Interleukin 6 receptors

Because severe symptoms emerged in many patients late following infected, when the SARS CoV-2 viral load was falling, localized inflammation played an early role of COVID-19 infections. Interleukin-6, a cytokine released by macrophages that triggers a proinflammatory response and is frequently high in COVID-19 patients, has emerged as one of the leading possibilities for mediating inflammation in COVID-19 (Rubin et al., 2021).

Interleukin-6 Proinflammatory cytokine is produced in response to infection and tissue damage and exhibits a complex biology as it can signal via different modes of action (Garbers et al., 2018). In classic signaling, IL-6 binds to the membrane-bound IL-6R, which is mainly expressed on hepatocytes and immune cells, and induces homodimerization of glycoprotein 130 (gp130). In the trans-signaling mode, IL-6 uses the soluble form of the IL-6R (sIL-6R). The IL-6: sIL-6R complex also induces gp130 homodimerization. IL-6 trans-signaling enables cells lacking the membrane bound IL-6R to be stimulated by IL-6. This mode of signaling is considered to cause proinflammatory properties (Hunter and Jones, 2015)

The Interleukin-6-receptor mediates the biological activities associated with IL-6, which consists of two parts, the first being the type I transmembrane signal transducer protein gp130 (CD130) and the other type I transmembrane glycoprotein termed IL-6R (CD126 or gp80) and the latter binds to IL-6 and the two with the first part of the receptor, thus this IL-6/IL-6R complex leads to IL-6 signal transduction, which includes activation of the signaling transduction pathways (JAK/STAT, ERK and PI3K) (Scheller et al., 2011).

Active IL-6 trans-signaling influences T-cell recruitment, activation, and apoptosis. According to Dominitzki et al. (2007), It can boost differentiation of Th17 cells and at the same time suppress the development of regulatory T cells (21). IL-6 trans signaling is the major route of IL-6 signaling to microvascular endothelial cells (EC), leading to EC activation, dysfunction, and deregulated inflammatory cell infiltration as published by Schmidt-Arras and Rose-John (2016). It has been implicated in the endotheliopathy in COVID-19, with a central role in the pathogenesis of ARDS and multi-organ failure (Teuwen et al., 2020)

Numerous readily soluble receptors are currently recognized for many different chemokines and cytokines, and they play a crucial role in controlling inflammatory reactions by working as antagonists or agonists of inflammatory mediator signaling. These soluble receptors operate as antagonists through impeding the biological function of ligands (Reddy et al., 2000). On the other hand, the soluble IL-6 receptor (sIL-6R) enhances the signaling process of IL-6 through the stimulation of populations of cells which possess the signaling transduction protein CD130 nevertheless do not exhibit mbIL-6R expression. It is noteworthy that a limited number of cellular types exhibit the expression of IL-6R on their cell membrane, thereby enabling them to exclusively react to IL-6 stimulation. The aforementioned cells include neutrophils, macrophages, and certain subsets of T lymphocytes, along with hepatocytes. In contrast to the IL-6R, CD130 exhibits ubiquitous expression (Scheller and Rose-John, 2006).

C-C chemokine receptor type 2

 Chemokines are small molecules that are crucial in the development of inflammatory illnesses in a manner stimulated by several types of immune cells. Chemokines are known to exert a crucial function in the immune system's reaction associated with inflammation, as they facilitate the recruitment of white blood cells to specific locations where an infection has occurred (Rotondi et al., 2007). Presently, a total of 50 chemokines and 20 receptors for chemokine. Chemokines are named after the most recent nomenclature, which categorizes them into the C, CC, CXC, and CX3C families based on their chemical structure. the chemical attraction of immunological cells at the location of the infection requires the binding of chemokines to their receptors (Bachelerie et al., 2013). As well as other functions performed by chemokines in the immune response, inflammatory and neoplastic diseases, and the regulation of angiogenesis (Coperchini et al., 2019). Recently, a variety of studies have examined the role of chemokines in infectious diseases related to SARS-CoV-2 infections. It appeared that specific chemokines could they have the emergence role about symptoms linked with COVID-19 is severity influenced (Li et al., 2020c).

