The pathogenicity of COVID-19 and the role of pentraxin-3: An updated review study.

In recent years, the COVID-19 pandemic has become one of the most crucial scientific issues in the world, and efforts to eradicate the disease are still ongoing. The acute inflammatory reaction associated with this disease is associated with several complications such as cytokine storm, multiple organ damage, lung fibrosis, and blood clots. PTX3, as part of the humoral innate immune systems, is one of the acute-phase proteins that perform various functions, such as modulating inflammation, repairing tissue, and recruiting immune cells. PTX3 is increased in people with SARS-CoV-2, and its level decreases with proper treatment. Therefore, it can be regarded as a suitable marker for the prognosis of the COVID-19 and evaluating the effectiveness of the treatment method applied. However, some studies have shown that PTX3 can be a double-edged sword and develop tumors by providing an immunosuppressive environment.

Introduction

Coronaviruses as the single-strand RNA viruses are at the size of 60 nm-140 nm and hold mainly spike-shaped protein owing to the main ligand for target cell entry [1]. Among the population, four main strains of the virus are more common, including HKU1, OC43, NL63, and 229E causing gentle respiratory disorder. In the past several years, it was demonstrated that animal β-coronaviruses transmission to humans happened and could give rise to severe disease. Three major types of diseases associated with coronaviruses have been detected so far, in the order of emergence including SARS (Severe acute respiratory syndrome; in Foshan, China, 2002, 8000 cases and 800 deaths), MERS (Middle East respiratory syndrome,), and COVID-19 (Coronavirus Disease 2019) [2]. In 2002, the first case of beta-coronavirus transmission from bats to humans was reported. The palm cats acted as a host-mediated for the virus and provided an easy route for its transmission. In 2012, in Jeddah, Saudi Arabia, a mysterious illness appeared as the “Middle East Respiratory Syndrome Coronavirus (MERS-COV)” that had spread through bats. In this case, the medial host was a dromedary camel, which infected 2,494 people and caused 900 cases of death [3], [4]. In December 2019, a pneumonia sickness of an unknown source was declared in Wuhan. A new form of coronavirus was reported in January 2020, known as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) [5], [6]. In early 2020, the pandemic infection was denominated as COVID-19 (Coronavirus disease 2019) by WHO. Since then, SARS-CoV-2 has been spreading over 200 countries while leading to social constraints and recession in society, and it has imposed several difficulties on health organizations and 3.9 million deaths. In some patients, the latency period of the disease can vary between 2 and 14 days [7], [8]. Very mild symptoms are identified in some infected patients without any symptoms of the disease. However, more severe symptoms are developed in the individuals with chronic diseases such as lung disease and diabetes and the elderly leading to “ARDS” (Acute Respiratory Distress Syndrome), as well as multiple organs failure with an abundant mortality rate. Presently, no effective drug exists for treating COVID-19 cases. This causes challenges in its management and control [9], [10], [11], [12], [13]. Given the fact that COVID-19 and its severe side effects are most dependent on acute inflammatory reactions, the study of inflammatory factors and their function is inevitable. One of these inflammatory factors is the PTX3 (Pentraxin 3), a superfamily of acute-phase proteins, which has significant functions in innate humoral immunity, such as regulating inflammatory responses, controlling complement pathways, affecting immune system cells, and tissue repair [14], [15]. In this review study, we are going to take a look at and discuss the role of PTX3 in COVID-19.

Pathophysiology of COVID-19

Generally, the disease clinical steps can be found and traced in 3 different phases each with specific features.

