Issue #95: Viruses, Vaccines and COVID-19: joining battle in the pneumonic lung

Written by Nobel Laureate Professor Peter Doherty

Last week (#94) we discussed how, in someone vaccinated against the spike protein of the original SARS-CoV-2 Wuhan strain who has then been infected with the Omicron variant, enlarged, ‘activated’, immune-effector T cells and B cells will start to move out of the lymphoid tissue in the head and neck region to travel, via the lymph, to the venous circulation. That process takes days and, of course, once the lung is infected, the mediastinal lymph nodes in the chest will also be involved. But this doesn’t mean that any of these new immune cells will move straight to sites of virus replication. Their only access is via the ‘highways, then minor byways’ of the vasculature.

Once in the circulation, our immune cells (or any antibodies that have been made in the lymphoid tissue) will flow in venous blood to the right side of the heart to then be pumped by the smaller right ventricle directly into the lung. There, at the capillary bed of the terminal lung alveoli, the red blood cells (RBCs) exchange CO2 for the air-supplied O2 that transforms the dark red of deoxygenated RBC haemoglobin (venous) to the bright red of the oxygenated form (arterial). The O2 -refreshed blood then travels via the four pulmonary veins, two each for the right and left lung, to the right ventricle, then the powerful left ventricle of the heart to be pumped around the body.

As a consequence, the first place our newly-minted immune plasmablasts (B cells) and CD8+ and killer T cells will potentially encounter the virus-producing ‘factories’ of infected epithelial cells is in the lung itself. The alveolar capillaries are already narrower than the diameter of ‘resting’ (the unactivated form) T cells and B cells, while our recently-stimulated white blood cells will be even bigger. This means their transit times are slowed and they will have longer to interact with any WBC (or leukocyte) ‘trafficking molecules’ that are expressed on vascular epithelium.

This is a complex story that I won’t try to address it in detail here. In brief, the ‘molecular language’ on the epithelial lining of the lung capillaries is altered by the secretion of cytokines, chemokines and so forth from both infected cells and invading inflammatory cells. These changes on vascular endothelium are then recognised by other, activation-induced ‘ligands’ on the surface of our immune WBCs, an interaction that triggers a process of migration (extravasation) out through the blood vessel walls into the adjacent infected lung tissue. When plasmablasts do this, they can differentiate to become local antibody producing plasma cells, perhaps sitting in lymphoid aggregates like the bronchus associated lymphoid tissue (BALT). With the CD8+ killer T cells, these ‘individual assassins’ then embark on their ‘search and destroy’ mission to eliminate virus infected cells in the lung.

That all sounds great, but there are potential downsides. While the extravasating WBCs that access the lung tissue of our Omicron-infected, vaccinated individuals will include immune cells that are recalled (from memory induced by the spike vaccine) or newly involved naïve (specific for Omicron) precursors, any other ‘activated’ WBCs will also head out into sites of virus-induced pathology. Those that have specific receptors (Ig molecules or TCRs) for some SARS-CoV-2 antigen may be more likely to ‘hang out’ there and not head back into the circulation. But, even if all the ‘irrelevant’ cells move on, remember that the infection is also likely to trigger B cell responses to internal components of the virus that have no known protective value and would only be supernumerary ‘space invaders’ in the lung (#93).

Why is this significant? The problem is that the lung is a very delicate organ that plays an essential physiological role: gas exchange from the RBCs that provides the O2 that is essential for life. The more virus-induced damage, the more inflammatory cell invasion and localisation, the less functional the lung becomes. This is pneumonia and, as we are all aware, the progression to severe forms of COVID-19 is marked by the need for O2, delivered by a mask from an oxygen line (or cylinder ‘by the bed’), to tracheal intubation in an intensive care unit (ICU), to having the blood bypass the lung and be oxygenated in a machine (ECMO). The latter equipment is, of course, in very short supply. Early on, the radiologists described hideous ‘ground glass lesions’ in the lungs of COVID patients. That outcome is best avoided.

So, how does vaccination help us? Think of it as a numbers game. The quicker we supply specific antibodies (Igs) that neutralise any free SARS-CoV-2 virions, the less lung cells will become infected and irretrievably damaged. The sooner we have killer T cells coming into the equation, the faster these virus-producing ‘factories’ will be eliminated. Whether a lung epithelial cell is ‘taken out’ by the virus or by the immune response, it will be just as ‘dead to us’. Stopping the progression of the lung infection by having vaccine-primed CD8+ T cells available fast truncates the infection, decreases the extent of ultimate lung damage and enhances our recovery. To be continued…