Tag: long covid immunology

First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody

Abstract:

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell biodistribution in humans. A 89Zr-labeled CD8-targeted minibody (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals (N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients (N = 5).
Kinetic modeling results aligned with T cell–trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.
Source: Omidvari N, Jones T, Price PM, Ferre AL, Lu J, Abdelhafez YG, Sen F, Cohen SH, Schmiedehausen K, Badawi RD, Shacklett BL, Wilson I, Cherry SR. First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody. Sci Adv. 2023 Oct 13;9(41):eadh7968. doi: 10.1126/sciadv.adh7968. Epub 2023 Oct 12. PMID: 37824612; PMCID: PMC10569706. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569706/ (Full text)

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Abstract:

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks.

In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression.

Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.

Source:Aguado, J., Amarilla, A.A., Taherian Fard, A. et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00519-6 https://www.nature.com/articles/s43587-023-00519-6 (Full text)

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses

Abstract:

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs.

In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).

These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.

Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43.

This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an ‘original antigenic sin’ (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease.

Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Source: Spatola M, Nziza N, Jung W, Deng Y, Yuan D, Dinoto A, Bozzetti S, Chiodega V, Ferrari S, Lauffenburger DA, Mariotto S, Alter G. Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses. Brain. 2023 Oct 3;146(10):4292-4305. doi: 10.1093/brain/awad155. PMID: 37161609. https://academic.oup.com/brain/article/146/10/4292/7158783 (Full text)

Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID

Abstract:

The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain plasma samples from 117 individuals during and 6 months following their acute phase of infection to comprehensively profile and assess changes in cytokines, proteome, and metabolome.

Network analysis reveals sustained inflammatory response, platelet degranulation, and cellular activation during convalescence accompanied by dysregulation in arginine biosynthesis, methionine metabolism, taurine metabolism, and tricarboxylic acid (TCA) cycle processes.

Furthermore, we develop a prognostic model composed of 20 molecules involved in regulating T cell exhaustion and energy metabolism that can reliably predict adverse clinical outcomes following discharge from acute infection with 83% accuracy and an area under the curve (AUC) of 0.96.

Our study reveals pertinent biological processes during convalescence that differ from acute infection, and it supports the development of specific therapies and biomarkers for patients suffering from long COVID.

Source: Wang K, Khoramjoo M, Srinivasan K, Gordon PMK, Mandal R, Jackson D, Sligl W, Grant MB, Penninger JM, Borchers CH, Wishart DS, Prasad V, Oudit GY. Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID. Cell Rep Med. 2023 Oct 18:101254. doi: 10.1016/j.xcrm.2023.101254. Epub ahead of print. PMID: 37890487. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00431-7 (Full text)

Long-term neurological implications of severe acute respiratory syndrome coronavirus 2 infections in neonates: Innate immune memory and chronic neuroinflammation

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause long-term neurological complications in adults. However, the mechanisms by which early-life SARS-CoV-2 infection increases the risk of abnormal neurodevelopment remain unknown.

Recent studies have shown an association with chronic proinflammatory cytokine/chemokine production in the central nervous system (CNS). Therefore, it was hypothesised that innate immune activation and induction of innate immune memory may play a potential role in the neonatal brain. Haematopoietic stem cells in the bone marrow are exposed to SARS-CoV-2, SARS-CoV-2 envelope protein (E protein), lipopolysaccharide (LPS)-bound spike proteins (S1 and S2 proteins), and damage-associated molecular patterns (DAMPs). Myeloid progenitors enter the stroma of the choroid plexus and are further directed to incessantly supply the brain parenchyma with resident innate immune cells. The S proteins-LPS complex can cross the blood–brain barrier and plays an important role in microglial and astrocytic inflammatory responses and innate immune memory.

Persistently activated microglia with memory release pro-inflammatory cytokines/chemokines which contribute to abnormal synaptic development in the frontal lobe and cerebellum, potentially leading to long-term neurological complications, similar to those observed in autism spectrum disorder (ASD). In addition, this hypothesis suggests that bacterial and fungal products may act as adjuvants to S proteins and may also explain why S proteins alone are insufficient to induce neuroinflammation in neonates.

