Issue #92: Viruses, Vaccines and COVID-19: the Omicron response

Written by Nobel Laureate Professor Peter Doherty

Last week (#91) we got to the point where one or more cells in our nose had become infected with the Omicron variant of SARS-CoV-2, to begin the process of making new virus particles (or virions). While it’s possible that SARS-CoV-2 can invade cells in direct contact without requiring ACE2 binding (and the possibility of blockade by neutralising antibodies), the main virus spread within us will reflect that virions released into the overlying layer of nasal mucus (#10) go on to infect other ACE2+ epithelial cells. Initially, that spread would be in the nose and upper respiratory tract then – the longer virus production phase continues –  deeper into our lungs. That’s why it’s good to avoid vigorous exercise as soon as you have any hint that you might be infected.

At this early stage we may also lose our sense of smell and taste. This sensory loss may reflect that, at least in the case of smell, the virus is infecting the supporting sustentacular cells rather than the sensory neurons themselves (#11). The latter is an undesirable scenario. The projections (axons) of those nerve cells link, via the ‘portals’ of the perforated, bony cribriform plate (at the top of the nose), to the olfactory bulb of the brain. Fortunately, there’s no consensus that brain infection is significant in COVID-19. Also, most who experience sensory loss seem to recover smell and taste in a month or two.

What can also happen early in SARS-CoV-2 infection is that newly made virions may enter our blood stream (viraemia) to be distributed around the body. This is where those relatively low concentrations of Omicron spike specific antibodies (Igs) that can become detectable in serum after the third (booster) shot of one of the mRNA vaccines may have a protective effect. Though these Igs may not be at high enough levels in mucus to prevent the initial infection of our olfactory epithelium, there may be enough in the blood to stop virus entry into the cells of our heart and kidneys, to prevent what may be permanent virus-induced damage to these vital organs.

As soon as the very first cells in our nose are infected they, and other cells in their neighbourhood, will start to produce innate immune defence molecules, notably the interferons and pro-inflammatory cytokines like interleukin 6 (IL-6) and interleukin 1 (Il-1). Part of the problem with SARS-CoV-2 is that it can block the production of type-1 interferons. That’s important, as interferons draining in lymph to the regional lymphoid tissue can kick-start the process (#39) of selective, mass recruitment of circulating white blood cells (WBCs) to those lymphoid sites where the primary (naïve) or ‘recall’ (from memory B cells and T cells) immune response develops (#85-91).

At the same time locally-produced molecules like IL-6 and IL-1 will induce changes in vascular endothelium that trigger the extravasation (from blood) of the ‘first-responder’ WBCs of the innate immune response, especially neutrophils, monocyte/macrophages (#7). These invaders then ramp up the local production of a broader spectrum of cytokines and chemokine that, as they increase in concentration in the blood, trigger processes in the brain that make us feverish (body temperature goes up), drowsy and headachy. Apart from such innate response elements acting locally to limit the extent of infection early on, those ‘central effects’ impact at the level of consciousness (#35) and are ‘nature’s way’ of telling us to slow down. While all this is going on we may, of course, have a runny nose and be sneezing and/or coughing.

As we’ve discussed at length (#85-91), though the vaccine-induced response happens in the lymph nodes of the armpit, the virus-specific ‘effector’ and memory B cells and T cells that are both clonally-expanded and differentiate there soon exit (after a week or so) to join the immune lymphocyte ‘diaspora’. Some from the B cell lineage find a new ‘home’ in the bone marrow, where they differentiated further to become the Ig producing plasma cells, while specific categories of memory T cells (the CD62Llo sets, #39, #87) recirculate from blood, to tissue to lymph.

The local immune response sites for the nose and oropharynx are the lymphoid aggregates of the tonsils and the submandibular, or cervical, lymph nodes that are much like those in the armpit. Some of the newly made infectious and non-infectious (defective) SARS-coV-2 virions will, either as intact particles or after being taken up by macrophages and dendritic cells, drain in mucus and lymph to these sites. The same is true for the breakdown products of infected cells. When it comes to the spike-protein specific component of this response, the antigen dose will initially be lower than that provided by a massive shot of spike mRNA in the arm, but unlike the situation where everyone has the same vaccine exposure, the ultimate dose of spike protein delivered by infection will vary depending on how long virus production continues.  We’ll join the battle again next week to look more closely at what’s happening in the lymphoid tissue. To be continued…