Step 1

During the first infection phase, the lung parenchyma is infiltrated by SARS-CoV-2 leading to proliferation. TMPRSS2 and ACE2 have vital roles in the SARS-CoV-2 cellular entry, the same as SARS-CoV. The spike protein S1 subunit connects to the ACE2 ligand located on the membrane of the target cells. The virus-specific spike protein is broken down by a protease enzyme, TMPRSS2, into two subunits, the S1, and the S2. The S2 subunit plays a primary role in the virus entering the host cell [16]. At cytoplasmic membranes, coronavirus genome transcription and replication happen. The discontinuous and continuous synthesis of RNA is mediated by the replicase complex. Then, about 16 virus-related subunits and some cellular proteins are made. Unlike the family of RNA viruses, the replicase complex just exists in SARS-CoV-2 for employment of some enzymes associated with RNA processing such as putative sequence-specific endoribonuclease, 2’-O-ribose methyltransferase, 3’ -to- 5’ exoribonuclease, and ADP ribose 1’- phosphatase. By incorporation of the replicated RNA into virions, budding from the host cell occurs. The response of the innate immunity and the presence of mild constitutional symptoms are the characteristics of this phase [17]. Followed by the viral invasion, the production of type I IFNs is activated, which promotes the downstream JAK-STAT signals to increase the expression of ISGs (IFN-stimulated genes). The macrophage presenting activity and NK cells leads to confine the spreading of the virus. It is proved that blocking the production of IFN by the SARS-CoV’s N protein is important directly for viral survival [18], [19]. Theoretically, the virus is effectively helped by the extended incubation period of viral infection to abscond from the innate immunity at an early infection stage. Nowadays, there is in dire need of more studies on innate immunity, especially related to monocyte-macrophages and type I IFN in COVID-19 patients; because any functional defect in this immune system part can lead to fatal pneumonia. The Function and response of Th1 cells are vital for virus clearance in adaptive immunity. T-dependent B cells are activated by helper T cells for the development of high-affinity antibodies against the virus. Virus-infected cells are directly killed by the cytotoxic T cells. Mainly, the signaling pathway of NF-kB is promoted by the helper T cells for the synthesis of pro-inflammatory cytokines [20].

Step 2

The presence of an inflammatory response, respiratory failure, and tissue damage are the characteristics of the pulmonary phase. In most cases, mild upper respiratory tract dysfunction is induced by the viral entry in human lung tissues [20]. According to scientists, type 2 alveolar cells are triggered by the viral replication and budding to undergo epithelial regeneration of cells and apoptosis, the same as SARS-CoV. COVID-19 obliged respiratory failure revealed various properties from that of typical ARDS, though it matches the serving state Berlin definitions. Non-cardiogenic pulmonary edema causes ARDS as a clinical complex syndrome of acute respiratory failure. The most prevalent clinical disorders are viral and bacterial pneumonia related to ARDS development. Briefly, injuring the lung by inflammatory conditions or infection causes inflammatory pathways. There are excessive cytokines levels. Alveolar cell damage and necrosis are resultant from developing oxidative stress, and the existence of excessive and dysregulated inflammation, cause [21], [22]. The protein-rich alveolar edema fluid is accumulated by the incremented epithelial and endothelial permeability. Following the defect in the alveolar barrier, the process of clearing and removing the alveolar fluid is challenged. More pronounced immune responses and inflammatory are triggered by the accumulation of cell necrosis and edema fluid. Impaired gas exchange is caused by the repletion of pulmonary fluid in the airspace and interstitium of the lung gives rise to impaired carbon dioxide excretion, hypoxemia, and acute respiratory failure [23]. Ground-glass infiltrates, hypoxia, and ARDS were developed by about 20% of the infected patients resulting in organs failures. Severe fibrosis and scarring of the respiratory system cells were found [18]. Some multinucleated giant cells were presented along with an extended alveolar lesion with a fibrin-enriched hyaline membrane. The decreased capability of mucociliary clearance and epithelium repairing in the elderly worsens the condition quickly and leads to death eventually [21].

Step 3

The damage to distant organs and the existence of systemic inflammation are the characteristics of the hyper-inflammation phase. This is caused by the hypercoagulable state and incremented host inflammatory response leading to multi-organ failure. Higher white blood cells quantity alongside lymphopenia and incremented plasma pro-inflammatory cytokines levels were found, particularly the higher levels of C-reactive protein (CRP), IL-10 IL-7 IL-6, IL-2, interferon-gamma inducible protein (IP) 10, G-CSF, macrophage inflammatory protein (MIP) 1α, MCP1 (monocyte chemoattractant protein 1), as well as TNF-α in patients who suffer from a severe type of COVID-19 [24], [25]. By such a “Cytokine storm,” intense-inflammatory-induced respiratory system injury is triggered with serious abnormalities like ARDS, MOF, acute heart/kidney/liver injury, septic shock, hemorrhage/coagulopathy, and bacterial infections. This is the same as the conditions for MERS-CoV and SARS-CoV infections [26]. According to the studies, the compounds with the progesterone basis could influence the susceptibility to infections and immune responses at various mucosal sites like the genital area, respiratory and gastrointestinal tract by changing the cellular activity and signaling, which in turn influence the infection results. By inhibition of producing the pro-inflammatory cytokines, incrementing the formation of anti-inflammatory cytokines within the course of the virus infection, and promoting repairing the damaged lung epithelium, these compounds can decrease the inflammation. Various outcomes and courses of COVID-19 may be affected by the difference in the sex steroids levels in females and males [27].

