SARS-CoV-2 variants impact the thymus and bone marrow differently
The reason for my quietude for a few days was my mother’s birthday, alas we are back, and will start lightly, this also gives me time to work on a piece I was eager to write for over 20 months but we lacked further evidence and potential mechanisms. The following piece is “good news” in many ways and is directly correlated with the following substacks.
SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice
Similar to the paper referred to above, the researcher here found similar dynamics, such as each variant having a very “unique” preference to infect and interfere with specific immune organs (called primary lymphoid organs), and as the virus evolved, it lost its capacity for thymus disruption at many levels, and it is often correlated (as many many many effects of the infection) with the severity of the disease.
Per all the research and evidence so far, Omicron is the de facto least pathogenic and damaging variant so far, but all variants affect the primary lymphoid organs (Bone Marrow, Thymus), and the more virulent the variant, more skewed to produce specific cells the immune system became, in this case, more myeloid cells, such as macrophages, monocytes, and neutrophils. In case you don’t remember, under certain conditions, these cells but neutrophils specifically can drive a significant amount of damage, both from a cellular to a tissue (physical) level.
Both Alpha and Delta affect the thymus severely, and the severity of infection drove more of the damage, as mentioned in the paragraphs above. By using their rat model to test different outcomes of different variants in many organs, they found that each variant impacts a different organ with more akin. Both Alpha and Delta affect the brain, but in this particular test, Delta had more Nucleocapsid protein in the brain than Alpha, which tells us that each variant will induce neurological inflammation via different mechanisms and pathways.
Lung pathology and immune responses induced by SARS-CoV-2 variants
To investigate the effects of infection with each SARS-CoV-2 variant on the respiratory tract, we analysed the histologic alterations and viral content in the lungs of infected k18-hACE2 mice. Lung lesions composed of immune infiltrates, mostly lymphocytes, macrophages and neutrophils, distributed in perivascular and peribronchiolar locations, as well as interstitial congestion and epithelial changes (thickened epithelium) were visible 6 days post-infection, mainly in delta- and omicron-infected lungs
However, viral RNA was detected in lungs of all infected mice, to levels that were similar for alpha and delta infections and lower for omicron infections. ). This likely reflects the ability of the host to control omicron infection in the lung.
Furthermore, infection of k18-hACE2 mice with the alpha variant resulted in marked alterations to the lung immune cell composition, namely a decrease in the frequency of CD11b+ cells, monocytes and recruited macrophages and a massive increase in neutrophils
Both Delta and Omicron had a similar level of getting in and infecting lung cells and similar type of immune cells your body would produce, but the main difference was the ability of the immune system to combat the infection, which was the most remarkable change between Delta and Omicron, at the time when Omicron surfaced it was feared to be worst than Delta which was causing severe pressure on the global health system.
In line with the evidence, the Alpha variant causes the most significant skewing of the cells and massively increases neutrophils, which in this case causes damage instead of aiding recovery.
Within the lymphoid branch, we observed a decreased frequency of CD19+ B cells for all variants, a specific decrease in the frequencies and numbers of CD4+ T cells in alpha-infected animals, and an increase in the representation of CD8+ T cells in the omicron infection.
Of note, k18-hACE2 mice infected with the alpha variant displayed low numbers of all immune cell populations in the lungs due to the highly reduced CD45+ cell numbers
Because several reports support that neutrophilia and lymphopenia act as complementary drivers of severe COVID-19 outcomes, we calculated the ratios of neutrophils to T or B cells for the three experimental infections. Only infection of k18-hACE2 mice with the omicron VOC resulted in decreased ratios of neutrophil to CD4+ and CD8+ T cells or CD19+ B cells. To gain insight into possible mechanisms underlying the differential lung recruitment of neutrophils versus monocytes/macrophages across the different infections, we measured the expression of ccl2, cxcl9 and cxcl2 in mice infected with the different SARS-CoV2 variants. We observed a higher expression of the ccl2 and cxcl9 genes, and a lower expression of the cxcl2 gene, in the case of delta and omicron infections . Given that CCL2 and CXCL9 attract monocytes/macrophages and CXCL2 neutrophils, the imbalance in their expression may at least in part explain the different immune cell composition observed.
If you missed some of my earlier substacks talking about immune skewing, it means losing the equilibrium between certain cells, and this creates a whole host of problems that can’t be listed here because each type of skewing will cascade into a dozen other molecular mechanisms which incidentally end up causing many pathologies.
The difference in the recruitment (body sending cells to a specific part of your body) and the skewing in neutrophils and CD4 and CD8 (T cells) was tested and found to be the differential expression of specific genes by each variant.
Severe SARS-CoV-2 infection promotes emergency myelopoiesis in the BM
Given the alterations in the mature hematopoietic compartment of SARS-CoV-2-infected k18- hACE2 mice which parallel those described in COVID-19 patients we hypothesised that infection with SARS-CoV-2 may skew the BM function and output. The composition of the hematopoietic progenitor populations in the BM of control or SARS-CoV-2-infected mice was thus analysed.
