Our species, Homo sapiens, wasn’t always threatened by plagues when it first came into existence. Since the very beginning of our species' appearance, we have been always battling infectious diseases as individuals or small groups, just like any other species. (Harari, 2011) However, we started to face one of our deadliest enemies as a whole, the plagues and other pandemics, when we first domesticated some animals and began to live in more proximity with them while we weren’t evolutionarily meant to (Harari, 2011). In the past, the spread of an epidemic in an area or the spread of a pandemic to several countries, sometimes across a continent or even the entire world had been almost impossible to control (Harari, 2011). Humans have always withstood these diseases throughout history but in fact they only managed to survive by limiting the spread of the disease until a herd immunity was obtained (Harari, 2011).

Only about a century after the world was hit by the 1918 flu pandemic, another pandemic emerged from the city of Wuhan located in the heart of China. In late December 2019, cases of an unknown pneumonia appeared in Wuhan and were soon linked to a wet seafood market (Shah et al., 2020). Due to the similarity of this new infection to the previous Severe Acute Respiratory Syndrome (SARS) infections, scientists immediately took action by screening the samples collected from the potentially infected people using pancoronavirus quantitative polymerase chain reaction primers exploiting available coronavirus genome sequence (Shah et al., 2020). Five samples turned out to be positive for the coronavirus which were further investigated and screened, using next-generation sequencing and phylogenetic analysis. The results identified a strain of coronavirus, initially named 2019-nCoV, responsible for causing the pneumonia (Shah et al., 2020). By February 2020, cases of this newly emerged virus had started to appear in other regions of the world (Shah et al., 2020). The World Health Organization declared this newly emerging disease caused by this now genomically sequenced virus a pandemic on March 11th, 2020 (Shah et al., 2020) when it was already affecting almost 150,000 people around the globe and as of January 15th, 2021 there are 94 million confirmed cases and 2 million confirmed deaths worldwide (The Johns Hopkins Coronavirus Resource Center, 2021).

Figure 1. Coronavirus Transmission. After the emergence of SARS-CoV in the early years of 2000s, scientists found extensive genetic similarity between the various virus strains. It was later concluded that these viruses are naturally hosted and evolutionarily shaped by bats, reaching humans through an intermediate host such as civets. (Adachi et al., 2020)

Coronaviruses are a large family of viruses that are naturally hosted and evolutionarily shaped by bats (Tang et al., 2020). It has been postulated that these viruses that cause respiratory diseases ranging from the common cold to severe acute respiratory syndrome in humans (Chen et al., 2020), are derived from the bat reservoir (Tang et al., 2020) as seen in Figure 1. Due to its genomic similarity to the previously identified coronavirus, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), 2019-nCoV was renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses (Shah et al., 2020). The newly emerged strain, similar to the SARS-CoV-1 that emerged as an epidemic in 2002 with a case fatality rate of about 10% and MERS in 2012 with a case fatality rate of about 34.4%, (Das, 2020) is a member of the β-CoV family (Chen et al., 2020). These three viruses share a number of causative agents but they differ genetically from the common cold human Coronaviruses (HCoV) (Pierce et al., 2020). However, the whole-genome sequence of SARS-CoV-2 revealed that it has a genome sequence 75% to 80% identical to the SARS-CoV (Chen et al., 2020) but has 96.2% similarity to that of a bat SARS-related coronavirus (SARSr-CoV; RaTG13) (Tang et al., 2020). This similarity of SARS-CoV-2 to the bat SARS-related coronavirus is significantly higher compared to the similarity of its predecessors, SARS-CoV (about 79%) and MERS-CoV (about 50%) (Tang et al., 2020). Although the origins of SARS-CoV-2 can be traced back to animals, just like its predecessors, it spreads much easier from human to human contacts (Pierce et al., 2020). It implies that the virus must have presumably crossed the species barrier and adapted to spread among the human population (Pierce et al., 2020).