Blood clot formation in the COVID-19

Vascular damage is induced by SARS-CoV-2. Then, the free platelets are subjected not only to endothelium but also collagen too and turn into the effective platelet. The essential factors are released by the activated platelets such as thromboxane A2, serotonin, prothrombin, and adenosine diphosphate further activating the platelets. Alternatively, to initiate the clotting process in the arteries, 12 coagulation factors are required. In brief, activation of factor XII results in the conversion of prothrombin to thrombin. Ultimately, fibrinogen converts to fibrin, making a fibrin network at the harmed site to clot blood. There are several significant and life-threatening complications associated with blood clots that are induced by the virus; for instance, venous thromboembolism pulmonary, disseminated intravascular coagulation, and embolism [28].

Immune response in SARS-CoV-2

Only recently effective vaccines have been developed in December 2020 for immunizing the COVID-19 patients. Though, the immune system can be operative in the natural response of the body to infections and pathogens [29]. The ACE2 is used by SARS-CoV-2 as a receptor for connecting to the host cells such as respiratory system epithelial cells. The TMPRSS2 has a vital role in the breakage of the ‘spike protein’ into S2 and S1 subunits. Thus, binding the virus to the target cell membrane is facilitated by S2 [30], [31], [32]. ACE2 regulates the Renin-Angiotensin System (RAS). Hence, RAS dysfunction may be caused by a reduction in ACE2 activity followed by SARS-CoV-2 infection impressing the electrolyte/fluid and blood pressure levels as well as the vascular permeability and boosting inflammation in the respiratory system [33], [34], [35]. In the case of contamination of coronavirus in cells expressing the TMPRSS2 and ACE2, diffusion multiplication of the virus can induce cell pyroptosis. Therefore, several factors are released associated with the cell injury such as nucleic acids, ASC and ATP, oligomers. Epithelial cells, lung alveolar macrophages, and adjacent endothelial cells can identify these molecular factors leading to the formation of pro-inflammatory compounds and chemokines like IL-6, CXCL10, MCP1 (monocyte chemoattractant protein 1), MIP1α (macrophage inflammatory protein 1α), and MIP1β. Macrophages, monocytes, and T lymphocytes are brought by these protein factors to the infection place. Thus, subsequent inflammation is increased with higher IFN-γ levels released by T lymphocyte cells. Hence, a novel pro-inflammatory response is initiated. This may lead to the chemotaxis of immune system cells to the lungs within an incomplete immune reaction. Let's put it this way the mass formation of pro-inflammatory cytokines is caused, thus damaging the lung tissue; moreover, different organs are damaged by spreading the resultant cytokine storm to other tissues [36], [37]. According to the new findings, PTX3 is one of the acute phase proteins that can play a significant role in the balance of inflammation. PTX3 can be synthesized by some tissues and cells of the immune system and constitutes part of innate humoral immunity. The function of this protein during the inflammatory process can be due to the complement system activation. For instance, it can involve in complement activation by interacting with factor H as a C3b parser, C1q synthesis through the classical pathway, and complex formation with MBL (mannose‐binding leptin) in the lectin pathway. Interestingly, PTX3 can also regulate inflammation by inhibiting neutrophil migration to the damaged sites [38], [39].

B cell immunity

The response of B cells can be assessed through follicular helper T cells for almost 7 days followed by the arrival of the first symptoms in COVID-19 patients. In these patients, the B lymphocyte response is usually first versus the N protein within 4-8 days after the beginning of the symptoms; however, in the next step, a specific antibody against the S protein is synthesized and released [40], [41]. During the second week of illness, protective antibodies are made, normally against protein S. Although, within the third week, neutralizing antibodies are found in most people. Furthermore, there is a specific region in the S1 protein subunit that is the main target of the antibodies synthesized in COVID-19 patients. This area is known as the "receptor-binding-domain (RBD)" comprising 193 amino acids. The infection process is initiated by attaching the RBD to the ACE2 represented on the host target cell [42], [43], [44].

By binding the complexes of coronavirus-antibody to the Fc receptors on immune system cells such as alveolar macrophages, the formation of pro-inflammatory mediators can be obliged like IL-8 and MCP1 enhancing the immune activity circumstances. The complement system is agitated by these complexes causing another unfavorable inflammation. Therefore, the design of high-throughput antibodies with no pro-inflammatory impacts while being able to neutralize the virus has been considered. For instance, by changing the Fc area of the antibodies or their glycosylation, it will have the modified affinity to bind to the Fc receptor [45], [46], [47].

