Immunopathology of coronavirus disease 2019 (COVID-19)

Severe coronavirus disease 2019 (COVID-19) is well known for pneumonia, lymphopenia, exhausted lymphocytes, and a cytokine storm. The significant antibody production whether protective or pathogenic in nature is yet to be determined [1]. Most patients with COVID-19 exhibit mild to moderate symptoms. However, approximately 15% progress to severe pneumonia and 5% eventually develop acute respiratory distress syndrome (ARDS), septic shock, and/or multiple organ failure [2-3].

Immunity can be of two types viz. innate and adaptive immunity. SARS-CoV-2 is a virus responsible for COVID-19 and this virus can activate both innate and adaptive immunity. Innate immunity refers to a non-specific immune response elucidated by the body system which is present earlier from birth. Meanwhile, adaptive immunity develops after exposure to an antigen. An antigen is a foreign substance or unique molecule of the pathogen (such as virus, bacteria, etc.) that brings about immune response resulting in the production of antibodies. Likewise, antibodies refer to the immunoglobulins produced mainly by plasma cells that neutralize pathogens circulating in the body. However, there is a condition of uncontrolled innate response and impaired adaptive response in COVID-19 infection. This type of immune response may lead to harmful tissue damage either locally or systematically as such. It has been observed that patients with severe form have lymphopenia as common features followed by a drastic reduction in numbers of CD4+ T cells, CD8+ T cells, B cells, and natural killer (NK) cells [2-5]. There is also a reduction in the percentage of monocytes, eosinophils, and basophils [4,7].

SARS-CoV-2 binds to the host cells by the help of spike protein with the host cell receptor called angiotensin-converting enzyme 2 (ACE2). Binding is further facilitated by cellular serine transmembrane protease of the host cell membrane called TMPRSS2. After this, the virus undergoes active replication, and the release of the virus causes the host cell to undergo pyroptosis and eventually release damage-associated molecular patterns. This molecular pattern includes ATP, nucleic acids, and ASC oligomers. Innate immunity is the first line of defense against virus infection. Following viral infection, activation of intracellular pattern recognition receptors senses the pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharide (LPS) of Gram-negative bacteria, lipo-teichoic acid (LTA) of Gram-positive bacteria, double-stranded RNA, uncapped mRNA, etc. However, PAMPs related to viral infection are important in this discussion. The recognition of PAMPs (as mentioned earlier i.e. ATP, nucleic acids, and ASC oligomers) is brought about by neighboring epithelial cells, endothelial cells, and alveolar macrophages. As a result, pro-inflammatory cytokines and chemokines including IL-6, IP-10, macrophage inflammatory protein 1 alpha (MIP1ɑ/CCL3), MIP1 β and MCP1, etc. are generated. These are the proteins that attract monocytes, macrophages, and T cells to the site of infection. This promotes further inflammation with the addition of IFNɣ produced by T cells and establishes a pro-inflammatory feedback loop. 

Adaptive immunity aids in the clearance of virus via activated cytotoxic T cells and simultaneous production of antibodies by B-cells targeting virus-specific antigens. It has been reported that patients of COVID-19 suffering from severe pneumonia has conditions of lymphocytopenia (lower lymphocyte counts) and higher plasma concentration with inflammatory cytokines such as IL-6 and tumor necrosis factor (TNF) [8-10]. IL-6 is a cytokine that stimulates B-cell differentiation into immunoglobulin producing cells. Hence, IL is also called a B-cell stimulatory factor (BSF). The increase of pro-inflammatory subsets of T cells, perforin, and granzymes could be responsible for the severe immune injury in the lungs of the severe patient [11]. Therefore, most patients with severe COVID-19 are accompanied by elevated serum levels of pro-inflammatory cytokines including IL-6, IL-1β, IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1ɑ, and TNF characterized as cytokine storm [11-14]. Cytokine storm is defined as the overproduction of cytokine caused by abnormal immune activation. In addition, C-reactive protein and D-dimers are found to be abnormally high.  In the late stages of the disease, cytokine storms are major attributes for disease progression and eventually death [12-14]. Thus, high levels of pro-inflammatory cytokines may lead to shock and tissue damage in the heart, liver, and kidney, as well as respiratory failure or multiple organ failure.

Figure 1. Immune Mechanisms Affected by COVID-19

SARS-CoV-2 Mediated Inflammatory Responses:

The inflammatory response (inflammation) occurs when tissues are in the process of injury by bacteria, trauma, toxins, heat, or any other cause. The damaged cells release chemicals including histamine, bradykinin, and prostaglandins, the result of which causes leaking of fluid from blood vessels into the tissues. This causes swelling and help in isolating foreign substance from further contact with body tissue. According to Fu et al (2020), there are two types of inflammatory response viz. Primary inflammatory responses and Secondary inflammatory responses by SARS-CoV-2 [15]. 

i) Primary Inflammatory Responses: It occurs early after viral infection before the appearance of neutralizing antibodies (NAb). These responses are driven by active viral replication, viral-mediated ACE2 downregulation and shedding, and host anti-viral response. Viral replication may cause massive epithelial and endothelial cell apoptosis and vascular leakage. This trigger the release of excessive pro-inflammatory cytokines and chemokines and the SARS-CoV-2 infection may also induce pyroptosis in macrophages and lymphocytes [16]. 

ii) Secondary Inflammatory Responses: It begins with the generation of adaptive immunity and NAb. The S-protein of the virus generates neutralizing antibodies i.e. the virus-anti-S-IgG complex by host cell immune response. When antiviral neutralizing antibodies cannot completely neutralize the virus, Fc receptor-mediated antibody-dependent enhancement (ADE) occurs. Then, this leads to viral endocytosis and infection of the target cell. Thus, the virus-NAb complex trigger FcR-mediated inflammatory response and acute lung injury. 

Virus-NAb complex binding to FcR can also activate the pro-inflammatory signaling pathway. It skews macrophage response to the accumulation of pro-inflammatory (M1 or classically activated) macrophages present in the lungs. The M1 macrophages after secreting inflammatory cytokines such as MCP-1 and IL-8 results in lung injury. Alternatively, antibody-dependent cell-mediated cytotoxicity (ADCC) may also be involved. 

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References

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