Tag: long covid immunology

The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms

Abstract:

Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms.

Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes.

Results: We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants.

Conclusions: Our findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

Source: Buck AM, Deitchman AN, Takahashi S, Lu S, Goldberg SA, Hoh R, Williams MC, Kerbleski M, Deveau TM, Munter SE, Lombardo J, Wrin T, Petropoulos CJ, Durstenfeld MS, Hsue PY, Kelly JD, Greenhouse B, Martin JN, Deeks SG, Peluso MJ, Henrich TJ. The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms. medRxiv [Preprint]. 2023 Mar 31:2023.03.30.23287923. doi: 10.1101/2023.03.30.23287923. PMID: 37034660; PMCID: PMC10081395. https://www.medrxiv.org/content/10.1101/2023.03.30.23287923v1.full-text (Full text)

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

Abstract:

Background: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19.

Methods: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis.

Results: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation.

Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals.

Conclusion: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Source: Gomes SMR, Brito ACdS, Manfro WFP, Ribeiro-Alves M, Ribeiro RSdA, da Cal MS, et al. (2023) High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients. PLoS ONE 18(4): e0283983. https://doi.org/10.1371/journal.pone.0283983 (Full text)

Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning!

Abstract:
Long COVID is an unpredicted sequel of COVID-19 disease documented nearly in half cases globally. Long COVID is multisystem syndrome with nonspecific symptoms and organic signs of unidentified pathology occurs after COVID-19 disease. Long COVID symptoms has been documented in some cases irrespective of disease severity or hospitalization. Long COVID symptoms has significant impact on quality of life in those cases suffered from disease in recent past and lingering to almost two years since infection.
Importantly, not all cases of COVID-19 were shown long COVID symptoms. Most common long COVID symptoms (ten in number) as joint pain, fatigability, chest discomfort, shortness of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. Pathophysiology resulting into long COVID manifestations is still not completely validated.
Researchers have reported ‘immune dysregulation’ and ‘coagulation abnormalities’ are probable pathophysiological mechanism for long COVID. Some of the long COVID effects shown complete reversibility including post COVID lung fibrosis. Reboot system to restore immune dysregulation and recovery in long COVID is real concern. Long COVID symptoms cases are more health conscious and usually follows pattern of doctor shopping due to underestimation by family physicians either due to lack of suspicion or lack of knowledge regarding treatment protocol.
Source: Shital Patil, Sanika Narkar, Jayashree Dahiphale, Vipul Raka, Shubham Choudhari. and Gajanan Gondhali. Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning! World Journal of Advanced Pharmaceutical and Medical Research, 2023, 04(01), 053–065. https://zealjournals.com/wjapmr/content/long-covid-symptoms-pathophysiology-and-possible-mechanisms-still-we-are-learning (Full text available as PDF file)

Immunological dysfunction and mast cell activation syndrome in long COVID

Abstract:

At least 65 million people around the world suffer from long COVID, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID and other postviral infection syndromes, so advances in research could also benefit other groups of patients.

Long COVID is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent SARS-CoV2 reservoir and other consequences of acute infection.

There is an activated condition of mast cells in long COVID, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS).

Diagnosis and treatment of MCAS in patients with long COVID will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.

Source: Sumantri, Stevent; Rengganis, Iris. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific Allergy ():10.5415/apallergy.0000000000000022, March 30, 2023. | DOI: 10.5415/apallergy.0000000000000022 https://journals.lww.com/apallergy/Fulltext/9900/Immunological_dysfunction_and_mast_cell_activation.2.aspx (Full text)

Thrombophilia and Immune-Related Genetic Markers in Long COVID

Abstract:

Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID.
Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients.
The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001).
Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.
Source: da Silva R, de Sarges KML, Cantanhede MHD, da Costa FP, dos Santos EF, Rodrigues FBB, de Nazaré do Socorro de Almeida Viana M, de Meira Leite M, da Silva ALS, de Brito MTM, da Silva Torres MK, Queiroz MAF, Vallinoto IMVC, Henriques DF, dos Santos CP, Viana GMR, Quaresma JAS, Falcão LFM, Vallinoto ACR, dos Santos EJM. Thrombophilia and Immune-Related Genetic Markers in Long COVID. Viruses. 2023; 15(4):885. https://doi.org/10.3390/v15040885 https://www.mdpi.com/1999-4915/15/4/885 (Full text)

Long COVID in autoimmune rheumatic diseases

Abstract:

Consequences of Corona Virus Disease-19 (COVID-19) in patients with rheumatic diseases (RDs) are clinically diverse. SARS-CoV-2 infection has been associated with various autoimmune and rheumatic manifestations over the past three years. Emerging evidence points to the possibility of Long COVID predisposition in rheumatic patients due to the changes in immune regulatory response. The aim of this article was to overview data on the pathobiology of Long COVID in patients with RDs.

Related risk factors, clinical characteristics, and prognosis of Long COVID in RDs were analyzed. Relevant articles were retrieved from Medline/PubMed, Scopus, and Directory of Open Access Journals (DOAJ). Diverse mechanisms of viral persistence, chronic low-grade inflammation, lasting production of autoantibodies, endotheliopathy, vascular complications, and permanent tissue damage have been described in association with Long COVID. Patients with RDs who survive COVID-19 often experience severe complications due to the immune disbalance resulting in multiple organ damage. Regular monitoring and treatment are warranted in view of the accumulating evidence.

Source: Fedorchenko Y, Zimba O. Long COVID in autoimmune rheumatic diseases. Rheumatol Int. 2023 Mar 30:1–11. doi: 10.1007/s00296-023-05319-0. Epub ahead of print. PMID: 36995436; PMCID: PMC10061411. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061411/ (Full text)

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Abstract:

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission).

Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point.

When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens).

In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

Source: Benedict D. Michael, Cordelia Dunai, Edward J. Needham, Kukatharmini Tharmaratnam, Robyn Williams, Yun Huang, Sarah A. Boardman, Jordan Clark, Parul Sharma, Krishanthi Subramaniam, Greta K. Wood, Ceryce Collie, Richard Digby, Alexander Ren, Emma Norton, Maya Leibowitz, Soraya Ebrahimi, Andrew Fower, Hannah Fox, Esteban Tato, Mark Ellul, Geraint Sunderland, Marie Held, Claire Hetherington, Franklyn Nkongho, Alish Palmos, Alexander Grundmann, James P. Stewart, Michael Griffiths, Tom Solomon, Gerome Breen, Alasdair Coles, Jonathan Cavanagh, Sarosh R. Irani, Angela Vincent, Leonie Taams, David K. Menon. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. medRxiv 2023.04.03.23287902; doi: https://doi.org/10.1101/2023.04.03.23287902 (Full text available as PDF file)

Incident autoimmune diseases in association with a SARS-CoV-2 infection: A matched cohort study

Abstract:

Objectives To investigate whether the risk of developing an incident autoimmune disease is increased in patients with previous COVID-19 disease compared to people without COVID-19.

Method A cohort was selected from German routine health care data covering 38.9 million individuals. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19.

Results In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69-15.42) and matched control groups (IR=10.55, 95% CI: 10.25-10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune diseases.

Conclusions SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.

Source: Falko Tesch, Franz Ehm, Annika Vivirito, Danny Wende, Manuel Batram, Friedrich Loser, Simone Menzer, Josephine Jacob, Martin Roessler, Martin Seifert, Barbara Kind, Christina König, Claudia Schulte, Tilo Buschmann, Dagmar Hertle, Pedro Ballesteros, Stefan Baßler, Barbara Bertele, Thomas Bitterer, Cordula Riederer, Franziska Sobik, Lukas Reitzle, Christa Scheidt-Nave, Jochen Schmitt. Incident autoimmune diseases in association with a SARS-CoV-2 infection: A matched cohort study. medRxiv 2023.01.25.23285014; doi:https://doi.org/10.1101/2023.01.25.23285014 (Full text)

The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: Analysis using 2D and 3D cultures

Highlights:

  • None of the SARS-CoV-2 original, delta, or omicron strains can infect neurons.
  • The SARS-CoV-2 original, delta, and omicron strains can infect microglia.
  • The CNS cells differentiated from hiPSCs are useful to investigate the infectivity of the virus.

Abstract:

COVID-19 causes neurological damage, systemic inflammation, and immune cell abnormalities. COVID-19-induced neurological impairment may be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which directly infects cells of the central nervous system (CNS) and exerts toxic effects. Furthermore, SARS-CoV-2 mutations occur constantly, and it is not well understood how the infectivity of the virus to cells of the CNS changes as the virus mutates.

Few studies have examined whether the infectivity of cells of CNS – neural stem/progenitor cells (NS/PCs), neurons, astrocytes, and microglia – varies among SARS-CoV-2 mutant strains. In this study, therefore, we investigated whether SARS-CoV-2 mutations increase infectivity to CNS cells, including microglia.

Since it was essential to demonstrate the infectivity of the virus to CNS cells in vitro using human cells, we generated cortical neurons, astrocytes, and microglia from human induced pluripotent stem cells (hiPSCs). We added pseudotyped lentiviruses of SARS-CoV-2 to each type of cells, and then we examined their infectivity. We prepared three pseudotyped lentiviruses expressing the S protein of the original strain (the first SARS-CoV-2 discovered in the world), the Delta variant, and the Omicron variant on their envelopes and analyzed differences of their ability to infect CNS cells. We also generated brain organoids and investigated the infectivity of each virus.

The viruses did not infect cortical neurons, astrocytes, or NS/PCs, but microglia were infected by the original, Delta, and Omicron pseudotyped viruses. In addition, DPP4 and CD147, potential core receptors of SARS-CoV-2, were highly expressed in the infected microglia, while DPP4 expression was deficient in cortical neurons, astrocytes, and NS/PCs.

Our results suggest that DPP4, which is also a receptor for Middle East respiratory syndrome-coronavirus (MERS-CoV), may play an essential role in the CNS. Our study is applicable to the validation of the infectivity of viruses that cause various infectious diseases in CNS cells, which are difficult to sample from humans.

Source: Kase Y, Sonn I, Goto M, Murakami R, Sato T, Okano H. The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: Analysis using 2D and 3D cultures. Exp Neurol. 2023 Mar 11;363:114379. doi: 10.1016/j.expneurol.2023.114379. Epub ahead of print. PMID: 36914084; PMCID: PMC10008041. https://www.sciencedirect.com/science/article/pii/S0014488623000638?via%3Dihub (Full text)

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID

Abstract:

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease.
Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease’s poor prognosis.
Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs’ phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta.
Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.
Source: Dhawan M, Rabaan AA, Alwarthan S, Alhajri M, Halwani MA, Alshengeti A, Najim MA, Alwashmi ASS, Alshehri AA, Alshamrani SA, AlShehail BM, Garout M, Al-Abdulhadi S, Al-Ahmed SH, Thakur N, Verma G. Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines. 2023; 11(3):699. https://doi.org/10.3390/vaccines11030699 https://www.mdpi.com/2076-393X/11/3/699 (Full text)