A current study reveals that a specific produced antibody versus the coronavirus particles is possibly preserved only for two months and for a short time; it can provide immunity to infected people. Similarly, in mild cases, a fast reduction in the antibodies titer is found. This is justified by the fact that the half-life of the IgG is about 21 days in COVID-19 cases. According to the experimental studies on the IgG and IgM antibodies level in COVID-19 subjects, these antibodies also exist in asymptomatic individuals. However, it should be noted that such patients have much lower antibody titers [48], [49], [50].

According to Sokal et al., memory B cells have a pivotal function in host immunity against viruses. Although their role in COVID-19 is relatively well known; but, complex issues remain unresolved. In this work, they reported a repertoire profiling of the B lymphocyte cells response within six months in patients with severe and mild COVID-19. An activated specific clone of B cells differentiates against SARS-CoV-2 antigens and produces antibodies. While neutralizing of coronavirus' RBD specific clones accumulated with time contributed highly to the considerably stable, recent memory B cell pool, highly mutated memory B cells were recruited in the initial response, such as pre-existing cross-reactive seasonal Beta-coronavirus-specific clones. Highlighting germinal center maturation, a clear accumulation of somatic mutations was displayed by these cells in the genes of their variable region over time. Generally, it was revealed that an antigen-based activation persisted and matured for more than 6 months followed by SARS-CoV-2 infection providing long-term immunity [51].

T cell immunity

Almost seven days followed by starting the disease symptoms, the responses of T cells against the cause of COVID-19 disease are traceable in the body. T CD8+ lymphocytes are significant for removing the virus-infected host cells. Albeit, throughout this process, T CD4+ lymphocytes effectively enhance the efficiency of both T CD8+ cells and B lymphocytes by secretion of various mediators [52]. In spite of the reports about lymphopenia and reduced circulating T lymphocytes count in patients, by these explorations, it was proposed that T lymphocytes are recruited from the peripheral blood into the infected site for restricting the illness. In patients possessing severe COVID-19, an intense form of the disease [53], [54], [55] is caused by the augmented T cell inability and reduced functional activity. The IL-2, TNF-α, and IFN-γ are expressed by SARS-CoV-2 specific T CD4+ cells. Thus, it is revealed that a Th1 response is presented by COVID-19 patients mostly through cellular immunity for eliminating the infection [56].

Alternatively, human T lymphocytes can be influenced by SARS-CoV-2 via CD147 on the T cell. Moreover, the expression of CD147 occurs in several tissues and cells, and it has a key role in cell migration, apoptosis, proliferation, metastasis, and differentiation of tumor cells, especially under hypoxic conditions [57].

MHC I (Type I major histocompatibility complex) proteins present viral-associated peptides to the CD8+ T lymphocytes when SARS-CoV-2 enters the host cells. Then, activation and triggering of the CD8+ T cells occur in order to cell proliferation, which causes clonal expansion and expands virus-based effector and memory T lymphocytes. Virus-infected host cells are lysed through CD8+ T cells; in the following step, the virus or viral components are processed by particular "antigen-presenting cells" such as macrophages and dendritic cells and provide peptides to T CD4+ lymphocytes through MHC-II molecules. Pathogens can be identified by B cells that are activated via a direct pathway or by interacting with CD4+ T cells [58], [59].

Despite the restricted immune response, primary investigations represented that patients who got rid of COVID-19 established specific memory T lymphocytes against the coronavirus, which can be traced within two years followed by recovery [60], [61].

NK cells immunity

Natural killer (NK) cells as a part of the innate immune system can target the virus-infected cells [62]. Through cytotoxic mechanisms, NK cells can potentially lyse abnormal cells and overlook normal cells expressing MHC. According to the studies, the inhibitory natural killer receptor can control the NK cells’ cytotoxicity function [63]. Based on the experimental works on the immune cell profiles, during COVID-19 infection, NK cell counts are reduced owing to the infiltration into the COVID-19- affected sites such as the lung [64], [65], [66]. T cells and NK cells are functionally affected by NKG2A (NK group 2A) receptor as a suppressing signaling transmitter; so that it can reduce cytotoxicity and cytokine production. According to the studies, there is an upregulation of NKG2A in people infected via SARS-CoV-2, while lower expression of markers, such as TNF-ɑ, IFN-γ, IL-2, and CD107 is noticeable as activator factors [66], [67]. In addition, it was indicated that a massive deal of damage is caused by the recruited NK cells' hyperactivation in the respiratory organ causing lung injury [68], [69].