Figure 2. Depiction of an Intact SARS-CoV-2 Virion. Four major structural proteins: spike (S), nucleocapsid (N), membrane (M) and envelope (E). Positive-sense single-stranded RNA genome is contained within the virion. Image created with BioRender.com

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses whose virions are composed of spike (S), envelope (E), membrane (M), nucleocapsid (N) and other accessory proteins (V’kovski et al., 2020) as seen in Figure 2. Through cryo-EM, SARS-CoV-2 virions are typically spherical in shape and ~100nm in diameter (Ke et al., 2020). The method of infection involves the binding of S proteins with human cell receptors for entry into human cells. For several coronaviruses, these include human aminopeptidase N (APN; HCoV-229E), angiotensin-converting enzyme 2 (ACE2; HCoV-NL63, SARS-CoV and SARS-CoV-2) and dipeptidyl peptidase 4 (DPP4; MERS-CoV) (V’kovski et al., 2020). CoV S proteins are further divided into subunits, S1 and S2, respectively, with the S1 subunit containing the surface-exposed receptor-binding domain (RBD) (V’kovski et al., 2020).

On the surface of the virion, various conformations of the S protein have been identified in SARS-CoV-2. S proteins are classified as “prefusion” or “postfusion” (Ke et al., 2020) as seen in Figure 3a. Figure 3b shows the various conformations: in an “open” prefusion conformation one or more of the three RBD copies are lifted from the spike surface and the “closed” prefusion conformation has all RBD copies flat against the spike surface (Ke et al., 2020). Receptor binding initiates the shift from prefusion to postfusion, “[bringing] the fusion peptide and the transmembrane domain together at one end of a long, needle-like structure centred around a three-helix bundle,” (Ke et al., 2020). 97% of all appearing S proteins are in a prefusion state, and the remaining 3% appear in the postfusion state (Ke et al., 2020). Human ACE2 was identified as the specific receptor that enables entry and subsequent infection by SARS-CoV and SARS-CoV-2, due to the similar makeup of the S proteins which have 76% shared amino acid identity (V’kovski et al., 2020).

Figure 3. a) Depiction of prefusion and postfusion Spikes. b) Alternate conformations of the prefusion spike with 3 RBDs closed, 1 RBD open and 2 RBDs open, from the superior view (top row) and from a lateral view (bottom row) at a 90 degree protrusion angle from the virion surface. Image taken and modified from Ke et al, 2020

Additionally, binding between the S protein and human ACE2 receptor differs between SARS-CoV and SARS-CoV-2, with research suggesting higher binding affinity in SARS-CoV-2 (V’kovski et al., 2020). One feature of the SARS-CoV-2 S protein is that it contains a new polybasic cleavage site at the S1-S2 boundary, which is not present in the SARS-CoV S protein (V’kovski et al., 2020). The newly acquired feature allows for the cleavage, or pre-processing of the S protein by furin (V’kovski et al., 2020). This process essentially primes the S protein for subsequent membrane fusion at the S1-S2 site (Ke et al., 2020). Thus, research would suggest that SARS-CoV-2 is more efficient than SARS-CoV at binding and entering human cells. Furthermore, it is important to note that SARS-CoV-2 also has various methods of immune evasion that make it so highly infectious and dangerous. One such example is the heavy glycosylation of S proteins, which acts as a shield and prevents the action of neutralizing antibodies on virions (V’kovski et al., 2020). The small percentage of postfusion S proteins present further shields prefusion forms from neutralizing antibodies, or alter immune response entirely by inducing a shift to production of non-neutralizing antibodies (Ke et al., 2020).

While the different forms of coronaviruses are unique structurally and lead to varying clinical manifestations, one aspect that is common among them is that adults experience more severe symptoms and are more likely to progress to acute respiratory distress symptoms (ARDS) than youth/children (Otto et al., 2020). ARDS is a life-threatening disease that leads to the development of non-hydrostatic pulmonary edema and eventually respiratory failure. Mortality associated with ARDS ranges from 35% to 46%, extremely high chances (Fan, Boride, Slutsky, 2018). As such, adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly more at risk than youth/children.

