality. In the setting of COVID-19 there are high levels of interleukin -6 which has lead to therapeutic intervention with a drug that inhibits interleukin-6 called toculizumab. The source of the interleukin-6 is the endothelium likely as a sequelae of mannan binding lectin pathway activation due to upregulation of nuclear factor kappa beta.

Interferons: Interferons are a type of cytokine that interferes with viral replications but also can activate other immune cells especially T cells and monocytes and upregulate antigen presentation by increasing the expression of major histocompatibility complex antigens. There are three main classes of interferons namely type I, type II and type III. The interferons cause the cells to produce enzymes that destroy both viral RNA and host RNA hence preventing the virus and the cell from replicating. There are many other interferon-stimulated genes (ISGs) that interfere with viral replication. Interferons are elaborated by monocytes especially plasmacytoid dendritic cells but in fact any cell has the ability to elaborate interferons.

Immunohistochemistry: Immunohistochemistry is a technique typically applied on biopsy material using certain chromagens such as a red chromagen or a brown chromagen called diaminobenzidine to visualize a specific protein. In the context of demonstrating the surface capsular proteins of SARS CoV-2 virus, specific immunohistochemical stains are performed to demonstrate these proteins. However in order to document the host response to the virus immunohistochemical stains to highlight specific proteins unique to an inflammatory cell type such as CD3 to highlight T lymphocytes or a particular cytokine such as interleukin 6 are also examined.

Mannan Binding Lectin: This is one of the three complement pathways and is part of the innate immune system. Many bacteria and certain viruses have mannose residues which are a type of surface glycoproteins that interact with the surface of the mannan binding lectin to result in the formation of MASP2, an equivalent to the C1 complex to produce C3 convertase by cleaving C4 into C4a and C4b and C2 into C2a and C2b.

Membrane: The membrane is in the context of SARS CoV-2 membrane and is part of the viral capsule. The SARS CoV-2 is a single stranded RNA virus intertwined with nucleocapsid and surrounded by a capsule called a capsid that is composed of certain proteins called. Membrane, envelope, and spike glycoprotein.

Myxovirus Resistence Protein A: This protein is a sign of positive type I interferon signaling and can be detected using immunohistochemistry as a means of documenting type I interferon signaling in tissue.

Perniosis: Another term for perniosis is chilblains. Perniosis developing during the COVID-19 pandemic is referred to as Covid toes. In the setting of COVID-19 associated perniosis, patients, typically asymptomatic or mildly symptomatic children and young adults, present with violaceous nodules and plaques most commonly on their toes although occasionally their hands. Other forms of perniosis include perniosis in the setting of lupus erythematosus and idiopathic perniosis, the patients are typically young adult females with a history of Raynaud’s phenomenon and where cold is a trigger. Enhanced interferon signaling is pathogenetically relevant and leads to an accumulation of many immune cells in biopsies of perniosis called lymphocytes and monocytes. 

Platelets: Platelets are the smallest of blood cells and became activated to contribute to the formation of blood clots. When a blood vessel is damaged, clots form that contain platelets. Platelets have no nucleus. They are fragments of cytoplasm derived from megakaryocytes. Only in mammals are platelets anucleated. In other animals they have nuclei and are called thrombocytes. The platelet plug will activate the coagulation cascade and result in the formation of fibrin.

Pseudovirions: These are noninfectious viral particles, typically protein without any intact DNA or RNA and therefore not capable of replication. Their presence would not be considered evidence of a true infection. In SARS CoV-2 infection proteins can dock to endothelial cells as a pseudovirion by the binding of spike glycoprotein witih ACE-2.

RT In Situ PCR: Situ Polymerase Chain Reaction (In situ PCR) is a powerful method that detects minute quantities of rare or single-copy number nucleic acid sequences in frozen or paraffin-embedded cells or tissue sections for the localization of those sequences within the cells.

SARS CoV-2: SARS CoV-2 is the causative agent of COVID-19. The virus is a single stranged RNA virus intertwined with a nucleocapsid. It has a capsule composed of three basic capsule proteins namely spike glycoprotein, membrane and envelope. There are binding sites on the spike glycoprotein for mannan binding lectin which is a key aspect of its pathogenicity. It gains access to the surface of the cell and then enters the cell through ACE-2. IT acquires entry into the cell through endocytosis.

Spike Glycoprotein: The spike glycoprotein is in the context of SARS CoV-2 spike glycoprotein and is part of the viral capsule. The SARS CoV-2 is a single stranded RNA virus intertwined with nucleocapsid and surrounded by a capsule called a capsid that is composed of certain proteins called membrane, envelope, and spike glycoprotein.

Thrombosis and thrombi: When the clotting pathway is activated, plugs are formed inside blood vessels composed of fibrin, platelets, and other component namely certain immunoglobulins. These plugs are called thrombi.

Thrombotic Retiform purpura of COVID-19: This rash is a very unique characteristically occurring at Acral sites that patients with severe COVID-19 develop. Retiform refers to net like (i.e. the rash has a net like appearance). The rash is red and purple because of damage to vessels and the formation of clots or thrombi and therefore is referred to as retiform purpura. The further qualifier of thrombotic is to emphasize the blood clots in small vessels seen under the microscope.

Terminal Lung parenchyma: The critical blood gas exchange unit in the lung is called the terminal lung parenchyma. It is composed of very delicate thin septated structures that contain the smallest blood vessels in the human body called capillaries that will absorb oxygen from the adjacent air sacs referred to as alveoli. If the capillaries are damaged they cannot perform that critical function of transmitting oxygen to the rest of the body.

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