Monocytes response

Monocytes are one of the mononuclear cells of white blood cells that are derived from myeloid precursors and circulate in the bloodstream. They possess a plasticity feature as well as the aptitude for differentiating to other cells like macrophages and dendritic cells [70]. There are two main subgroups of monocytes with different features including monocytes CD16-/CD14++ known as classical and monocytes CD16+ classifying into CD16++/CD14+ and CD16+CD14++ cells (non-Classical) [71]. Researchers have shown that some of the important functions of monocytes, such as cytokine secretion and chemotaxis, are impaired during coronavirus infection. Presently, a pattern of remodeled cytokine profiles and chemokine was proved in COVID-19 patients’ monocytes. This change in the cell has a role in the incompetent responses chain, thus boosting the SARS-CoV-2 damaging and causing an increment in mortality [72], [73]. Generally, a reduction in monocyte count was reported in infected patients and indicating that the monocytes’ phenotype in intense cases includes CD14+ monocytes frequently, as well as CD16+ inflammatory monocytes applying inflammatory activity via secretion of IL-6 in COVID-19 [74].

Neutrophil response

Eliminating the pathogens through the phagocytosis process is the main responsibility of neutrophils. They are also responsible for releasing the “Neutrophil Extracellular Traps”, a type of innate response, to restrict virus and cytokine to inhibit replication [75], [76], [77]. The chromatin fibers in these NETs interact with certain enzymes and neutrophil-specific factors, such as myeloperoxidase, neutrophil elastase, and cathepsin G [78]. NETs have a dual opposite role; in this way, the main contribution of these traps have been illustrated in the anti-inflammatory process. On the other hand, they can accelerate tissue damage too [79], [80]. The results of a study revealed that activation of these cells and degranulation are sorely activated procedures in COVID-19 disease [81]. An autopsy obtained from people who have died from the SARS-CoV-2 demonstrated neutrophil localization and penetration in capillaries of the lungs alongside colonization to alveolar space; hence, inflammation in the respiratory system’s lower overall part is justifiable [82], [83]. Moreover, immature neutrophils and ineffective mature neutrophils are reported in COVID-19 sickness [84]. Obviously, a high raised level of CXCL-2, chemokines, and CXCL-8 is documented in the bronchoalveolar fluid of patients that can develop recruiting of neutrophils to the infection site [85], [86]. This phenomenon can be one of the major causes of ARDS due to long-term inflammation caused by hyper-activated neutrophils [87]. What is more, some toxic factors are secreted by neutrophils possibly contributing to ARDS as well [88]. Some ROSs such as superoxide radicals and H2O2 can be made after a respiratory burst via neutrophil cells. Ultimately, oxidative stress is developed by this mechanism which is related to the cytokine storms and blood clots in patients with COVID-19 [89], [90].

Different variants of the SARS-CoV-2

There have been diverse mutations of SARS-CoV-2 creating different variants since the diagnosis and spread of COVID-19. Regardless of the global program of the vaccination to defeat the virus, deep concern has been caused by the arrival of new variants. The variants and their properties are presented in Table 1.

Table 1

Most important variants of the SARS-CoV-2 and features [138], [139].

Variant	Origin Country of the virus	Mutation	Characteristics
AlphaB.1.1.7	United Kingdom	• N501Y • P681H • NTD deletions	• Susceptible to neutralization by mAb • Increases virus replication
BetaB.1.351	South Africa	• K417N, E484K and N501Y • NTD mutation	• Reinfections • Reduced susceptibility to mAbs • Associated with reduced vaccine efficacy
GammaP.1	Brazil	• N501Y, E484K and K417T • NTD mutations	• High infection rate • cause disease in patients formerly infected with previous variants • Reduction in neutralizing activity
DeltaB.1.617.2	India	• T478K, L452R, P681R. • orf3, orf7a	• Increased transmissibility • associated with high-level reduced bamlanivimab susceptibility
OmicronB.1.1.529	South Africa	• G339D, S371L, S373P, K417 N, S375F, N440K, G446S, S477 N, T478K, Q493R, E484A, G496S, N501Y, Q498R, and Y505H	• More infectious • High transmission rate • More reinfections

Pentraxin family of proteins

The pentraxin superfamily consists of similar domains and is seen as a pentameric structure. According to the length of the protein sequence, the pentraxin family can be classified into two main groups, long pentraxin, and short pentraxin. C-reactive protein and serum amyloid P are kinds of short pentraxins and on the other hand, PTX4, PTX3, neuronal pentraxin receptor, neuronal pentraxin 2, and neuronal pentraxin 1 are long pentraxins. Several studies have shown that the members of this protein superfamily have different functions. For example, CRP and serum amyloid P play a role in regulating the immune system as short pentraxins. Their roles in immune adjustment include removing mutant cells, triggering inflammation, and acting against pathogen invasion. In addition, neuronal pentraxin is involved in the development of the central nervous system, and pentraxin-3 plays a central role in activating the immune system, tissue repair, and tumor progression. Researchers have shown that the increases in pentraxin-3 concentration in the blood can be considered a marker to detect the onset of inflammation [91].

