Preprint Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism, 2026, Carroll+

[SNT Gatchaman]

Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism

Spoiler: Authors

Daniel D Carroll; Kamacay Cira; Jack Archer; Jason Shapiro; Ue-Yu Pen; David Tieri; Lucia Leonor; Neda D Roofchayee; Samantha S Yee; Marc Wahab; Igor J Koralnik; John C Alverdy; Arjun S Raman; Lavanya Visvabharathy

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness.

Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naive individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection.

We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells.

Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications.

This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.

Web | DOI | PDF | Preprint: BioRxiv | Open Access

 

[SNT Gatchaman]

Introductory paragraph —

Infections of all types have increased worldwide after the COVID-19 pandemic. Over the past 3 years (2022-24), there have been outbreaks of viral Mpox 1, co-occurring epidemics of respiratory syncytial virus (RSV), influenza, and COVID-19 2, as well as increased rates of bacterial infections in hospitalized patients above pre-pandemic levels 3.

Co-occurring epidemics, particularly with pathogens that occupy the same host niche, were previously considered rare. Epidemiological studies on respiratory viral infection cases from 2005-13 found negative temporal correlations between influenza virus, RSV, and other common cold virus rates, demonstrating an ecological “competitive inhibition” when multiple pathogens target the same host niche 4. However, this pattern has been upended by COVID-19. Frequent observations of co-occurring respiratory virus outbreaks 5 as well as elevated herpes virus reactivation 6 and Staphylococcus aureus infections 7 occur during and proximal to a COVID-19 infection.

Explanations put forth have ranged from increased hospital usage during the COVID-19 pandemic 8 to greater use of antibiotics 9, but none of these explain why infection rates continue to increase in the present day. We propose an alternate hypothesis: that COVID-19 may affect T cell memory responses to other pathogens by reprogramming mitochondrial metabolism.

(Don't forget lock-downs, masking and immunity debt - but hey let-it-rip why not.)

 

[SNT Gatchaman]

Here, we demonstrate that antigen-specific memory T cells from post-COVID individuals show lower glycolysis usage and disordered mitochondrial metabolism in response to commonly encountered childhood and environmental pathogens. Critically, we studied samples from individuals who were initially COVID-naïve, i.e. they had never been exposed to SARS-CoV-2 at the time of blood collection. Using matched samples from the same individuals, we compared T cell memory responses in pre-COVID and post-COVID peripheral blood mononuclear cells (PBMCs) to Influenza A virus (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV). Despite unchanged antigen-specific memory T cell percentages, post-COVID memory T cell responses exhibited reduced coordination across glycolysis, fatty-acid synthesis/oxidation, and OXPHOS pathways relative to pre-COVID responses, a pattern associated with higher PD1 expression.

 

[ScoutB]

Using matched samples from the same individuals, we compared T cell memory responses in pre-COVID and post-COVID peripheral blood mononuclear cells

Very foggy atm so just throwing a question out there — were the pre-COVID samples then sitting around frozen for longer than the post-COVID samples? Could this affect things?

 

[rvallee]

Explanations put forth have ranged from increased hospital usage during the COVID-19 pandemic 8 to greater use of antibiotics 9, but none of these explain why infection rates continue to increase in the present day. We propose an alternate hypothesis: that COVID-19 may affect T cell memory responses to other pathogens by reprogramming mitochondrial metabolism.

A little of this, a little of that, but there will never be any way to assess the consequences of encouraging infections as being good for health as long as they are "mild", when mild is explicitly defined as "no need to go to the hospital" (with emphasis on need, as in a physician will absolutely agree it was the right thing to do), and it's guaranteed that it has played a role, it's just impossible to accurately check.

We saw the numbers of other common infections basically drop down to zero when measures were put in place. Then they rebounded, and it's not because of the junk concept of "immunity debt" but because almost all governments encouraged infections as being good for health! They maximized the spread of infections, especially through children, to get it over with by sacrificing those vulnerable. The initial increase actually reinforced the narrative, since it's very difficult to actually check, but we've long past that and the narrative is mostly going strong for political reasons.

There still hasn't been any comparative study comparing places with strict measures to places with barely at all, because it would completely debunk the Big Lie, if done well. It's very likely that this is a common low-level problem that has always existed, that other infectious pathogens have similar impacts, in fact it was pointed out as a reason to not bother with Long Covid because Influenza is similar, and our institutions have decided that what this means is that they should continue not caring about it, just don't look.

The way it was done guaranteed it would be impossible to tell what's true and what's false. Everything was mixed and blurred together, making it impossible to untangle the causes. Because the pandemic was treated as a PR problem that affected the wealth of rich people more than any other thing.