The varying clinical manifestations of SARS-CoV-2 in adults compared to youth/children are further emphasized in a study conducted by Pierce et al. Adult patients were seen to experience a severe form of the disease when compared to children and youth. In the study, patients less than 24 years of age were classified into the “children and youth” category, otherwise known as the pediatric group, while adults were any patients older than the age of 24 (Pierce et al., 2020). The study found pediatric patients to spend shorter stays at the hospital, required decreased mechanical ventilation, and lower mortality compared to adults (Pierce et al., 2020).

An exception to the mild symptoms of SARS-CoV-2 infection in young patients is the development of the multisystem inflammatory syndrome in children (MIS-C). This is common in patients who are infected with SARS-CoV-2 and are under the age of 21. MIS-C is characterized by fever, inflammation, recent SARS-CoV-2 infection, and any diseases associated with cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic health (Feldstein et al., 2020). Most frequently, MIS-C is found to affect the cardiovascular system (Feldstein et al., 2020). Currently, the reasons for children/youth experiencing mild symptoms of SARS-CoV-2 infection compared to adults and the children that end up getting MIS-C versus those that do not are unknown (Pierce et al., 2020).

Despite the overall trend observed between the pediatric and adult patient groups, because the clinical manifestation of SARS-CoV-2 infection was heterogenous, the patients were further subdivided into 5 groups as seen in Table 1 (Pierce et al., 2020). The first group consisted of pediatric patients who did not require ventilation and presented with minor symptoms such as a fever (Pierce et al., 2020). The second group consisted of pediatric patients diagnosed with MIS-C (Pierce et al., 2020). The third group included adult patients who recovered from the SARS-CoV-2 infection and did not need mechanical ventilation during the recovery process while the fourth group was made up of adult patients who did require mechanical ventilation or passed away (Pierce et al., 2020). Lastly, the fifth group consisted of pediatric patients who were not diagnosed with MIS-C and required mechanical ventilation as a result of developing progressive respiratory disease (Pierce et al., 2020).

Table 1. Clinical Manifestation of SARS-CoV-2 in 5 Patient Groups

(Pierce et al., 2020)

Additionally, another study conducted by Milani et al. suggests that the difference in the clinical manifestation in children and adults when infected with SARS-CoV-2 may also contribute to how the virus spreads. Unlike the previous study which focused on symptomatic patients, this research article focused on asymptomatic patients (Milani et al., 2020). For instance, Milani and colleagues found that asymptomatic adults are more likely to carry the virus than asymptomatic children. To further elaborate, approximately 1% of asymptomatic children and 9% of asymptomatic adults have been tested positive for the virus (Milani et al., 2020). This showcases that children play a less prominent role in contributing to the spread of the virus than adults. Moreover, this study along with the one previously mentioned suggest that not only is the clinical manifestation of SARS-CoV-2 infection severe in symptomatic adults, but asymptomatic adults are also at a higher risk in further developing the disease and spreading it as opposed to youth/children.

Figure 4. The Inflammatory Response. The four signs of an inflammatory response: pain, redness, heat, and swelling. Resident macrophages (purple) sample the virus and release inflammatory mediators such as chemokines. Circulating neutrophils (pink) are recruited by chemokines to the site of infection. Image created with BioRender.com

In general, upon infection or injury our body will produce an inflammatory response, as seen in Figure 4. The four signs of an inflammatory response are pain, heat, redness and swelling. In the context of CoV-2, this response happens in the lungs. During infection, blood vessels dilate in order to increase circulation to the infected area. This enables cell recruitment lead to swelling, and the increase in blood flow at the surface of our skin is responsible for the signs of heat and redness. In addition, as cells begin to migrate into the infected area, the pressure on pain receptors and release of pro-inflammatory mediators are responsible for tenderness at the given area (Inflammation, n.d.).

