This post is being written during the time of coronavirus pandemic, when the scientists are still attempting to understand SARS-CoV-2. There are still studies been conducted to know more about the virus in order to develop a vaccine or a medication.
This post is written in an attempt to discuss about the way SARS-CoV-2 is transmitted from one person to another and the effect of the virus on the human body; that is the pathogenesis, based on the data available. Here we go,
• Transmission:
The first cases of the CoVID-19 disease are thought to be transmitted through animal to human transmission in the Huanan Seafood Wholesale Market of Wuhan. Later it was found that, the SARS-CoV-2 could successfully transmit from human-to-human. The human to human transmission (fig 1) occurs through:
– Respiratory droplets are generated during coughing and sneezing. These are more than 5-10 μm in diameter, and due to their large size they settle down before evaporating. These infectious droplets can be inhaled by the healthy individuals, causing him/her to be infected.
– Aerosol transmission can occur in closed spaces. These are virus carrying liquid particles, less than 5 μm in diameter. Due to smaller size, they can remain airborne for a longer period of time and can be inhaled by the healthy individual.
– Close contact with the infected person can transmit the infection. That is the infection can spread among family members, friends, colleagues or even through health workers, etc.
– Indirect/ Fomite routes: It has been observed that the virus remains active/viable on the surfaces for time as long as 1-4 days. Infection can spread through such contaminated surfaces, called as fomites. When such objects are touched by healthy person, the hands can pick the viruses which can then enter the person when he/she touches mouth, eyes or nose with contaminated hands.
(Just for info: Read the article titled ‘Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1’)
Mother-to-child transmission of COVID-19 during pregnancy is not yet been verified, but the virus has not been detected in amniotic fluid, breastmilk, or other maternal samples. However, the child can get infected through person-to-person transmission after birth.
(Just for info: Read the article titled ‘No SARS-CoV-2 detected in amniotic fluid in mid-pregnancy’.)
The symptomatic people spread COVID-19; however, the asymptomatic individuals also can transmit the virus. Therefore quarantine and isolation is the best way to contain this epidemic and is being applied in many countries across the globe. Maintaining distance from the patients can really help limit the spread.
• Pathogenesis of COVID-19
Once a person inhales the virus through respiratory droplets or aerosols, it binds to epithelial cells in the nasal cavity and starts replicating to produce more viral particles. An innate immune response is initiated against the virus by the body. One of the response is the production of excess mucus, to prevent the infection from spreading. This production of mucus causes rhinorrhea or runny nose. Inflammation also occurs at the site of viral infection, which may cause fever.
At this stage, the virus is detectable, using the nasal swabs. The infection is also transmissible at this early stage, sometimes when the person is still asymptomatic (something which differs from the SARS-1), .
The infection can be limited to this stage, depending on the health, age and immunity of the person, and the patient experiences mild to moderate symptoms. This is observed in around 80% of the cases where patients experience only fever and rhinorrhea.
However, if the virus is able to infect the respiratory system further down the throat and later lungs, the severity of the disease increases. The more severe symptoms includes dry cough, difficult breathing, muscle pain, fatigue, decreased leukocyte counts, pneumonia, as in case of around 15% of the patients. This includes older adults and people having serious underlying medical conditions. The most serious symptoms include, multiple organ failure or dysfunction, eventually causing death, as in around 5% of the cases.
– One of the main cause of severe symptoms in COVID-19 is Acute Repiratory Distress Symptoms (ARDS). Other mechanism that contributes to the the severity of the COVID-19 is Renin-Angiotensin System downregulation.
• Acute Repiratory Distress Symptoms (ARDS):
ARDS is a serious condition causing pulmonary damage. This condition is characterised by fluid filling up into the lung effecting the exchange of gases, i.e. oxygen and carbon dioxide. One of the main mechanisms for ARDS is the cytokine storm.
– Cytokine storm is a fatal inflammatory response resulting from the release of a huge amount of inflammatory cytokines and chemokines produced by the immune cells. This results in the destruction of not only the virus-infected cells, but also of the neighbouring healthy cells. This process can eventually lead to a systemic damage.
(Just for info: Read this review paper to know more about cytokine storm in general.)
In case of COVID-19 the cytokine storm takes place in the lungs. As SARS-CoV-2 reaches the lungs, it infects and reaches the alveoli (see fig 2).
