Tag: T-cells

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to Two Years Following COVID-19

Abstract:

The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role.

We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes.

Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection.

We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms.

We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.

Source: Michael J Peluso, Dylan M Ryder, Robert Flavell, Yingbing Wang, Jelena Levi, Brian H LaFranchi, Tyler-Marie M Deveau, Amanda M Buck, Sadie E Munter, Kofi A Asare, Maya Aslam, Walter Koch, Gyula Szabo, Rebecca Hoh, Monika Deswal, Antonio Rodriguez, Melissa Buitrago, Viva Tai, Uttam Shrestha, Scott Lu, Sarah A Goldberg, Thomas Dalhuisen, Matthew S Durstenfeld, Priscilla Y Hsue, J D Kelly, Nitasha Kumar, Jeffrey N Martin, Aruna Gambhir, Ma Somsouk, Youngho Seo, Steven G Deeks, Zoltan G Laszik, Henry F VanBrocklin, Timothy J Henrich. Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to Two Years Following COVID-19. medRxiv 2023.07.27.23293177; doi: https://doi.org/10.1101/2023.07.27.23293177 https://www.medrxiv.org/content/10.1101/2023.07.27.23293177v1.full.pdf+html (Full text available as PDF file)

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection.
Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS.
This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease.
This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.
Source: Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(15):11937. https://doi.org/10.3390/ijms241511937 https://www.mdpi.com/1422-0067/24/15/11937 (Full text)

Comparison of T-cell Receptor Diversity of people with Myalgic Encephalomyelitis versus controls

Abstract:

Objective: Myalgic Encephalomyelitis (ME; sometimes referred to as Chronic Fatigue Syndrome or CFS) is a chronic disease without laboratory test, detailed aetiological understanding or effective therapy. Its symptoms are diverse, but it is distinguished from other fatiguing illnesses by the experience of post-exertional malaise, the worsening of symptoms even after minor physical or mental exertion. Its frequent onset after infection might indicate that it is an autoimmune disease or that it arises from abnormal T-cell activation.

Results: To test this hypothesis, we sequenced the genomic loci of a/d, b and g T-cell receptors (TCR) from 40 human blood samples from each of four groups: severely affected people with ME/CFS; mildly or moderately affected people with ME/CFS; people diagnosed with Multiple Sclerosis, as disease controls; and, healthy controls. Seeking to automatically classify these individuals’ samples by their TCR repertoires, we applied P-SVM, a machine learning method. However, despite working well on a simulated data set, this approach did not partition samples into the four subgroups, beyond what was expected by chance alone.  Our findings do not support the hypothesis that blood samples from people with ME/CFS frequently contain altered T-cell receptor diversity.

Source: Joshua J Dibble, Ben Ferneyhough, Matthew Roddis et al. Comparison of T-cell Receptor Diversity of people with Myalgic Encephalomyelitis versus controls, 19 July 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3164397/v1]  https://www.researchsquare.com/article/rs-3164397/v1 (Full text)

Divergent Adaptive Immune Responses Define Two Types Of Long Covid

The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination.

Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29).

The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups.

Multiplexed antibody analyses to 30 different viral antigens showed that LC-patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC-patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC-group.

These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

Source: Jérôme Kervevan, Isabelle Staropoli, Dorsaf Slama, Raphaël Jeger-Madiot, Françoise Donnadieu, Delphine Planas, Marie-Pierre Pietri, Wiem Loghmari-Bouchneb, Motolete A. Tanah, Rémy Robinot, Faroudy Boufassa, Michael White, Dominique SALMON and Lisa A. Chakrabarti. Front. Immunol. Sec. Viral Immunology. Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1221961 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221961/abstract

Use Of Total-Body Pet Imaging To Identify Deep-Tissue Sars-Cov-2 Viral Reservoirs And T Cell Responses In Patients With Long Covid

Project Summary:

This study is the first in the world to use advanced imaging technologies to identify deep tissue SARS-CoV-2 reservoirs and T cell activity in LongCovid study participants. Specifically the team will use longitudinal ImmunoPET-CT imaging of radiolabeled SARS-CoV-2-specific monoclonal antibodies (mAbs) to identify SARS-CoV-2 tissue reservoirs in individuals with Long COVID. The project team is also using ImmunoPET-CT imaging to identify the spatial and temporal dynamics of tissue-based T cell activity in Long COVID study participants.

Tissue biopsy samples from the lymph node and gut will also be collected from Long COVID study participants undergoing imaging. These tissue samples will be analyzed for SARS-CoV-2 RNA, spike, and nucleocapsid proteins, other chronic viruses (e.g., Epstein-Barr virus and cytomegalovirus), and cellular immune responses. Data collected on the tissue samples will be correlated with the imaging data, so that potential viral reservoirs and T cell activity in study participants can be validated by overlapping methods.

Read full article HERE.

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

Source: Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2023 Jan 19;24(3):2010. doi: 10.3390/ijms24032010. PMID: 36768336; PMCID: PMC9916395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916395/ (Full text)

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Abstract:

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis.

Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses.

Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

Source: Kailin Yin, Michael J. Peluso, Reuben Thomas, Min Gyoung Shin, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Urania Argueta, Monica Lopez, Daisy Valdivieso, Kofi Asare, Rania Ibrahim, Ludger Ständker, Scott Lu, Sarah A. Goldberg, Sulggi A. Lee, Kara L. Lynch, J. Daniel Kelly, Jeffrey N. Martin, Jan Münch, Steven G. Deeks, Timothy J. Henrich, Nadia R. Roan. Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2. bioRxiv 2023.02.09.527892; doi: https://doi.org/10.1101/2023.02.09.527892 https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1.full (Full text)

Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study

Abstract:

Background: Currently, there is scant information regarding the features associated to the persistence of post-COVID-19 syndrome, which is the main aim of the present study.

Methods: A cohort study of 102 COVID-19 patients was conducted. The post-COVID-19 symptoms were assessed by a standardised questionnaire. Lymphocyte immunophenotyping was performed by flow cytometry and chemokines/cytokines, neutrophil extracellular traps, the tripartite motif 63, anti-cellular, and anti-SARS-CoV-2 IgG antibodies were addressed in serum. The primary outcome was the persistence of post-COVID-19 syndrome after six months follow-up.

Results: Thirteen patients (12.7%) developed the primary outcome and had a more frequent history of post-COVID-19 syndrome 3 months after infection onset (p = .044), increased levels of IL-1α (p = .011) and IP-10 (p = .037) and increased CD57 expression in CD8+ T cells (p = .003). There was a trend towards higher levels of IFN-γ (p = .051), IL-1β (p = .062) and IL-6 (p = .087). The history of post COVID-19 in the previous 3 months, obesity, baseline serum MIP-1α and IP-10, and CD57 expression in CD8+ T cells were independently associated with the persistence of post-COVID-19 syndrome.

Conclusion: Our data suggest an important relationship between a pro-inflammatory state mediated through metabolic pathways related to obesity and increased cellular senescence as a key element in the persistence of post-COVID-19 syndrome at six months of follow-up.

Source: Torres-Ruiz J, Lomelín-Gascón J, Lira Luna J, Vargas-Castro AS, Pérez-Fragoso A, Nuñez-Aguirre M, Alcalá-Carmona B, Absalón-Aguilar A, Balderas-Miranda JT, Maravillas-Montero JL, Mejía-Domínguez NR, Núñez-Álvarez C, Llorente L, Romero-Ramírez S, Sosa-Hernández VA, Cervantes-Díaz R, Juárez-Vega G, Meza-Sánchez D, Rull-Gabayet M, Martínez-Juárez LA, Morales L, López-López LN, Negrete-Trujillo JA, Falcón-Lezama JA, Valdez-Vázquez RR, Gallardo-Rincón H, Tapia-Conyer R, Gómez-Martín D. Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study. Infect Dis (Lond). 2023 Jan 13:1-12. doi: 10.1080/23744235.2022.2158217. Epub ahead of print. PMID: 36637466. https://www.tandfonline.com/doi/full/10.1080/23744235.2022.2158217 (Full text)

SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

Abstract:

Evolution of SARS-CoV-2 in immunocompromised hosts may result in novel variants with changed properties. While escape from humoral immunity certainly contributes to intra-host evolution, escape from cellular immunity is poorly understood. Here, we report a case of long-term COVID-19 in an immunocompromised patient with non-Hodgkin’s lymphoma who received treatment with rituximab and lacked neutralizing antibodies.

Over the 318 days of the disease, the SARS-CoV-2 genome gained a total of 40 changes, 34 of which were present by the end of the study period. Among the acquired mutations, 12 reduced or prevented the binding of known immunogenic SARS-CoV-2 HLA class I antigens. By experimentally assessing the effect of a subset of the escape mutations, we show that they resulted in a loss of as much as ~1% of effector CD8 T cell response. Our results indicate that CD8 T cell escape represents a major underappreciated contributor to SARS-CoV-2 evolution in humans.

Source: Stanevich OV, Alekseeva EI, Sergeeva M, Fadeev AV, Komissarova KS, Ivanova AA, Simakova TS, Vasilyev KA, Shurygina AP, Stukova MA, Safina KR, Nabieva ER, Garushyants SK, Klink GV, Bakin EA, Zabutova JV, Kholodnaia AN, Lukina OV, Skorokhod IA, Ryabchikova VV, Medvedeva NV, Lioznov DA, Danilenko DM, Chudakov DM, Komissarov AB, Bazykin GA. SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19. Nat Commun. 2023 Jan 10;14(1):149. doi: 10.1038/s41467-022-34033-x. PMID: 36627290; PMCID: PMC9831376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9831376/ (Full text)

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – indications for their potential involvement in the development of Long COVID?

Abstract:

Background: Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms.

Objective: The objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVID.

Design: A systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE (via Pubmed) and Web of Science.

Results: The literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome’s etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population.

Conclusions: Persistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies.

Source: Haunhorst S, Bloch W, Javelle F, Krüger K, Baumgart S, Drube S, Lemhöfer C, Reuken P, Stallmach A, Müller M, Zielinski CE, Pletz MW, Gabriel HHW, Puta C. A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – indications for their potential involvement in the development of Long COVID? Front Immunol. 2022 Dec 13;13:1070994. doi: 10.3389/fimmu.2022.1070994. PMID: 36582234; PMCID: PMC9792979. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792979/ (Full text)