Figure 5. Branches of Immunity: Innate and Adaptive Immunity

This bodily response is the result of the immune system. The immune system can be broken up into two divisions: innate and adaptive immunity, as seen in Figure 5. Although different in terms of response time, specificity, protection and nature, the two systems work alongside each other to eliminate infection and restore patient health. In the case of SARS-CoV-2 infection, both systems are crucial and diminished responses may contribute to a poor clinical outcome in COVID-19 patients.

Innate immunity is the immediate defense mechanism that occurs in all living organisms. Within the first few hours, to days of pathogen exposure, the innate immune system is responsible for clearing infection and eliciting an adaptive immune response (Alberts, Johnson, Lewis, 2002). Innate immune responses have broad specificity, lack memory, and recognition of pathogens remains constant over time. The key functions of innate immunity are to: prevent the attachment and entry of pathogenic microbes, while enabling the growth of beneficial microbes; recognize, control, and eliminate danger; induce an inflammatory response and recruit cells to the site of infection; elicit the appropriate adaptive immune response (Ashkar, 2019).

Innate immunity relies on both a humoral and cellular response (Figure 5). It involves molecules such as cytokines, antimicrobial peptides, and complement proteins - all of which are part of the humoral response. It also relies on epithelial cells, macrophages, neutrophils, natural killer (NK) or natural killer T (NKT) cells, and innate lymphoid cells (LICs) - all of which are part of the cellular response (Ashkar, 2019).

Figure 6. Mechanical and Chemical Barriers of Intrinsic Innate Immunity (Ashkar, 2019).

Epithelial Cells

Epithelial surfaces, such as skin and the inner lining of the lungs, are made up of epithelial cells which provide physical protection from the external environment (Alberts et al., 2002). These cells are a part of the intrinsic innate immune system. In addition to chemical barriers, epithelial cells provide a mechanical barrier which prevents the attachment and colonization of pathogens (Figure 6). The epithelial cells that line the lung are especially important as they are joined by tight junctions, enable the movement of mucus by cilia, and release antimicrobial proteins (Ashkar, 2019).

Phagocytosis is an important means of non-specific innate killing. Monocytes, macrophages, neutrophils, and dendritic cells, are all phagocytic cells of innate immunity. These cells are capable of engulfing pathogens in order to destroy them; where seeking pathogens is typically receptor mediated.

Monocytes

Monocytes are derived from the bone marrow and circulate in the blood and spleen. Through pattern recognition receptors, they recognize danger signals, present antigen and secrete chemokines, and proliferate in response to infection and injury (Chiu & Bharat, 2016). Monocytes are also capable of differentiating into macrophages and dendritic cells once they are in specific tissues (Chiu & Bharat, 2016).

Macrophages

Conversely, macrophages are considered terminally differentiated cells that phagocytose pathogens or toxins, secrete chemokines, and migrate to local lymph node beds through lymphatics where they present processed antigens (Chiu & Bharat, 2016). They are known to be efficient at phagocytosis as they contain a great number of various receptors on their surface (Alberts et al., 2002). Moreover, these long-lived cells are present in large numbers in various tissues where infection typically arises, including the lungs (Alberts et al., 2002). In order to prevent damaging the alveoli, tissue resident macrophages are quiescent in the absence of infection and become activated during an infection such as SARS-CoV-2 (Liu et al., 2019). Lung macrophages, in particular, are further recruited upon SARS-CoV-2 infection and have been found to maintain levels of inflammation in patients who display ARDS (Liu et al., 2019). In addition to phagocytosis, upon viral infection activated macrophages secrete a range of cytokines such as IL-6, IL-8, IL-1, IL-12, and TNF (Liu et al., 2019). These cytokines have various systemic effects on the body including fever and further production of other antiviral proteins.

Figure 7. Macrophage Phagocytosis. Pathogen binds to receptors on the surface of the macrophage, is internalized in the phagosome, and is then destroyed in the phagolysosome (Ashkar, 2019).

