**3. Interaction of virus with the immune system**

Manifestations of COVID-19 is extremely heterogeneous, with a wide clinical spectrum varying from asymptomatic infection through mild upper respiratory and conducting airways infection, to severe pneumonia leading to fatality [24, 26]. Recognizing the machinery for the virus invasion into the host body and its interaction with the host immunity will facilitate the prevention and treatment of the COVID-19. Infection with SARS-CoV-2 has two distinct clinical phases: primary and secondary inflammatory phases. The primary phase involves the invasion of viral in the host and its replication and the inflammatory phase involves exaggerated host immune response towards the virus. Augmented host immune response eventually results in fast and uncontrolled deterioration and worsening

of respiration and ultimately emerges the need for hospitalization [27, 28]. SARS-CoV-2 is a lower respiratory tract virus and enters the host through a specific receptor i.e., ACE-2, resulting in pneumonia in severe cases. It chiefly consists of four structural proteins including nucleocapsid polymer, small envelope glycoprotein, membrane glycoprotein and spike polymer, as well as numerous accessory proteins. Spike protein projected from the surface of the virus is responsible for the attachment with ACE-2 assists the invasion of viruses into the host cells [29]. ACE2 is mainly expressed on the lung, kidney, intestine and epithelial cells of blood vessels. It is worth mentioning that spike protein is considered as the potential target in the vaccination against COVID-19. The innate and the adaptive immunity pathways are two pieces of machinery of the host immune system against foreign pathogens [30]. To effectively deal with and rapidly control the spread of viral infection, the innate immunity activates and concomitantly stimulates the adaptive immunological reactions. The innate system is the first-line defense against the pathogen which comprises of external defense mechanism (e.g. epithelial cells or the mucous membranes in the nasopharynx, lung, gut, periodontium and skin), nonspecific phagocytic leukocytes (macrophages and neutrophils) as well as serum proteins [30, 31]. Adaptive immune build up in a long time includes a specific response i.e., production of protein molecules known as antibodies that react with the antigens of infectious agents to eradicate the virus and to forbid progression of the disease to severe stages [32]. The host immune system via frequently interacting innate and adaptive mechanisms defends against external pathogens. Better management and prevention of disease requires timely identification of disease as well as its influence on the immune system. The disease complexity is further noticeable when it is reported variability in susceptibility to severe infection and mortality in certain sections of the population. However, earlier literature reported that the viral infection alerts immune system operations and influences immunoglobulin levels, antibody generation, phagocytosis, lymphocyte transformation etc. [33]. Similarly, SARS-CoV-2 also impacted the innate and adaptive immunity of the host.

## **3.1 Impact of SARS-CoV-2 on innate immunity**

It has been reported in numerous studies that interleukin-6 (IL-6) is upregulated in patients affected with SARS-CoV-2 [24]. IL-6 is chiefly produced by monocytes or macrophages. IL-6 employs immune mediators and results in the cytokine storm, which cause tissue damage and uncontrolled systemic inflammation [34]. Moreover, inflammatory cytokines including chemokines, interferon-gamma (IFN-γ), IFN-γ induced protein 10 (IP-10), tumor necrosis factor (TNF-α), interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) are observed to be augmented in patients affected with COVID-19 [24]. Lactate dehydrogenase is a marker of pyroptosis and is also found to be augmented in patients affected with COVID-19, and is considered to be correlated with the severity of the disease as well as the rate of mortality. Innate immune response was observed to be activated in COVID-19 patients, but unsuccessful to commence robust interferon (IFN) responses. The deficient of IFN responses could probably result in insufficiency in confining the viral load and viral infection at the initial stage of disease progression [34]. There is limited literature regarding the mechanisms underlying the SARS-CoV-2 induced mitigation of IFN responses. Macrophages play important role in immune responses against viral infection. ACE2 receptors are found to be expressed on the surface of macrophages [35]. This leads to increased susceptibility of macrophages to SARS-CoV-2 infection. This signifies that macrophages may serve as a possible reservoir of the COVID-19 virus [36].

*The Role of Complementary and Alternative Medicines in the Treatment and Management... DOI: http://dx.doi.org/10.5772/intechopen.100422*

## **3.2 Impact of SARS-CoV-2 on adaptive immunity**

Stimulation of the innate immunity subsequently activates the adaptive immunity. Thymus cells (T cells) and bone marrow- or bursa-derived cells (B cells) are key players in adaptive immunity. Effector T cells mediate cellular response against the virus by either directly killing the cells infected with the virus or by discharging regulatory and pro-inflammatory mediators. B cells mediate the humoral responses by producing neutralizing antibodies (NAbs). The released NAbs in turn obstruct the interaction between the spike protein of SARS-CoV-2 and ACE2 expressed on the surface of the cell membrane and thus block the invasion of the virus into the host cell. On the contrary, the virus-specific antibodies interact with complementary receptors expressed on the exterior of the host cell and thus assist the entrance of the virus into the host cells. This is termed antibody-dependent enhancement (ADE) [37]. The NAbs titer is reported to be associated with disease severity [38]. However, there is a range of levels of NAbs among various patients, demonstrating the individual variation in immune responses towards viral infection. Cellular immunity is another intend of the adaptive immune system is against viral infections including the cluster of differentiation 4 (CD4) and the cluster of differentiation 8 (CD8) positive T cells. CD4 and CD8 are glycoproteins that serve as a co-receptor for the T-cell receptor (TCR). CD4+ T releases cytokines, which help cytotoxic T cells and B cells. On the other hand, the CD8+ T cells after being activated eradicate the infected cells. Depletion as well as the exhaustion of peripheral CD4+ and CD8+ T cells are reported in COVID-19 patients [39]. This depletion and exhaustion of T cells may be due to the augmented level of IL-6 in COVID-19 patients [40].
