Nature . SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans

[tetano]

Nature


. 2021 May 24.
doi: 10.1038/s41586-021-03647-4. Online ahead of print.
SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans


Jackson S Turner[SUP] 1 [/SUP], Wooseob Kim[SUP] 1 [/SUP], Elizaveta Kalaidina[SUP] 2 [/SUP], Charles W Goss[SUP] 3 [/SUP], Adriana M Rauseo[SUP] 4 [/SUP], Aaron J Schmitz[SUP] 1 [/SUP], Lena Hansen[SUP] 1 5 [/SUP], Alem Haile[SUP] 6 [/SUP], Michael K Klebert[SUP] 6 [/SUP], Iskra Pusic[SUP] 7 [/SUP], Jane A O'Halloran[SUP] 4 [/SUP], Rachel M Presti[SUP] 4 8 [/SUP], Ali H Ellebedy[SUP] 9 10 11 [/SUP]



Affiliations

• PMID: 34030176
• DOI: 10.1038/s41586-021-03647-4

Abstract

Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies[SUP]1-7[/SUP]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent individuals have a significantly lower risk of reinfection[SUP]8-10[/SUP]. Nonetheless, it has been reported that anti-SARS-CoV-2 serum antibodies experience rapid decay in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against this virus may be short-lived[SUP]11-13[/SUP]. Here we demonstrate that in patients who experienced mild infections (n=77), serum anti-SARS-CoV-2 spike (S) antibodies decline rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titers correlated with the frequency of S-specific BMPCs obtained from bone marrow aspirates of 18 SARS-CoV-2 convalescent patients 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy subjects with no history of SARS-CoV-2 infection. We demonstrate that S-binding BMPCs are quiescent, indicating that they are part of a long-lived compartment. Consistently, circulating resting memory B cells directed against the S protein were detected in the convalescent individuals. Overall, we show that SARS-CoV-2 infection induces a robust antigen-specific, long-lived humoral immune response in humans.

 

[sharon sanders]

snip

People who were infected and never had symptoms also may be left with long-lasting immunity, the researchers speculated. But it’s yet to be investigated whether those who endured more severe infection would be protected against a future bout of disease, they said.

“It could go either way,” said first author Jackson Turner, PhD, an instructor in pathology & immunology. “Inflammation plays a major role in severe COVID-19, and too much inflammation can lead to defective immune responses. But on the other hand, the reason why people get really sick is often because they have a lot of virus in their bodies, and having a lot of virus around can lead to a good immune response. So it’s not clear. We need to replicate the study in people with moderate to severe infections to understand whether they are likely to be protected from reinfection.”

Ellebedy and colleagues now are studying whether vaccination also induces long-lived antibody-producing cells.

https://medicine.wustl.edu/news/good-news-mild-covid-19-induces-lasting-antibody-protection/

 

[sharon sanders]

And then there are situations like this.....so...?

Covid-19: Researchers find higher than expected reinfections with P.1 variant among the Brazilian Amazon

 

[JJackson]

What is unknown at the moment is the relationship between antibody levels and the correlate of protection they provide. In the acute phase of a disease B cells, whose surface receptor match antigenic sites of the pathogen, will proliferate and differentiate into plasma cells which then produce vast quantities of the antibodies that match their activated surface receptors. Most of these die off once the acute phase has passed as do the antibodies they produced. A few will remain and migrate to the bone marrow and are the memory B cells. Occasionally they leave to circulate in the blood and lymph nodes 'looking' for a re infection - if they find 'their' antigen again they will start dividing and producing their antibodies.

The unknown, for this disease, is what level of antibodies, and by extension B cells, equates to what degree of protection from both reinfection and, failing that, symptomatic disease. Even a small number of resident memory cells will help by initiating a targeted response, compared to a naive individual, but will there be enough to limit viral proliferation to manageable levels and for how long will that level be maintained?

While a lot of the focus has been on antibodies, neutralising antibodies and the B cells that produce them it is only one part of the equation. T cells are also critical at moping up the infection and have a similar life cycle. The B cells are involved in stopping the virus getting into cells while CD8 T cells kill those cells that have been infected, preventing more virus being produced, and CD4 T cells accelerate and refine the B cell response. Both are involved in bringing other immune cells to the point of infection - in short they all need each other to work effectively in concert having lots of any one is not enough.

 

[Vibrant62]

What I puzzle over is the infection patterns of 'seasonal' coronavirus infections. Our immunity to these is not long lasting, hence we catch these annually or every couple of years. Why is this? Many studies are pointing towards a fairly long lived B and T cell set of responses in SARS-Cov-2, even if the antibody response wanes....but theoretically, the SARS Cov-2 virus should not be all that different in its basic premise of how it operates to those already commonly circulating in humans.

We also know that the family of coronaviruses - alpha and beta - are prone to creating antibody dependent enhancement types of responses, so perhaps a shorter lived immunity has evolved in humans and is protective against this sort of reaction when challenged at a later date by a substantially different SARS-Cov-2 virus or one of its alphacoronavirus or betacoronavirus cousins?

What I have not been able to find is sequence analyses of past common cold coronaviruses to see if their genetic make-up is significantly different every few years. There is some data to suggest that recombination is common in this class of virus, even between its cousins - so maybe we do generate efficient, even lifelong, immunity to our initial virus exposure, but that does not hold if a major segment has been replaced with a version from a different coronavirus i.e each time we catch a common cold, is it because it is an entirely novel variant? But the conservation of large sections of the virtual genome and its epitopes means it has become a 'mild' and seasonal disease?

Hopefully some of the research going on may help us to understand what is going on at detailed immunological response level soon. Then we will know if herd immunity can ever be an achievable goal or not, or if we just have to go through a number of sequential exposures to gain enough underlying immunity for it not to produce the same levels of disease as we currently see.

 

[JJackson]

Vibrant you may find some of the answers you are looking for in TWiVs with Stan Pearlman and Ralph Baric. I recall Stan explaining that in MERS nearly all camels are seropositive and that baby camels, who only suffer very mild symptoms, all get it and that in older camels, imported from Australia where it is not endemic, it can cause more severe disease but for Arabian camels repeat challenges mean they always have some protection and it is not a problem. This seems to be similar to RSV in humans and probably common cold CoVs. Ralph Baric also speculated this would happen with SARS-CoV-2 once one generation of adults had it or been vaccinated. In TWiV 664 they discussed this paper https://www.nature.com/articles/s41591-020-1083-1 which looks at longitudinal reinfection and seroprevelence in blood samples taken from prepandemic humans who keep a diary of cold symptoms. It shows that even if they were unaware of having had a cold they had clear declines and spikes in antibody levels indicating viral challenge topping up protection without inducing disease. TWiVs with Ralph (591, 661) or Stan (538,626, 602) but I can not recall exactly which ones I am remembering from.
My personal guess is this will become a permanent addition to our seasonal cold & flu season where it will fall in the spectrum, re severity, is less clear. The latest introduction of seasonal CoVs was OC43 which is thought to have come from cattle about 80 years ago so is recent enough to have shown up in the historical records if it had been anything like as severe as COVID but the others were much earlier and could have been severe but unidentified. My feeling is it is probably at the high end of the older human CoVs, in terms of clinical impact at introduction, and will be more like flu, than a cold, at least for a few decades while it reaches an equilibrium with its new host.