Neutrophils

Neutrophils are a second type of phagocytic cell which are efficient at engulfing bacteria. Thus, they are considered microphages. Importantly, neutrophils are the first cells to migrate to the site of infection; although unlike macrophages, abundant numbers of these cells are found circulating in the blood and are short-lived (Alberts et al., 2002).

Phagocytosis

In order to detect pathogens, macrophages and neutrophils display recognition receptors, such as toll-like receptors (TLRs) and receptors that recognize the Fc region of antibodies. As seen in Figure 7, upon recognition of the pathogen, the plasma membrane of macrophages and neutrophils surround the pathogen to form the phagosome (Alberts et al., 2002). In the phagolysosome, through a combination of degradative enzymes, antimicrobial peptides, and reactive oxygen species such as NADPH oxidase, phagocytic cells destroy pathogens (Alberts et al., 2002). Moreover, phagocytic cells further elicit an inflammatory response through the release of signalling molecules that induce adaptive immunity (Alberts et al., 2002).

During viral infection, infected cells release molecules such as interferons (IFNs), which act to prevent viral replication and spreading thus, IFNs are important antiviral cytokines. These mediators are particularly important for amplifying APC antigen presentation to T cells (Le Page, Génin, Baines, & Hiscott, 2000). There are three types of IFNs: type I, type II, and type III. Type I interferons are secreted by virally infected cells, and type II interferons (i.e. IFN-γ) are mainly secreted by T cells, NK cells and macrophages (Le Page et al., 2000). In regard to activation, IFNs are responsible for activating macrophages, inducing B cell immunoglobulin switching, inducing apoptosis, and inhibiting cell growth (Le Page et al., 2000).

Macrophages

Macrophages’ response to IFN‐γ induces antimicrobial and antitumor mechanisms as well as the up‐regulation of antigen processing and presentation pathways (Schroder, Hertzog, Ravasi, & Hume, 2004). IFN‐γ controls leukocyte attraction, directs growth, maturation, and differentiation of many cell types, enhances NK cell activity, and regulates B cell functions (Schroder, Hertzog, Ravasi, & Hume, 2004).

Natural Killer Cells

Moreover, upon induction of interferons, natural killer (NK) cells are activated and carry out innate killing (Alberts et al., 2002). NK cells are the most important innate lymphoid cells (ILCs), which can be broken up into three subsets: cytotoxic, regulatory, and cytokine producing (Ashkar, 2019). Through cell-to-cell interaction, NK cells induce direct cell cytotoxicity, leading to apoptosis of the infected cell. These cells have the ability to spontaneously kill through the release of perforin and granzyme granules (Ashkar, 2019).

Interleukin-8 (IL-8) is a cytokine produced by various tissue and blood cells (Bickel, 1993). Interleukin-8 distinctly attracts and activates neutrophils in inflammatory regions, with weak effects on other blood cells (Bickel, 1993).

Macrophages secrete other chemokines such as IP-10, which has pro-inflammatory properties and acts as a modulator of angiogenesis (Gotsch et al., 2007).

Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages (Deshmane, 2009). Monocyte migration from the bloodstream across the vascular endothelium is required for the surveillance of tissues, as well as for the response to inflammation (Deshmane, 2009).

IL-17A is a proinflammatory cytokine that causes epithelial cells to secrete neutrophil chemoattractant chemokines (Geha et al., 2017). Cells that produce IL-17A include TCRα/β T cells, TCRγ/δ T cells, and CD45+CD4+TCR−IL-7R+ type 3 innate lymphoid cells (ILC3s), which reside at mucosal surfaces (Geha et al., 2017). Other sources of IL-17A include dendritic cells (DCs), macrophages, neutrophils, and NK cells (Geha et al., 2017).

Interleukin 6 (IL-6) is another proinflammatory cytokine produced in response to infections and injuries of the tissue (Tanaka et al., 2014). Its defense mechanisms include the stimulation of acute phase responses, hematopoiesis, and immune reactions (Tanaka et al., 2014).

