Thread by @jeffgilchrist

What is going on with our immune cells after COVID-19 infection?

This thread will explore some of the impacts of COVID infection on our immune system even after people are recovered including:
- Missing naive T-cells
- Exhausted T-cells
- Loss of B-cell maturation

🧵1/

- Hyper-activated inflammatory response
- Immune system is impeded post-infection
- Immunological dysfunction persists 8+ months
- Depletion and dysfunction of dendritic cells
- Impairs ability to fight fungal infection
- Unprecedented autoimmunity

2/

- Infected immune cells (monocytes)
- Persistent loss of smell from T-cells
- Persisting CD4+ and CD8+ T-cell activation 12+ months

An unrolled one-page web view for this long thread that may be easier to read or share can be found here (

https://twitter.com/jeffgilchrist/status/1605955896030265344

). 3/

A new study found that a subset of naive T-cells usually found in healthy individuals were absent from recovered people, suggesting a post-infection inflammatory stage ( frontiersin.org/articles/10.33… ). H/T: @vipintukur 4/

Naive immune cells are important when you get infected by a new pathogen so they can be activated and develop/differentiate into T and B-cells that are specific to that pathogen to fight it. Without enough naive cells, the response from your immune system is weakened. 5/

To learn more about how your immune system works, you can watch this Immunology 101 for Non-immunologists video by @VirusesImmunity ( ). 6/

People who recovered from COVID-19 exhibited a hyper-activated response with loss of B-cell maturation which suggests an impeded post-infection stage. 7/

The study also found a higher expression of T-cell exhaustion markers in the recovered compared to healthy individuals and those with active COVID-19 infection. "This indicates that a larger population of the T cells are exhausted post recovery from the COVID-19." 8/

COVID-19 patients exhibited a reduced presentation of the pathway that alerts the immune system to virally infected cells (MHC Class-I) to killer T-cells (CD8+ receptors) and dysregulated presentation (MHC Class-II) to helper T-cells (CD4+) which was restored in the recovered. 9/

They also found both COVID-19 *and* recovered patients exhibited inflammatory responses in monocytes and T-cells, and elevation of immunological, stress, and antiviral responses in T-cells, Natural Killer (NK) cells, and monocytes. 10/

A study found that immunological dysfunction persists for more than 8 months following initial mild-to-moderate COVID-19 infection (

https://twitter.com/jeffgilchrist/status/1587063523951222785

). 11/

Dendritic cells (DC) recognize viral infections and trigger multiple parts of the immune system to respond. They activate helper T-cells which then stimulate B-cells to create antibodies against the pathogen. 12/

A study found a long-lasting reduction in dendritic cells and functional impairment of those cells in the blood of COVID-19 patients ( journals.plos.org/plospathogens/… ). 13/

"Depletion and functional impairment of DCs beyond the acute phase of the disease may have consequences for susceptibility to secondary infections and clinical management of COVID-19 patients." 14/

A second study confirms the impaired functions and reduced numbers of dendritic cells persist even 7 months after infection resulting in "a catastrophe for the immune system during SARS-CoV-2 infection." ( frontiersin.org/articles/10.33… ). H/T: @TRyanGregory 15/

What else can go wrong? It turns out that dendritic cells are important in starting the immune response to RSV infection and help determine the impact on the adaptive immune response ( ncbi.nlm.nih.gov/pmc/articles/P… ). 16/

On top of that they are important contributors to defending against Strep bacterial infection ( journals.asm.org/doi/10.1128/IA… ). 17/

COVID-19 also impairs the immune response to the fungus Candida albican including showing signs of T-cell exhaustion ( frontiersin.org/articles/10.33… ) and a second study found defective antifungal immunity in patients with COVID-19 ( frontiersin.org/articles/10.33… ). H/T: @fitterhappierAJ 18/

This leaves people at higher risk for secondary infections from fungal infections that the WHO has warned is becoming a major issue and where thousands of people died from fungus after COVID infection in India (

https://twitter.com/jeffgilchrist/status/1587063576434466817

). 19/

Nocardiosis is a disease caused by bacteria that can be found in soil and water which can affect the lungs, brain, and skin that is most common in people with weakened immune systems who have difficulty fighting off infections ( cdc.gov/nocardiosis/ ). 20/

Dr. Fisman wrote COVID-19 does appear to be an immune-injuring virus after reviewing a report of disseminated (two or more sites on the body) nocardiosis following infection, with post-viral leukopenia (lower than normal white blood cell count) (

https://twitter.com/DFisman/status/1603854850311061504

). 21/

It looks like persistent post-COVID smell loss which can last months to years is associated with immune cell infiltration and altered gene expression in olfactory epithelium ( science.org/doi/10.1126/sc… ). H/T: @EricTopol 22/

"These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss." 23/

Several studies have shown indicators and markers of autoimmunity (immune response attacking body's own health cells or tissues) present with and after infection (

https://twitter.com/jeffgilchrist/status/1508762216325165056

). 24/

In the summer I wrote a whole week's worth of tweets about how COVID impacts T-cells and other parts of the immune system
including COVID infecting monocytes which you can find here (

https://twitter.com/jeffgilchrist/status/1541407514222280705

). 25/

@RaffyFlynnArt was kind enough to put together a thread of important papers on post-COVID immune dysregulation including ones showing dramatically reduced numbers of T-cells and persistently activated T-cells 12+ months later (

https://twitter.com/RaffyFlynnArt/status/1602033509568225280

). 26/

@AndrewEwing11 put together a list of 25 papers/articles (

https://twitter.com/AndrewEwing11/status/1588306678814056449

) providing evidence for post-COVID immune deficiency and another thread with 36 more references (

https://twitter.com/AndrewEwing11/status/1604982674933923847

). 27/

Dr. Anthony Leonardi (@fitterhappierAJ) has been trying to warn the scientific community about the negative impact of COVID-19 infection and harms on the immune system since 2020 ( frontiersin.org/articles/10.33… ). 28/

Earlier this year @fitterhappierAJ published a paper on a potential mechanism for how this might be happening ( frontiersin.org/articles/10.33… ). 29/

Dr. Leonardi points out that T-cell exhaustion is not limited to just people with Long COVID and you can go from "normal" to having Long COVID and the exhausted T-cells (

https://twitter.com/fitterhappierAJ/status/1590382668914786304

). 30/

The research study he is referring to found an unexpected result where people with milder COVID-19 infections had a weaker CD8+ T-cell response which also showed signs of T-cell exhaustion ( science.org/doi/10.1126/sc… ). 31/ Click "Show replies" 👇 to continue.

The T-cells got so much immune system stimulation that they become less effective. 32/

The people who survived severe disease had higher numbers of memory immune cells while people with milder disease still had some memory cells but appear to be exhausted and dysfunctional so may not be effective for long enough ( lji.org/news-events/ne… ). 33/

Something important to note is that while all of these impacts on the immune system have been found, it is not yet known just how broad the impact is on the population, how long each of them might last or if they will eventually heal on their own. 34/

For a virus that governments no longer seem to consider a problem, there doesn't seem to be much funding to investigate these kinds of things in more depth. 35/

Does the virus cause some kind of negative impact on everyone's immune system to some extent or only certain subgroups of people? How do reinfections impact the immune system, do vaccines reduce the chance of immune issues and to what extent? Lots of questions still remain. 36/