The biological and viral the characteristics of SARS-CoV-2 exhibit resemblances to those observed in two previous pandemic coronaviruses, so it is assumed that the chemical messenger signature of COVID-19 patients contains analogous mediators of inflammation. In contrast, SARS-CoV-2 has a greater incidence of transmission as well as a mortality rate that is lower compared to MERS and SARS-CoV (Jafarzadeh et al., 2020).

 Chemokine receptors are crucial in regulating leukocyte trafficking and thereby orchestrating immune responses. Thus, chemokine receptors are critical in all aspects of immune responses including adaptive immunity in lymphoid organs, early influx of innate immune cells and migration of cells in inflamed tissues. Their expression is tightly regulated and depends on the immune milieu. Imbalance or perturbations in the homeostasis of chemokine and chemokine receptor expression are associated with inflammatory (Oo et al., 2010).

In myeloid cells, T lymphocyte, and NK cells, a pro-inflammatory of chemokine receptors for many chemoattracts types especially CCR2 are expressed. These chemoattracts receptors coordinate the immune system's responses occurring inside the airways, such as allergies, TB, and influenza. CCR4, CCR5, and CXCR6 on the other hand, the predominant expression of these kinds of receptors is observed for both naïve as well as adaptive T cells, and they have a crucial role in regulating the passage of lymphoid cells towards the respiratory alongside mucosal regions. Immune cell homing to the skin requires CCR4, whereas CCR9 controls cell migration to mucosal tissues (Liechti et al., 2022).

Thus, chemokine receptors can induce nonredundant, tissue-specific cell migration. Severe COVID-19 has been associated with perturbations in chemokine levels as well as expression of chemokine receptors highlighting their importance in immunopathology (Brownlie et al., 2022).

 Moreover, it is interesting to note that hyperinflammation generated by numerous pathogenic viruses, like H1N1 and H5N1, could potentially aid in the elucidation of the impact of chemokines involved in the development of inflammatory reactions in opposition for COVID-19 (Hayney et al., 2017).

 Therefore, recognizing the SARS-CoV-2 chemokine signature and distinguishing it from non-COVID-19 pathogenic microbial ARDS would minimize complications and decrease mortality. Although resident alveolar macrophages are beneficial in the early stages of the disease, infiltrating monocytes and macrophages are essential in the progression of COVID-19 (Khalil et al., 2021), Infiltrated monocytes as the major leukocytes migrated into the infected lungs, and excessive secretion of cytokines and chemokines by these immune cells can lead to remarkable severe lung inflammation in SARS-CoV-2 patients (Swiecki and Colonna ,2011).

Although various chemoattractant mediators induce monocyte migration, CCL2 is often expressed quickly by stromal and immune cells upon activation of pattern recognition receptors (PRR) or cytokine secretion (Palomino and Marti, 2015). CCL2 is primarily produced in the lungs by alveolar macrophages, T cells, and endothelial cells, while CCR2 is mainly upregulated on the surface of monocytes, macrophages, and T cells in an inflammatory condition (Henrot et al., 2019). According to (Xu et al., 2020b), the expression of CCR2 in extracellular matrix (ECM) glycosaminoglycans (GAGs), CCL2 can stimulate monocyte recruitment into the infected lungs, where they trigger calcium influx, produce oxygen radicals, and express integrin in COVID-19 patients. Elevated levels of CCL2 and CCL7, two chemokines potent at the recruitment of CCR2 monocytes, have also been found in BALF from patients with severe COVID-19 (Zhou et al., 2020b). In COVID-19, the inflammatory cytokine storm is closely related to the development and progression of ARDS. The serum levels of cytokines are significantly increased in patients with ARDS, and the degree of increase is positively correlated with mortality rate (Douda et al., 2011).

