The Pathophysiology of COVID-19

AHMAD NISAR – Exploring the pathophysiology of a disease is like dissecting a machine to understand how its individual parts — its gears, nuts, wires, and bolts — interlock and interact to execute a single, seamless task. Diseases like viral infections and cancer are corruptions of our cellular machinery, but their pinpoint disruption of specific processes like transmembrane signaling or cell cycle progression demonstrates how microscopic changes can cascade into afflictions that ravage the entire body. A famous phrase from the field of chaos theory in mathematics states that “a butterfly beats its wings on one continent, causing a hurricane in another.” Much like the proverbial butterfly, a simple virus — self-replicative clumps of genetic material sheathed by a lipid membrane — can balloon into a massive storm ravaging not just individual people, but whole societies as well. This is most apparent with the ongoing COVID-19 pandemic. Therefore, the purpose of this article will be to explore how the coronavirus operates at a cellular level to inflict systemic damage on the body — and in the process, illuminate the beautiful and multivarious interaction of our cells and organs to sustain the fragility of human life. 

COVID-19 infection begins with inhalation of aerosolized droplets excreted by coughing, sneezing, or fecal-oral contact. The main site of viral infiltration within the respiratory tract is in the alveolar sacs (at the site of gas exchange in the lungs), specifically in the Type II pneumocytes lining the interior membrane of alveoli. The primary function of Type II pneumocytes is to produce pulmonary surfactant — a phospholipid detergent that decreases internal surface tension — to prevent external pressure from collapsing alveoli. The coronavirus membrane is covered with ‘spike proteins’, the most potent of which is the ‘S-spike’ protein. Just as a key opens a specific lock, the S-spike binds to an Angiotensin-Converting Enzyme-2 Receptor (ACE2) on the outside of the cellular membrane, normally responsible for lowering blood pressure by hydrolyzing a vasoconstrictor protein into a vasodilator. This interaction is a critical moment. Once the ACE2 receptor is bound to the COVID-19 S-spike, the virus unloads its positive-sense single-stranded RNA (ssRNA) into the Type II pneumocyte. 

Having been injected into the alveolar cell, the raw ssRNA takes on a life of its own. RNA is rapidly translated into polypeptide chains by taking advantage of ribosomes, while more ssRNA copies are generated by co-option of RNA-dependent polymerases latent in the cell. Viral polypeptides are cleaved and fused to construct functioning components of new viruses — lipid membranes, spike-proteins, capsids, etc.. All these nucleocapsids and spike proteins being printed by hijacked cellular machinery converge to form new viral bodies. After a large enough density of these bodies develops, the emergent viruses erupt to lyse the host pneumocyte and are released into the surrounding alveolar environment. 

This ingenious, internal destruction of cells is not, however, met with little resistance. In response to infection, Type-II pneumocytes release inflammatory signals that stimulate macrophages, intimidating immune cells responsible for consuming and lyzing disruptive cellular matter including viruses, neoplastic cells, and debris. Macrophages secrete cytokines like Interleukin-1, -6, and Tumor Necrosis Factor-𝞪, chemical signals that herald the onset of a targeted inflammatory response at a site of significant infection. Cytokines induce dilation of the endothelial cells and blood channels surrounding alveoli. The smooth muscles of vessels dilate and endothelial cells in the intercellular space contract, allowing for vasodilation and increased capillary permeability. While this normally stimulates increased blood flow to sites of infection, in the context of COVID-19, this reaction is in fact highly dangerous.  Plasma leaks into interstitial spaces around pulmonary cells, resulting in increased pressure on and fluid invasiveness into alveoli (called ‘alveolar edema’ or swelling). This added pressure, coupled with a deficit in surfactant-producing Type II pneumocytes, forces the total collapse of alveolar sacs. Alveolar collapse leads to diminished gas exchange (CO₂ for O₂) which results in hypoxemia (blood-oxygen deficit). The viral infection starts manifesting itself into deadly respiratory symptoms. 

The cytokines previously mentioned also induce neutrophil invasion to the site of inflammation. Neutrophils indiscriminately ‘attack’ viral infiltration by releasing reactive oxygen species and proteases. These stopgap measures cause collateral damage to alveolar cells (type I and II pneumocytes), further disrupting surfactant production and clogging overburdened alveoli with a collection of protein debris, dead cellular material and interstitial plasma fluid — compounding hypoxemia caused by the actual virus. This debris and dead matter is violently coughed up by the body, tearing up the mucinous protective lining in our lungs.  Hypoxemia also induces release of chemoreceptors targeted at the sympathetic nervous system, inducing a higher respiration rate and heart rate. The cytokine storm also accumulates in the hypothalamus, a key mediator between the central nervous and endocrine systems. In response, the hypothalamus releases prostaglandins like PG2 that raise the body’s temperature, a symptom known as fever.

Through a confluence of hypoxemia, cytokine storms, and damage to the lung’s mucinous lining, inflammation of the lungs afflicts the rest of the body through Systemic Inflammatory Response Syndrome (SIAS). Cytokines induce capillary permeability throughout the body, decreasing blood volume and causing accumulation of waste products in the bloodstream (as the kidneys and liver do not receive adequate blood flow), ultimately culminating in septic shock, hypotension, and potentially multi-system organ failure. It is important to note that these symptoms are certainly not an eventuality for everyone infected with COVID-19, but they are more likely to occur with increased age, pre-existing conditions or other vulnerabilities, especially with the lack of a vaccine to prevent viral infection. However, the severity of these symptoms demonstrates the intimate connections between the respiratory, immune, cardiovascular, endocrine, and nervous systems — as well as the fragility and vulnerability of the human lives we care for.