Immune function is essential for our survival. Humans are constantly under attack from organisms that exist in our environment, both internal and external. Coronavirus – 19 is the newest viral pathogen that has mutated to test human’s immune systems. The goal of immunity is eliminating the virus without damaging the host.
The current COVID-19 infection has brought into clear focus the intricacies of the immune system. Almost every stimulus has an inhibitor that winds down the response. When the virus is not removed, the stimulus persists and is not inhibited. The result is tissue damage.
The lung is the primary target of the COVID-19 infection. Viruses enter cells through receptor mediated endocytosis. Endocytosis is a process where the cell cover wraps around invading structures (virus, protein for example). This process is facilitated by receptors for certain proteins that can be used by a virus to invade cells.
In the lung, the primary structures that allow for oxygen exchange are the alveoli. The alveoli contain a very thin cell membrane to allow this gas exchange to occur. The normal alveolar cell membrane consists of type I (AT1) and type II (AT 2) cells that form the tight barrier to exclude fluid from the membrane and lung. The AT 2 cells are prone to viral infections possibly because of angiotensin converting enzyme 2 (ACE-2) receptors on their surfaces. The activation of the ACE-2 receptor results in the stimulation of adaptor-related protein kinase 1 (AAK1) complex that causes the outer structure of the endosome (clarthrin) to form in AT 2 cells. That activation allows a firm endosome to move through a cell to a lysosome where the acidic environment allows for the formation of viruses or breakdown of proteins. Disruption of AAK1 could interrupt the passage of the virus into cells and the intracellular assembly of viral particles.
A London-based artificial intelligence company searched a data base for currently approved drugs for mechanisms of action that would interrupt the production of virus. Baricitinib, a JAK 1 and 2 inhibitor, is an approved biologic therapy for rheumatoid arthritis that has the potential to disrupt viral replication. Janus kinases activate pathways in cells that result in the activation of DNA in cell nuclei. JAK 1 and 2 cause the activation of signal transducer and activator of transcription (STAT) pathway. This pathway produces cytokines that have a variety of effects on immune function. Inhibition of the JAK 1 and 2 pathways in rheumatoid arthritis results in control of joint inflammation. The usual dose of baracitinib in RA is 2 mg daily.
A clinical trial including lopinavir/ritonavir (an anti-HIV drug) 200mg/50mg 2 tabs every 12 hours for 10 days, hydroxychloroquine 400 mg every 12 hours for 10 days, baricitinib 2 mg daiy for 10 days, and sarilumab (anti-IL-6) biologic 200 mg subcutaneous once has started for the treatment of COVID- 19 infection in 1000 patients. These agents are thought to have the potential to change the internal environment of cells or their replicative capabilities. The results are due in 2021. Clinical trial NCT04321993.