Tregs and Covid-19

The main problem with severe COVID-19 infection is the inflammatory response leading to intubation; a more severe inflammatory response can lead to low blood pressure and multisystem organ failure.

Altered Immune Signature Linked to Long-Covid

Most people with Covid-19 recover within two weeks. Some, as reported in [15], with so-called Long Covid (symptoms lasting longer than three weeks), continue to experience excessive fatigue, breathlessness, headache, insomnia, muscle fatigue and pains, chest pains, persistent cough, intermittent fevers and brain fog. 

The study finds about 10% had symptoms for a month, with between 1.5 and 2% after three months. The median age of those with Long Covid is 45, and women are more likely to be affected.

In a study, scientists in University of Manchester have discovered that, significantly, an immune signature associated with long-Covid patients:^[5,6] 

Changes to B cells - a type of lymphocyte - that occur during the peak of COVID-19 hospitalization were largely restored by 6 months of convalescence. However, changes to T cells persisted into COVID-19 convalescence.

The signature present in the long-Covid patients was characterized by the team as having high levels of cytotoxic T cells – which can destroy other cells - as well as elevated production of special types of proteins called type-1 cytokines.

Potential Treatment for Covid-19 Patients with Tregs

Researchers are “scrambling to come up with answers” in their quest to identify optimal strategies to treat and prevent the novel coronavirus.  One option may come in the form of regulatory T (Treg) cells, which the body naturally produces to diminish inflammatory responses and begin the process of tissue repair.^[2] 

The normal function of regulatory T cells is to dampen the body’s immune response. Early in an infection, while there is an inflammatory state, Treg cells also are produced. The inhibitory signal basically starts at the same time as the inflammatory signal and the body stays in balance. 

In patients with severe COVID-19 infection, Treg cells as a whole are markedly decreased, and that is why many of scientists believe there is such an intense inflammatory response. So, the scientists are investigating whether they could replace naturally occurring Treg cells from an exogenous source.

However, Tregs can also have paradoxical effects on antiviral responses.^[8,9] 

Some studies have suggested that by limiting late immune responses to an infectious agent, Tregs minimize associated tissue damage while at the same time preventing or diminishing pathogen clearance.^[10-12]  

On the other hand, it has been proposed that during viral infection, Tregs lose their suppressor capacity in response to engagement of virus-sensing mechanisms such as Toll-like receptor (TLR) signaling.^[13]  

Another study suggests that effector T cells responding to infection might become resistant to Treg-mediated suppression as a result of exposure to proinflammatory cytokines and increased costimulatory signals.^[14]

Clinical Trial

Currently, there is a clinical trial in Phase 2 using Tregs as its strategy for treating the COVID-19 patients conducted by Johns Hopkins University.

This double blind randomized placebo controlled study will test the hypothesis that the DNA methyltransferase inhibitor decitabine will augment the T cells known as Tregs, whose pro-repair function will help promote resolution of COVID-19 Acute Respiratory Distress Syndrome ( ARDS).

References

1. Current Priority Ranking for Enrolling Hospitalized Patients in COVID-19 Clinical Trials
2. Decitabine for Coronavirus (COVID-19) Pneumonia- Acute Respiratory Distress Syndrome (ARDS) Treatment: DART Trial (DART)
3. The first 12 months of COVID-19: a timeline of immunological insights
4. Regulatory T-cell therapy shows promise for COVID-19-related respiratory distress
5. Altered immune signature linked to Long-Covid
6. Alterations in T and B cell function persist in convalescent COVID-19 patients
7. Symptoms  Linger for Months for Many Covid Survivors
8. Lund, J.M., Hsing, L., Pham, T.T., and Rudensky, A.Y. (2008). Coordination of early protective immunity to viral infection by regulatory T cells. Science. 320, 1220–1224.
9. Almanan, M., Raynor, J., Sholl, A., Wang, M., Chougnet, C., Cardin, R.D., and Hildeman, D.A. (2017). Tissue-specific control of latent CMV reactivation by regulatory T cells. PLoS Pathog. 13, e1006507.
10. Belkaid, C. A. Piccirillo, S. Mendez, E. M. Shevach, D. L. Sacks, Nature 420, 502 (2002).
11. Y. Belkaid, B. T. Rouse, Nat. Immunol. 6, 353 (2005).
12. B. T. Rouse, P. P. Sarangi, S. Suvas, Immunol. Rev. 212, 272 (2006).
13. G. Peng et al., Science 309, 1380 (2005).
14. C. Pasare, R. Medzhitov, Science 299, 1033 (2003).
15. Long Covid casts a lasting shadow over workers