The diagram above represents the infiltration from the blood vessels of the immune cells (see below) into the lung alveoli sack with a cytokine storm lurking in the background.

One target of the COV-2 virus is the protein angiotensin-converting enzyme 2 (ACE2) found on airway (lung) endothelial and epithelial cells, enterocytes of small intestine and kidney cells. The common signs of COVID-19 infection are like the common cold and comprises respiratory symptoms – dry cough, fever, shortness of breath, and breathing difficulties.  In severe cases, infection can cause pneumonia, acute respiratory distress syndrome, kidney failure, and death.

REVIEW OF IMMUNITY When the COV-2 virus infects a person’s body, the cells with the virus are changed such that two types of immune responses are triggered. The most immediate response is the INNATE IMMUNITY, which recruits cells to migrate to the affected area. These cells can be visualized (similar to the old game “Pac Man”) where granulocytes, macrophages/monocytes and eosinophils that engulf the infected cells and release pro-inflammatory and toxic mediators. This response elicits the formation of reactive free radicals, peroxides and digestive enzymes and sends out protein signals (called cytokines), to recruit even more cells (chemotaxis). This extraordinarily strong pro-inflammatory race can result in a cytokine storm (see below) that can lead to the patient’s death.

The secondary response over time, days/weeks is called ADAPTIVE IMMUNITY. This immunity allows more precise and appropriate responses and prepares the body for future similar infections.  This system also has defects, such as autoimmunity when the immune system attacks your body, for example in systemic lupus, or over-reaction to allergens. This immunity recruits B lymphocytes which produce antibodies that can neutralize toxins (tetanus or venoms) and bind pathogens and direct their destruction. Antibodies can be detected for the COVID-19 response and many companies are developing an antibody test to reveal that a person was previously infected by COV-2 virus. The T lymphocytes directly kill pathogens and pathogen infected cells of the body by binding to the infected cell and inducing the formation of “holes” in the cell membrane destroying the cell.  A maladaptation is auto immunities such as in multiple sclerosis (MS), or responses to antigens similar to “hay fever” or to poison oak/poison ivy. Activation of both the T and B lymphocytes may lead to an immunity against the COV-2 virus because of the infection or through a vaccination.

COV-2 VIRUS IMMUNITY

Since the prevalent entry of COV-2 virus is through the airways, whereupon they infiltrate the lower respiratory track, where people derive most of their oxygen.  Within a day or two, the innate immunity cells (see above) are recruited to destroy virus-infected cells and remove cell debris causing inflammation and edema. This exacerbated inflammation at the site and the over-reaction of the immune system, can result in acute respiratory distress syndrome (ARDS). ARDS is defined as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the absence of edema of cardiogenic origin. In other words, the ability to fill the air sacks (alveoli) with air/oxygen is compromised because of the edema (liquid) leaking out of the capillaries serving the alveoli. These capillaries are a sheet of tightly packed cells (endothelial cells) which form the tubes that move blood in the parts of the lungs where oxygen is exchanged from air to blood. The membranes are damaged allowing the fluid to leak out between the cells. This fluid (edema) not only decrease the oxygen exchange capacity of the patient but also allows for infiltration of the pneumonia virus/bacteria exacerbating the symptoms. Because there is less oxygen to support the internal organs, they start to fail.

At some point, breathing support, supplied by a ventilator, alleviates the strain on the muscles involved with breathing, caused by not enough oxygen.  But ventilators force air/oxygen into the lungs, also are associated with increased infection since it is easier for bacteria/virus to be delivered to your lungs. Additionally, there are other problems that are associated with ventilators, blood clots, collapsed lung (the pressure of the gas from the ventilator could escape causing the lung to collapse), and scarring of the lung tissue making it less elastic. Recently, silent hypoxia, extremely low oxygenation of peripheral tissues, has been suggested as common in COVID-19 infected patients before recognition of ARDS or pneumonia symptoms.

During this time, a cytokine storm can occur….

CYTOKINE STORM, over-reaction by the Immune System

Sometimes the immune system overreacts and causes harm. It can be evident within 2 days after the onset of the infection, resulting in lung inflammation and edema leading to respiratory distress. If left untreated, it can increase the risk of mortality in patients, even in young patients with strong immune reactions. The body uses protein cytokines that are released by many different cells, including those of the immune system, and the lung including epithelial and endothelial cells,  where they coordinate the body’s response against infection and trigger inflammation. The name ‘cytokine’ is derived from the Greek words for cell (cyto) and movement (kinos).  There are several clinical trials directed toward toning down the cytokine storm in severely affected COVID-19 patients.

TREATMENTS AND VACCINES

Most of the scientific efforts all over the world are focused on finding a treatment that can be used in patients that have been infected. From virus neutralizing antibodies, ACE2 inhibitors to avoid virus entrance in the cells, to stopping the replication machinery that the virus uses inside human cells. Hundreds of different treatments are being tested with the goal to find an efficacious treatment as soon as possible.

Vaccines to avoid new contaminations will take longer to develop. The scientist needs to find the correct injectable substances (dead virus, parts of virus, purified single proteins or genetic material from the virus). All these efforts need proof they work in animals first, then will have to show the treatment is safe for patients and finally increases the protection against the virus. This long process together with the fact that the virus has the capacity to mutate, necessarily means that we will have to wait for many months or even years until we are able to produce a proper vaccine against COVID-19.

THIS IS WHAT MarinBio CAN DO:  MarinBio scientists are experts in molecular biology and molecular virology of these and other infectious RNA agents, especially the nature and recognition of coronaviral receptors, viral RNA synthesis using QPCR, and the molecular interactions governing viral pathogenesis and virion particle assembly and transmission. MarinBio scientists have over 25 years of experience helping our clients to develop, qualify and validate viral or cell-based assays or RNA/DNA tests as well as a protein involved viral enzyme, anti-inflammatory drug potency immunoassays or other quantitative bioassays. Our scientists have developed and manufactured a GMP 90-minute ELISA test used in multiple hospitals for acute sickle cell crisis patients. For further information please contact MarinBio at info@marinbio.com or call 415 883 8000 or visit our website at www.marinbio.com.