Pentraxin 3

PTX-3 as the primary long pentraxin was detected 3 decades ago. In some cells like fibroblasts, endothelial, and epithelial cells, it is induced by TNF-alpha and interleukin-1 beta (IL-1beta). In addition, PTX3 can synthesize in human antigen processor cells like macrophages, dendritic cells, and monocytes that induced by non-viral and viral infectious agents [92]. PTX3 is a critical component of the innate immunity humoral arm and a vital inflammatory mediator. The PTX3 expression levels are much lower in serum and tissues of normal subjects and elevate quickly upon inflammatory stimuli [93], [94], [95]. The human PTX3 gene is placed on chromosome 3q band 25 and includes three exons, the first two of which encode for the N-terminal domain (amino acids 18–179) and the signal peptide, respectively. The third exon is encoded for the C-terminal domain presenting the pentraxin signature (amino acids 179–381) [96]. Enhancer-binding elements are contained in the PTX3 promoters. During proteosynthesis, the final effect of PTX3 is fine-tuned on its target structures. According to literature, Selective promoter factor 1 (SP1), nuclear factor-kappa B (NF-κB), and activator protein-1 (AP-1) are the most dominant ones. Briefly, the basal transcription of PTX3 is enhanced by AP-1 whereas, the binding region of NF-κB works when inflammatory cytokines such as IL-1β and TNF-α are present in the environment. These transcription factors are complemented in their activities of proteosynthesis-modulating through enzymatic biochemical mechanisms. Scientists have shown that if the lung epithelial cells are exposed to inflammatory conditions, the TNF-α can increase the expression of the PTX3 mRNA; nonetheless, the PTX3 protein synthesis is not dependent on the transcription of the NF-κB. Alternatively, PTX3 is made through the “c-Jun N-terminal kinase” path. In endothelial cells, TNF-α and IL-1β induce the PTX3 expression in a good way. Then, within an acute cellular alteration, converting the endothelial cell occurs from an anti-inflammatory phenotype to a pro-inflammatory and pro-coagulant cellular surface [97], [98], [99]. The structure, sources, and functions of PTX3 are illustrated in Fig. 1.

Fig. 1

Pro-inflammatory cytokines are the primary trigger for PTX3 production from various cells. Released PTX3 is involved in the processes of regulating inflammation, tissue regeneration, and clearing pathogens through different mechanisms.

Pentraxin 3 and COVID-19

There is a lower circulating PTX3 level in healthy human circumstances (<2 ng/ml); however, its value will increase sharply at the onset of inflammation. Acute lung injury and ARDS are the characteristics of tissue damage related to hyper-activation of the innate immunity in the lung [95].). PTX3 is a crucial component of humoral-innate-immunity that contributes to resisting pathogens and controlling inflammation. PTX3 and CRP are very similar together, and both belong to the acute phase family of proteins. Furthermore, some studies have suggested PTX3 as an ideal marker for inflammation and infection screening in humans. In these conditions, the local production by various types of cells at inflammatory sites and releasing the preformed protein through neutrophils against primary pro-inflammatory cytokines or microbial particles account for the increase of PTX3 level [100], [101], [102]. Preliminary results of a study showed that the SARS-CoV-2 induces and enhances the expression of PTX3 transcript in two respiratory tract epithelial cell lines, A549 and Calu-3 [103]. According to the analysis RNA and sequencing of purified monocytes from the peripheral blood mononuclear cells, single-cell level attained from COVID-19 patients, PTX3 is expressed selectively by COVID-19 monocytes and neutrophils [104]. PTX3 can play a role in modulating inflammation through two major pathways, the former by interfering with the recruiting of selectin-based neutrophils and the latter by controlling the complement cascade pathway [105]. It is found that uncontrolled complement activation has a significant role in COVID-19 disease pathogenesis, representing a proper therapeutic target. Some scientists believe that high PTX3 protein titers in people with the SARS-CoV-2 indicate a failed negative adjustment of uncontrolled inflammation [106]. The recent studies revealed the deep profiling of immune responses in COVID-19 and relevant signatures as prognostic indicators or disease classifiers. For example, studies showed PTX3 as a hard endpoint, a confident prognostic indicator of short-term death, better than other markers like CRP and IL-6 [107].