Source: Tatsuro Nobutoki. Long-term neurological implications of severe acute respiratory syndrome coronavirus 2 infections in neonates: Innate immune memory and chronic neuroinflammation. Medical Hypotheses, Volume 181, December 2023, 111204 https://www.sciencedirect.com/science/article/pii/S0306987723002001 (Full text)

Long-COVID is Associated with Impaired Red Blood Cell Function

Abstract:

COVID-19 disease, caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2), induces a broad spectrum of clinical symptoms ranging from asymptomatic cases to fatal outcomes. About 10-35% of all COVID-19 patients, even those with mild COVID-19 symptoms, continue to show symptoms, i. e., fatigue, shortness of breath, cough, and cognitive dysfunction, after initial recovery.

Previously, we and others identified red blood cell precursors as a direct target of SARS-CoV-2 and suggested that SARS-CoV-2 induces dysregulation in hemoglobin- and iron-metabolism contributing to the severe systemic course of COVID-19. Here, we put particular emphasis on differences in parameters of clinical blood gas analysis and hematological parameters of more than 20 healthy and Long-COVID patients, respectively.

Long-COVID patients showed impaired oxygen binding to hemoglobin with concomitant increase in carbon monoxide binding. Hand in hand with decreased plasma iron concentration and transferrin saturation, mean corpuscular hemoglobin was elevated in Long-COVID patients compared to healthy donors suggesting a potential compensatory mechanism. Although blood pH was within the physiological range in both groups, base excess- and bicarbonate values were significantly lower in Long-COVID patients.

Furthermore, Long-COVID patients displayed reduced lymphocyte levels. The clinical relevance of these findings, e. g., as a cause of chronic immunodeficiency, remains to be investigated in future studies.

In conclusion, our data suggest impaired erythrocyte functionality in Long-COVID patients, leading to diminished oxygen supply. This in turn could be an explanation for the CFS, dyspnea and anemia. Further investigations are necessary to identify the underlying pathomechanisms.

Source: Kronstein-Wiedemann R, Tausche K, Kolditz M, Teichert M, Thiel J, Koschel D, Tonn T, Künzel SR. Long-COVID is Associated with Impaired Red Blood Cell Function. Horm Metab Res. 2023 Oct 27. doi: 10.1055/a-2186-8108. Epub ahead of print. PMID: 37890507. https://pubmed.ncbi.nlm.nih.gov/37890507/

Relevance of complement immunity with brain fog in patients with long COVID

Abstract:

Introduction: This study aimed to elucidate the prevalence and clinical characteristics of patients with long COVID (coronavirus disease 2019), especially focusing on 50% hemolytic complement activity (CH50).

Methods: This retrospective observational study focused on patients who visited Okayama University Hospital (Japan) for the treatment of long COVID between February 2021 and March 2023. CH50 levels were measured using liposome immunometric assay (Autokit CH50 Assay, FUJIFILM Wako Pure Chemical Corporation, Japan); high CH50 was defined as ≥59 U/mL. Univariate analyses assessed differences in the clinical background, long COVID symptoms, inflammatory markers, and clinical scores of patients with normal and high CH50. Logistic regression model investigated the association between high CH50 levels and these factors.

Results: Of 659 patients who visited our hospital, 478 patients were included. Of these, 284 (59.4%) patients had high CH50 levels. Poor concentration was significantly more frequent in the high CH50 group (7.2% vs. 13.7%), whereas no differences were observed in other subjective symptoms (fatigue, headache, insomnia, dyspnea, tiredness, and brain fog). Multivariate analysis was performed on factors that could be associated with poor concentration, suggesting a significant relationship to high CH50 levels (adjusted odds ratio [aOR], 2.70; 95% confidence interval [CI], 1.33–5.49). Also, high CH50 was significantly associated with brain fog (aOR, 1.66; 95% CI, 1.04–2.66).

Conclusions: High CH50 levels were frequently reported in individuals with long COVID, indicating a relationship with brain fog. Future in-depth research should examine the pathological role and causal link between complement immunity and the development of long COVID.

Source: Hagiya H, Tokumasu K, Otsuka Y, Sunada N, Nakano Y, Honda H, Furukawa M, Otsuka F. Relevance of complement immunity with brain fog in patients with long COVID. J Infect Chemother. 2023 Oct 20:S1341-321X(23)00261-1. doi: 10.1016/j.jiac.2023.10.016. Epub ahead of print. PMID: 37866620. https://www.sciencedirect.com/science/article/abs/pii/S1341321X23002611

Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome

Abstract:

Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling.

Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection.

Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups.

Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.