TNF (or TNFα) is a key mediator of both acute and chronic systemic inflammatory reactions, that results in tumor cell necrosis and apoptosis (Chu, 2013). TNF can induce its own secretion, as well as stimulate the production of other inflammatory cytokines and chemokines (Chu, 2013). TNFα is mainly produced by macrophages (Chu, 2013).

Figure 8. Adaptive Immunity. Dendritic cell (yellow) travels through the lymphatic system to the lymph node, where it presents viral antigen to Naive T cells . In addition to other factors, this results in T cell activation. Activate T cells induce B cell differentiation into antibody secreting plasma cells. Antibodies and T cells perform antiviral responses. Adapted from “Adaptive Immunity,” by BioRender.com (2021). Retrieved from: https://app.biorender.com/biorender-templates

Adaptive immunity occurs only in higher organisms such as jawed vertebrates (Ashkar, 2019). Starting at roughly day five, to weeks of pathogen exposure, the adaptive immune system is responsible for destroying resilient pathogens and the toxic molecules they produce (Alberts et al., 2002). Unlike the innate immune system, these responses are destructive and result in high levels of inflammation (Alberts et al., 2002). Moreover, in contrast to innate responses, adaptive responses have high specificity, long term memory, and recognition by the adaptive immune system improves overtime (Ashkar, 2019). In this way, adaptive immunity is able to distinguish between particular pathogens and provide long-lasting protection to viral or bacterial pathogens (Alberts et al., 2002).

Similarly to innate immunity, adaptive immunity depends on both a humoral and cellular response (Figure 5). However, these responses are carried out by white blood cells known as lymphocytes. The humoral response is carried out by B lymphocytes (or B cells) which secrete antigen specific antibodies: proteins called immunoglobulins (Alberts et al., 2002). An antigen is any substance that is capable of eliciting an adaptive immune response. The cellular response is carried out by T lymphocytes (or T cells) (Alberts et al., 2002).

Antigen Presenting Cell (APC) is a name given to any cell which displays endogenous viral products and/or exogenous bacterial products to T cells for T cell activation (Figure 8). Dendritic cells, macrophages and monocytes are all professional APCs that initiate T cell development. Specifically, APCs display surface major histocompatibility complexes (MHCs) and are responsible for secreting IFN-γ, IL-12 and IL-15 (Stampfli, 2019). APCs are important immune cells as they process antigen and present them on their MHCs. Notably, T cells require antigen presentation on MHCs in order to undergo maturation and differentiation. In Grifoni et al., a reduction in APC function lead resulted in immune evasion by SARS-CoV-2.

There are two subsets of T cells: CD4+ T cells (T helper cells), and CD8+ T cells (cytotoxic T cells). T helper (Th) cells have dual functionality. These cells are responsible for producing cytokines, some of which are necessary for CD8+ T cell activation, and stimulating B cells to generate antibodies for the humoral immune response (Cano & Lopera, 2013) (Figure 8). Th cells are especially important for regulating the deletion and amplification of specific immune cells (Monsalvo et al., 2011). There are a number of Th cells: Th1, Th2, Th9, Th17, Th22, T follicular helpers (Tfh), and T regulatory cells (Tregs). The Th cells are identified based on the type surface markers and cytokines they produce (Cano & Lopera, 2013). Tregs express cell surface markers CD4 and CD25. Due to this, Tregs can also be referred to as CD4+ CD25+ T cells. Tregs are especially important in preventing immune cells from responding to self-antigen, which helps prevent autoimmune diseases (Cano & Lopera, 2013). Th1 cells produce IFN-γ and elicit a strong immune response to intracellular pathogens (Cano & Lopera, 2013).