In each alveolus, there are two types of alveolar cells: alveolar type 1 and alveolar type 2 (see fig 3). Alveolar type 1 cells is involved with the gas exchange with the capillaries surrounding the alveoli, and the alveolar type 2 cells synthesize the surfactants, which reduce the surface tension in the alveoli.
The SARS-CoV-2 infects and destroys the alveolar type II cells (aka type II pneumocytes). The damaged cells signal the macrophages to arrive at the site of infection. Once at site, the macrophages secrete the repertoire of cytokines and chemokines, leading to cytokine storm. Interleukin 1, interleukin 6 and tumor necrotic factor TNF α are the main players in the cytokine storm.
– Interleukin 1 is a potent pro-inflammatory cytokine, which triggers vasodilation, induces fever and hyperalgesia (increased pain sensation). IL-1 also leads to local fluid build-up or edema, which fills up the alveoli (fig 4). The layer of fluid doesn’t allow the inhaled air to reach the alveolar cells and further to the capillaries, making the gas exchange difficult. Due to this impaired gas exchange, the breathing becomes difficult, that is dypsnea is caused, and the patient may need to be put on the ventilator.
Also, as the gas exchange becomes difficult, the body is unable to receive the adequate amount of oxygen and the hypoxia takes place. This leads to heart beating faster in an attempt to supply more oxygen to the cells of the body.
– Interleukin 1 also increases the number of adhesion molecules in endothelium cells enhancing the migration of neutrophils and lymphocytes to the area. The migration of neutrophils and lymphocytes increases the severity of the inflammation, causing lung injury.
– Interleukin 6, has pro-inflammatory effect, induces fever and results in the synthesis of acute phase proteins by the liver.
– TNF α, too, is a pro-inflammatory cytokine which induces cachexia (muscle wasting and weight loss), fever and apoptosis or necrosis of other cells. Other effects of TNF-α include vasodilation and edema formation, resulting in pneumonia (filling of air spaces in lungs with fluid).
All the factors, like lung injury, pneumonia can further lead to acute respiratory disease, septic shock, multi organ failure and even death
• Renin-angiotensin system (RAS) downregulation:
The dysfunction of RAS further aggravates the severity of the disease. Now, ACE2 enzyme plays an important role in the renin-angiotensin system (RAS). It aids in lowering the blood pressure by degrading Angiotensin II to generate Angiotensin 1-7 (fig 5). As a result, it is a critical regulator of blood volume and systemic vascular resistance. It is also involved in the stimulation of haematopoiesis and maintainence of circulating white blood cells.
As we know from the previous post, SARS-CoV-2, binds and attaches to the ACE2 for its entry into the host cell, which adversely effects the functions of these proteins.
Also, lung highly expresses ACE2 and is an important site of systemic Angiotensin II synthesis. Usually, during ARDS, the RAS works to maintain oxygenation. However, in case of COVID-19, the ACE2 is bound by the viral S1 protein subunit, leading to complete pulmonary damage with enhanced inflammation and vascular permeability.
Another fact that makes ACE 2 an important factor, is that it is also a target for the treatment of hypertension. Medications in such patients results in an upregulation of the ACE2 receptor, increasing the risk of severe symptoms in such patients.
(Just for info: Read this review paper to know more about ACE2 and it’s role in RAS.)
Presence of ACE2 on the testes’ Leydig cells may affect male fertility. It is observed that the serum luteinizing hormone (LH) increases considerably resulting in an decreased testosterone (T) to LH ratio in COVID-19 patients, which can cause hypogonadism
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All these mechanisms and processes can gradually cause damage to other organs such as the heart, the liver, the kidneys due to virus infection, medications, immune response or hypoxia. Patients eventually die of multiple organ failure, acute respiratory distress syndrome, arrhythmias, heart failure, and kidney failure.
‘Hence it’s wiser to stay home and stay safe’
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Visit WHO website to know about the current situation.
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References:
Cascella et al (2020) Features, Evaluation and Treatment Coronavirus (COVID-19) NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
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Kuba et al (2006) Angiotensin-converting enzyme 2 in lung diseases.Current Opinion in Pharmacology 6(3):271-276.
Rothan and Byrareddy (2020) The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity 109: 102433.
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https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html
COVID-19 Transmission Dynamics, April 20, 2020. American Society for Microbiology.
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