Issue #85: Viruses, Vaccines and COVID-19: into the lymph nodes

Written by Nobel Laureate Professor Peter Doherty

Our very personal experience of COVID-19 begins when we breathe in air containing the SARS-CoV-2 virus and it attaches, via the receptor binding domain (RBD) on its projecting spike (S) protein, to an ACE2 molecule on the surface of a nasal epithelial cell. That attachment allows the virus particle (virion) to enter the cytoplasm, take off its protein/lipid ‘coat’ and free the RNA that enables the virus to replicate itself many times over (#82). As newly-made virions are released from the virus-producing cell ‘factory’, some will go on to infect other cells in us or (after being coughed or sneezed out) in others and some will drain in nasal mucus to the lymphoid tissue of the tonsils and adenoids (if they haven’t been surgically removed) and the cervical lymph nodes (CLNs) in our neck. Either there, or along the way, virus will also have been taken up by macrophages and dendritic cells (DCs), the main antigen-presenting cells of our immune system.

In the process of SARS-CoV-2 replication, some 29 different proteins are made, most of which are non-structural (NSPs) and are not present in the virion (#82). All of that material, along with products from the destroyed ‘factory cells’, will also be picked up by macrophages and dendritic cells and end up in the lymphoid tissue where it will potentially stimulate an immune response. When it comes to the protective antibodies (#21) that bind directly to the virions and block infection, the main ‘target’ is the spike RBD. But there are also other antigenic sites on the spike, membrane and envelope proteins (all of which are on the surface of the virus) that can potentially be recognised by antibodies and ‘label’ the virus for macrophage engulfment and destruction, or for the further attachment of ‘destroyer’ molecules in the complement cascade. Otherwise, antibodies made against any of the NSPs are unlikely to be of value when it comes to blocking any further infection within us.

Both the NSPs and the structural proteins can, though, be broken down to give peptides that, when bound to our own transplantation molecules, act as the ‘antigens’ for immune CD4+ ‘helper’ and CD8+ ‘killer’ T cells (#29, #33). The CD4s produce various lymphokines, like interleukin 2, that are important for promoting the differentiation of the B cells that give rise to both the antibody-producing plasma cells (#18) and the CD8 killers that eliminate the virus infected cells (#34). At the same time, ‘help’ is also essential for antibody class-switching (IgM to IgA or IgG) in the B cell compartment (#22), and the establishment of memory B cell and T cell populations that can be ‘recalled’ if we are infected a second time.   

As all of this is happening, the infected cell may, from the time of virus entry, be making defence molecules like the interferons, while the macrophages and DCs can also be producing ‘pro-inflammatory’ cytokines and chemokines as they register ‘danger’ following the engulfment of material from the virus-damaged cells (#20). These secreted chemicals can enter our blood stream to have effects in the brain (#79) that lead to fever and drowsiness, while some will flow to (or be produced in) the lymphoid tissue following the localisation of the DCs to that site.

What ‘innate immune’ molecules (especially interferon) also do in any respiratory infection is to induce molecular changes on the walls of the vasculature (small blood vessels) that cause circulating B cells and T cells to exit the circulation and accumulate in the adenoids, tonsils and CLNs. Once the virus gets down into the lung, the mediastinal lymph nodes (MLNs) in the chest will also be involved. This recruitment of white blood cells (WBCs) can cause substantial enlargement of the CLNs and MLNs, leading to a transient lymphopenia and a fall in circulating WBC counts.

Vaccine injected into the arm will find its way via the lymph to the regional, axillary lymph nodes (ALNs) in our armpit (#84). The processes occurring in the ALNs are essentially similar to those happening in the adenoids, tonsils, CLNs and MLNs following SARS-CoV-2 infection, though with notable exceptions. The first is that the vaccines currently available in Australia provide the genetic information (mRNA for Pfizer and Moderna, and DNA to make mRNA for AstraZeneca) for only one virus protein, the SARS-CoV-2 spike (#84). Soon, we may also have access to the recombinant protein Novovax vaccine (#84), which delivers spike made outside our body along with a saponin ‘adjuvant’ to stimulate the innate response. The other major difference is that the vaccines are a ‘single-hit’ system – they can’t multiply themselves, infect other cells and will soon disappear – while replicating virus will provide more and more antigen to the lymph nodes until the infection is cleared as the virus-producing factory cells are eliminated. To be continued…