On the other hand, CD8+ T cells are cytotoxic T cells that directly destroy malignant or virally infected cells. They do this through inducing apoptosis by release of cytotoxic granules or expression of death ligands (Cano & Lopera, 2013). CD8+ T cells also release important mediators such as IFN-γ , TNF-α, and IL-2 (Cano & Lopera, 2013). The production of IFN-γ is crucial for recovering from infection, and T cells are responsible for this prominent IFN response (Chen et al., 2020). However, induced late T cell responses may amplify pathogenic inflammation outcomes in some patients (Grifoni, 2020).

Figure 9. The Humoral Antibody Response in Three Ways. Antibodies will bind to the pathogen (antigen) on the surface of the B cell. The antigen is processed into peptides which activates Th cells. Signals between the Th cell and the B cell allows for the differentiation of the B cell into a plasma cell, secreting a specific antibody. These antibodies protect the host from infection in three ways. 1) Neutralization: By binding to the pathogen, the pathogen is unable to infect the skin cells, therefore inhibiting its toxic effects. 2) Opsonization: By coating the pathogen, the antibodies can enable accessory cells, which recognize the Fc portions of antibodies, to ingest and kill the pathogen. 3) Complement activation: Complement proteins can strongly enhance opsonization, and can directly kill some bacterial cells (Janeway et al., 2001).

B lymphocytes are cells that induce a humoral adaptive immune response. The B cell receptor (BcR) undergoes many phases of gene rearrangement and selection before releasing it as immunoglobulins. Interactions with antigen presenting T cells allow for the production of specific antibodies that aid in pathogen neutralization or destruction (Stampfli, 2019).

The extracellular spaces of the body are protected by the humoral immune response, in which antibodies produced by B cells destroy extracellular microorganisms and prevent the spread of intracellular infections (Janeway et al., 2001). Antigens trigger the activation of B cells and their differentiation into antibody-secreting plasma cells and usually require Th cells (Janeway et al., 2001).

There are three main ways in which antibodies can contribute to immunity (Figure 9). Neutralization, in which the antibodies bind to the pathogen, preventing the binding of viruses and intracellular bacteria to the target cell surface (Janeway et al., 2001). Neutralization also prevents bacterial toxins from entering cells. Next, antibodies can defend the host through phagocytosis in either of two ways. Opsonization refers to antibodies coating the pathogen, and these antibodies are then recognized by Fc receptors on phagocytic cells (Janeway et al., 2001). The receptors will bind to the constant C region of the antibody and phagocytosis will occur. Alternatively, complement activation is another way phagocytosis can occur. Through the binding of complement proteins to the pathogen, complement receptors will bind to phagocytes, opsonizing the pathogen further (Janeway et al., 2001). Lysis can also occur with certain microorganisms by pore formation in their membranes. The isotype or class of antibodies produced determines which mechanism is utilized (Janeway et al., 2001).

Antibody interactions may be strictly between antibody and cognate antigen or may be between antibody-antigen immune complexes and immunoproteins or effector cells expressing Fc receptors (Tay et al., 2019). The Fc receptor-dependent function of antibody-dependent cellular phagocytosis (ADCP) provides mechanisms for clearing the virus and virus-infected cells, as well as for stimulating downstream adaptive immune responses via antigen presentation, or by secretion of inflammatory mediators (Tay et al., 2019).

Figure 10. Levels of Defense: Intrinsic Innate Barrier, Innate Immunity, Adaptive Immunity

In conclusion, there are two different levels of immunity. The first level, innate immunity, includes the intrinsic barrier. It is immediate, nonspecific and present at birth. The second level, adaptive immunity, is specific and improves with age as one is exposed to pathogen. These two levels of immunity are the main differences in the clinical manifestations of pediatric and adult SARS-CoV-2 patients. Pediatric patients had a shorter length of stay, required decreased mechanical ventilation, and had lower mortality compared to adults with more severe symptoms. In order to explain these differences, three key immunological responses that differ in children and adults were discussed in Pierce et al. These responses are cytokine production, the cellular T cell response and the humoral antibody response. By further understanding these mechanisms, we can come up with new drugs and vaccines to eliminate the spread of SARS-CoV-2.

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