The vascular endothelium plays an intricate function in inflammation and immune modulation, an axis for the disturbance of coronavirus infection. According to reports from medical centers, there is a direct correlation between the severity of the disease and uncontrolled activation of the immune system, which leads to macrophage activation syndrome, cytokine storm, and immune exhaustion. Such a hyper-inflammatory mode deteriorates the vascular system, with the resultant EC dysfunction. ECs undergo a transition to an activated state participating in host defenses by the circulation of inflammatory mediators like IL-6, IL-1, DAMPs, and PAMPs. Localized inflammation is promoted by activated ECs by induction of pro-inflammatory gene expression, the attraction of immune cells, promotion of attracting of inflammatory cells to the infected or injured tissues, vascular leak by incrementing the endothelial permeability [64], [108]. As mentioned earlier, PTX3 can increase following COVID-19 and subsequently increase the endothelial damage caused by SARS-CoV-2. PTX3 has a role in endothelial dysfunction and vascular inflammation through different mechanisms. A noticeable relationship has been confirmed between endothelial dysfunction and PTX3 along with various pathogenetic pathways. Inflammatory cells are modulated by PTX3, thus inducing vascular inflammation. It reduces NO synthesis, prevents cell duplication, and changes the functions of endothelial cells. The effect of “fibroblast growth factor 2 (FGF2)” is hindered by PTX3 via creating a molecular complex with such molecules and inactivating them. Though, some factors block the PTX3-FGF2 interaction such as the “tumor necrosis factor-inducible gene 6 protein (TSG-6)”. Endothelial dysfunction and vascular inflammatory response are promoted by interaction with P-selectin. Furthermore, the matrix metalloproteinases synthesis is directly increased by PTX3 or through inhibiting the NO production. Clinically, PTX3 has a positive correlation with flow-mediated dilation, arterial hypertension, and intima-media thickness. Hence, PTX3 is clearly included in the pathogenesis and assessment of endothelial dysfunction [109].

Extensive studies today have well established the role of macrophage-M1 and macrophage-M2 in the COVID-19 [110]. Briefly, macrophages-M1 can be induced by IFN-γ and produce inflammatory cytokines, such as IL-1, TNF-α, iNOS, and IL-6. These factors provide the conditions for killing viruses, cancer cells, and other pathogens, and dead cells are removed through phagocytosis in the next step. So, macrophages-M1 are contributed to the maintenance of body homeostasis via anticancer effects and infection defense. Inordinate immune responses give rise to inflammatory diseases and chronic inflammation; Therefore, it seems that the function of these cells should be adjusted. Conversely, macrophages-M2 have a role in immune tolerance and tissue repair. Macrophages-M2 are differentiated by cytokines including IL-13 and IL-4. They also can suppress the inflammatory response through IL-10, TGF, and arginase [111]. In a study conducted by Hao Zhang et al., they demonstrated that PTX3 is involved in the migration, infiltration, M2-polarization of macrophages and regulates an immunosuppressive microenvironment [112].

Pentraxin 3 and tissue repair

Beyond its contribution as the first resistance barrier against pathogens, Innate immunity is a vital component in initiating tissue repair. Specific DAMPs are sensed by the innate immune system cellular arm regulating the inflammatory responses at the damaged areas. The innate immunity humoral arm has complex and different roles including the regulation of immune cell migration and activation to regulate the remodeling cell activity as well as clearance of apoptotic cells [113], [114], [115]. For example, fibrosis is regulated by SAP by inhibition of the macrophages’ alternative activation through FcγRs or by modulation of immune cell activities through DC-SIGN [116], [117], [118]. Complement system components and pentraxins have also interacted with elements existing within the extracellular matrix (ECM). Therefore, further regulatory roles of the innate immune system are indicated within the tissue response to injury. Moreover, there are various ECM components that improve opsonic activity like fibronectin, osteopontin, mindin, and vitronectin interact with microbes [119], [120]. After the tissue damage, induction of PTX3 occurs in the blood and locally against IL-1β amplification and TLR activation. Fascinatingly, it was reported that PTX3 is among the genes compelled by thrombin in monocytes. At the wound sites, PTX3 is released by neutrophils, within the clot and in the macrophages pericellular matrix and mesenchymal PDGFRα+FAP+ cells indicating that the wound site is invaded collectively [121], [122], [123].