Angiotensin Converting Enzyme-2 Receptor

 The angiotensin conversion enzyme 2 receptor is a transmembrane polypeptide which is abundantly synthesized located on the extracellular surface of various kinds of cells. The enzyme within controversy is responsible for the production smaller proteins through the cleavage of the bigger protein angiotensinogen. These small proteins subsequently play a regulatory role in cellular functions, SARS-CoV-2 utilizes its spike-like protein for effectively attach with ACE2 receptors. This interaction is crucial for the subsequent entry and infection of cells in the host. Therefore, ACE2 serves as a receptor and cellular entryway for the viral infection responsible for COVID-19.

 The ACE2 protein functions as the principal target of SARS-CoV-2, facilitating its cellular infectious. The angiotensin converting enzyme 2 (ACE2) is expressed in a wide range of different kinds of cells as well as tissues, which includes the heart, pulmonary system, blood vessels, kidneys, the liver, and digestive system. The epithelial cells that line some tissues and form barriers to protection contain it (Sharma et al., 2020).

Coxsackievirus and Adenovirus receptor (CAR)

Adenoviruses (AdVs) are common human pathogens that generally cause typical cold symptoms in healthy individuals, but infections can progress to acute respiratory distress syndrome (ARDS) and disseminated disease, with up to 50% mortality in ARDS patients (Lynch and Kajon,2016). Epidemic AdV outbreaks occur in closed or crowded communities, particularly among children (Lion,2019). In highly susceptible, immunosuppressed populations, such as in the transplant setting, AdV infections can also be highly lethal, depending on serotype, AdV can also cause gastroenteritis with prolonged fecal shedding, or keratoconjunctivitis that can lead to blindness (Ismail et al.,2019)

Viral infections first require viral entry into the host cell, and entry is mediated by cellular receptors. Significant research efforts have resulted in the discovery of several different primary receptors and co-receptors for human AdVs (hAdVs), In general, hAdV can be divided into seven different groups, A-G, and almost all but group B AdV use the coxsackievirus and adenovirus receptor (CAR) as a primary receptor. While not yet understood, the convergence of several distinct viruses on a single protein as a primary receptor indicates that CAR manifests beneficial characteristics as a viral receptor. These factors may range from the essential nature of CAR in developmental and adult biology, to receptor localization, to the molecular pathway for internalization of viruses into the host cell (Greber and Flatt,2019).

The coxsackievirus and adenovirus receptor (CAR) is an essential multifunctional cellular protein that is only beginning to be understood. CAR serves as a receptor for many adenoviruses, human group B coxsackieviruses. While named for its function as a viral receptor, CAR is also involved in cell adhesion, immune cell activation, synaptic transmission, and signaling (Lim et al.,2008). The human CXADR gene that encodes CAR is found on chromosome 21q21.1 and has eight exons spread over ~ 80 kB of genomic DNA. While several studies have looked for genetic polymorphisms within exonic regions of human CXADR, very few changes have been found and most have been synonymous changes indicating the strength of genetic conservation (Thoelen et al.,2002).

Adenovirus tropism is heavily contingent on the generation of particular virus receptors. The attachment of several human-associated adenovirus serotypes, such as adenovirus types 2 alongside 5, is facilitated through the presence of coxsackievirus and adenovirus receptor (CAR), which is an exterior cell receptor. The association among the level of expression of its receptors with the sensitivity of specific cell types for the transfer of genes through Ad2 as well as Ad5 is currently observed (Cohen et al., 2001).

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مواضيع ذات صلة

Acute viral hepatitis

Antiviral Chemotherapy

Humoral Immune Responses to SARS-CoV-2 Infection

Cellular Immune Responses to SARS-CoV-2

Pathogenesis of SARS-CoV-2

Epidemiology of SARS-CoV-2

PARVOVIRIDAE

تركيب فيروس التهاب الكبد الوبائي نوع ب الخفي

REPLICATION OF VIRUSES AN OVERVIEW

مرض الجدري Smallpox

Human Herpesvirus Types 6 And 7

Viral Nucleic Acid