Whereas the lineage-Sca-1 - c-Kit+ (LK) population was decreased in mice infected with the alpha and the delta variants, this population was increased in the case of the omicron infection.
In contrast, the frequency of granulocyte/macrophage progenitors (GMPs) was significantly increased in mice infected with the alpha variant, unchanged in those infected with the delta variant and decreased upon omicron infection.
The main difference associated with the less severe omicron infection was thus an inversion of the CMP/GMP proportions when compared to the more severe alpha and delta infections. Infection of k18-hACE2 mice with all variants resulted in an increase in the frequency of lineage -Sca-1 + c-Kit+ (LSK) cells, which was more pronounced in the case of the delta and the omicron infections.
Collectively, these data suggest that infection of mice with SARS-CoV-2 variants remodels the hematopoietic progenitor compartment in the BM, mainly through an increase in myeloid-biased populations which likely sustains myeloid amplification.
The lineage Sca-1 - c-Kit+ mentioned and analyzed here belong to bone marrow cells, and it is far too complex to be discussed here in depth, but the simplified version is these are lymphoid precursor cells, and they decrease in mice infected with both Alpha and Delta, and per the underlying theme here, they increase in Omicron, which can explain the difference in expression of certain immune cells in Omicron, and the body’s ability to fight the virus.
Thymopoietic alterations in SARS-CoV-2-infected k18-hACE2 mice
Strikingly, the thymus of delta- and alpha-infected mice presented increasingly alterations in the frequencies of double negative (DN), double positive (DP) and single positive (SP) thymocytes (Figure 6B; and Figure S4C and D for non-infected controls). These developmental defects led to a significant reduction in the number of DP and SP4 and SP8 T cells.
Infection of mice with the omicron variant had the least impact in the thymus. Collectively, these data suggest that the capacity of the thymus to maintain normal T cell development is severely compromised in the course of SARS-CoV-2 infection.
Finally, the disruption of the thymus composition markedly correlated with disease severity, with a strong positive correlation established between severe disease and the frequencies of DN, SP4 and SP8 and a negative one with DP cells (Figure 7D). In conclusion, by analysing the impact of different SARS-CoV-2 variants on the broad immune response, we found immune alterations at the site of infection, blood, BM and thymus that correlated with the severity of SARS-CoV-2 infection in mice.
The following paragraph from the Discussion section voices a similar observation I made many months ago, based on the same evidence the authors cite.
Unlike some other “writers” attempt to push, the infection of immune cells by SARS-CoV-2 using varied receptors is always abortive, meaning the cell always dies and the death is often an inflammatory type of death. It has been me and a few other more competent and smart people this is most likely a defense mechanism, the body attempting to halt any form of established infection in these cells, thus bearing an inflammatory cost to the body.
The thymus is one of the most important organs in the body, and it is directly linked not only to immune health, but your overall (long-term) function and health, and changes to it will undoubtedly lead to changes in response to other types of infections and pathogens. This is tangentially related to the concept of “inflammaging”, which you can (I personally recommend most to read this one) below.
My recent NAC, Metformin impacting Long Covid already covers and abrogates most of these effects, in the end, in a very very very very simplistic manner of summarizing vast amounts of information and research, you just need to tackle inflammation and oxidative damage done by a viral infection to limit all these short-comings.
Later today I will cover a new paper that bears bad news for vaccine designers, and give us a lot more answers than we bargained for.
I appreciate the support of those who choose a paid subscription, or who decide to buy me a coffee whenever they feel like it, and everyone who shares my Substack. This work wouldn’t be possible.
Happy Birthday to Your Mum!!! Great to hear you got your priorities right!!!
Thank you for this insightful article! There is something so refreshingly deeply meaningful and humane about the way you tackle your insights about Covid (and pretty much everything you share with us). I can not but notice with excitement and respect that you have a rare talent, capacity and lucidity to dive deep and come up with multitude of usable truths about the topics of your research. That feels refreshing and invigorating! Why? Because it takes us on the journey of expanding our understandings of the phenomena you cover, while also empowering us with practical things (NAC, Metformin) we can use to keep ourselves safe.
Sometimes I get sick when I read substacks that have nothing but bad news in terms of how Covid will kill us all with rare cancers, amyloid, prions etc As if those people who are capable of discovering all those pathways of destruction could not/would not (or for whatever reason choose not to) share with the world what is it that can keep us safe ….as if they have never heard of Maj. Gen Chen Wei who invented an interferon spray inhibitor for SARS, took over WIV kept her 1400 stuff safe…as if US DOD through JPEO-CBRND and DARPA funding and the HHS through BARDA did not CHOOSE to suppress the availability of that interferon spray inhibitor but instead continued the mRNA Vxs without prerequisite safety data. US Academia and virologists are so corrupted on so many levels that I often wonder how much more bullshit we have to keep listening before it becomes obvious to EVERYBODY who is bullshitting who and why.
"each variant having a very “unique” preference to infect and interfere with specific immune organs" - so interesting.