Besides, PTX3 can be involved in tissue remodeling indirectly by regulating inflammation. The inflammatory response is regulated by PTX3 by acting on inflammatory cell attracting. Such an influence is mediated by the PTX3 capacity interacting with the P-selectin including the PTX3 N-linked glycosidic moiety. In other words, leukocyte rolling on the endothelium is inhibited by the interaction between P-selectin and PTX3 resulted. Hence, leukocyte recruitment is reduced by PTX3 prescription in vivo in models of pleurisy, ischemia/reperfusion-induced kidney damage, and acute lung injury [105], [124]. Interestingly, the main anomalies in liver, lung, and skin injury have been found in models of PTX3-deficient mice that referred to redundant fibrin accumulation and incremented collagen deposition accompanied by the dominant function of the fibrin as a provisional matrix protein guiding consequent repair. Such phenotypes are the attributes of the PTX3 interaction via the NH2-terminal domain with plasminogen and fibrinogen /fibrin at acidic pH promoting the degradation of fibrin [125].

Pentraxin 3 and pulmonary fibrosis

Pulmonary fibrosis is one of the life-threatening and most critical complications of COVID-19, which increases mortality [126]. Pathologically, there are more than 200 different conditions in pulmonary fibrosis that are distinguished in terms of inflammation and scar tissue of the lung. The first symptoms of pulmonary fibrosis are manifested by the spread of scar tissue, which includes fatigue, shortness of breath, dry cough, and dysfunction of the respiratory system [127]. As a progressing scarring disease, pulmonary fibrosis occurs in the lungs, with the characteristics of the injury and alveolar epithelial cells hyperplasia of and fibroblasts, consistent deposition of ECM, accumulation of inflammatory cells, and scars formation. The beginning of an inflammatory response and existing immune infiltrate are attracted a huge deal of attention, which develops and endures a fibrotic and damaging context in the lungs [128], [129]. Attaching to various ligands, such as growth factors, microbial moieties, ECM proteins, and complement components, PTX3 exerts its function. It is upregulated to perform a protective impress in different lung disorders [130], [131], [132]. The protective function of PTX3 is reported in lung infections in various pathological settings such as SARS and pneumonia. Researchers by using PTX3 null mice have shown that PTX3 deficiency can lead to an abnormal innate immune response in the lungs and cause acute lung damage [133], [134]. According to Federica et al., PTX3 is made during fibrosis in wild-type mice. They revealed that the induction of fibrotic tissue in the lungs is limited by the accumulation of PTX3 in the Tie2-PTX3 mice’s stroma compartment, with decreased collagen deposition and fibroblast activation, while reducing the immune infiltrate recruitment. On the other hand, an exacerbated fibrotic response was represented by PTX3-null mice along with the reduced survival against BLM treatment. They revealed the protective contribution of the endogenous PTX3 during lung fibrosis. Hence, it is facilitated to investigate the novel PTX3-driven therapeutic methods for the disease [135].

Conclusion

With the outbreak of the SARS-CoV-2, the international community affected by the COVID-19 has incurred high costs; despite the widespread vaccination program against this disease, we are still witnessing people becoming infected with the virus. COVID-19 is an inflammatory disease that presents symptoms in three different clinical phases and gradually becomes a severe and fatal disease. Life-threatening complications include blood clots, vascular damage, cytokine storm, multiple organ failure, and pulmonary fibrosis. Different acute-phase molecules and proteins can be detected during infection; PTX3 is one of them. PTX3 can be induced by TNF-α and IL-1β in cells, such as endothelial, epithelial, and fibroblasts, and can also be synthesized in macrophages, monocytes, and dendritic cells. Different functions of PTX3 have been identified today. It is involved in regulating inflammation, repairing tissue, controlling the complement pathway, recruitment of immune cells, and endothelial dysfunction. Sometimes PTX3 acts as a double-edged sword in humans. For instance, Wesley et al. indicated that overexpression of PTX3 promotes tumor growth, invasion, and metastasis by providing an immuno-suppressive condition [136]. On the other hand, Stebbing et al. showed that the PTX3 level in COVID-19 increases significantly, and if patients are treated, the PTX3 titer will decrease [137]. All in all, these findings suggest that PTX3 can be a reliable marker for the prognosis of the disease; and by examining its level during treatment, we can ensure the effectiveness of the treatment used.

Compliance with Ethical Standards

NA

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Funding

There is no financial support for this study.

CRediT authorship contribution statement

Conceptualization, writing original draft: Ria Margiana. Supervision, validation, and review: Satish Kumar Sharma.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability

Not applicable

Consent to Participate

Not applicable

Competing Interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.