Source: Sanhueza S, Vidal MA, Hernandez MA, Henriquez-Beltran ME, Cabrera C, Quiroga R, Antilef BE, Aguilar KP, Castillo DA, Llerena FJ, Fraga Figueroa M, Nazal M, Castro E, Lagos P, Moreno A, Lastra JJ, Gajardo J, Garcés P, Riffo B, Buchert J, Sanhueza R, Ormazába V, Saldivia P, Vargas C, Nourdin G, Koch E, Zuñiga FA, Lamperti L, Bustos P, Guzmán-Gutiérrez E, Tapia CA, Ferrada L, Cerda G, Woehlbier U, Riquelme E, Yuseff MI, Muñoz Ramirez BA, Lombardi G, De Gonzalo-Calvo D, Salomon C, Verdugo RA, Quiñones LA, Colombo A, Barría MI, Labarca G, Nova-Lamperti E. Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome. Front Med (Lausanne). 2023 Oct 6;10:1271863. doi: 10.3389/fmed.2023.1271863. PMID: 37869162; PMCID: PMC10590130. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10590130/ (Full text)

Monocytes subpopulations pattern in the acute respiratory syndrome coronavirus 2 virus infection and after long COVID-19

Abstract:

Introduction and objective: The present study sought to characterize the pattern of monocyte subpopulations in patients during the course of the infections caused by SARS-CoV-2 virus or who presented long COVID-19 syndrome compared to monocytes from patients with zika virus (Zika) or chikungunya virus (CHIKV).

Casuistry: Study with 89 peripheral blood samples from patients, who underwent hemogram and serology (IgG and IgM) for detection of Zika (Control Group 1, n = 18) or CHIKV (Control Group 2, n = 9), and from patients who underwent hemogram and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 at the acute phase of the disease (Group 3, n = 19); and of patients who presented long COVID-19 syndrome (Group 4, n = 43). The monocyte and subpopulations counts were performed by flow cytometry.

Results: No significant difference was observed in the total number of monocytes between the groups. The classical (CD14++CD16–) and intermediate (CD14+CD16+) monocytes counts were increased in patients with acute infection or with long COVID-19 syndrome. The monocytes subpopulations counts were lower in patients with infection Zika or CHIKV.

Conclusion: Increase in the monocyte subpopulations in patients with acute infection or with long COVID-19 syndrome may be an important finding of differentiated from the infection Zika or CHIKV.

Source: Pereira VIC, de Brito Junior LC, Falcão LFM, da Costa Vasconcelos PF, Quaresma JAS, Berg AVVD, Paixão APS, Ferreira RIS, Diks IBC. Monocytes subpopulations pattern in the acute respiratory syndrome coronavirus 2 virus infection and after long COVID-19. Int Immunopharmacol. 2023 Oct 5;124(Pt B):110994. doi: 10.1016/j.intimp.2023.110994. Epub ahead of print. PMID: 37804653. https://www.sciencedirect.com/science/article/abs/pii/S156757692301319X

Unraveling Post-COVID-19 Immune Dysregulation Using Machine Learning-based Immunophenotyping

Abstract:

The COVID-19 pandemic has left a significant mark on global healthcare, with many individuals experiencing lingering symptoms long after recovering from the acute phase of the disease, a condition often referred to as “long COVID.” This study delves into the intricate realm of immune dysregulation that ensues in 509 post-COVID-19 patients across multiple Iraqi regions during the years 2022 and 2023.

Utilizing advanced machine learning techniques for immunophenotyping, this research aims to shed light on the diverse immune dysregulation patterns present in long COVID patients. By analyzing a comprehensive dataset encompassing clinical, immunological, and demographic information, the study provides valuable insights into the complex interplay of immune responses following COVID-19 infection.

The findings reveal that long COVID is associated with a spectrum of immune dysregulation phenomena, including persistent inflammation, altered cytokine profiles, and abnormal immune cell subsets. These insights highlight the need for personalized interventions and tailored treatment strategies for individuals suffering from long COVID-19.

This research represents a significant step forward in our understanding of the post-COVID-19 immune landscape and opens new avenues for targeted therapies and clinical management of long COVID patients. As the world grapples with the long-term implications of the pandemic, these findings offer hope for improving the quality of life for those affected by this enigmatic condition.

Source: Maitham G. Yousif, Ghizal Fatima and Hector J. Castro et al. Unraveling Post-COVID-19 Immune Dysregulation Using Machine Learning-based Immunophenotyping. 2023. https://arxiv.org/ftp/arxiv/papers/2310/2310.01428.pdf (Full text)