Tag: long covid immunology

Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases

Abstract:

Thromboembolic complications and excessive inflammation are frequent in severe COVID-19, potentially leading to long COVID. In non-COVID studies, we and others demonstrated that circulating Reelin promotes leukocyte infiltration and thrombosis. Thus, we hypothesized that Reelin participates in endothelial dysfunction and hyperinflammation during COVID-19.

We showed that Reelin was increased in COVID-19 patients and correlated with the disease activity. In the severe COVID-19 group, we observed a hyperinflammatory state, as judged by increased concentration of cytokines (IL-1α, IL-4, IL-6, IL-10 and IL-17A), chemokines (IP-10 and MIP-1β), and adhesion markers (E-selectin and ICAM-1).

Reelin level was correlated with IL-1α, IL-4, IP-10, MIP-1β, and ICAM-1, suggesting a specific role for Reelin in COVID-19 progression. Furthermore, Reelin and all of the inflammatory markers aforementioned returned to normal in a long COVID cohort, showing that the hyperinflammatory state was resolved. Finally, we tested Reelin inhibition with the anti-Reelin antibody CR-50 in hACE2 transgenic mice infected with SARS-CoV-2. CR-50 prophylactic treatment decreased mortality and disease severity in this model.

These results demonstrate a direct proinflammatory function for Reelin in COVID-19 and identify it as a drug target. This work opens translational clinical applications in severe SARS-CoV-2 infection and beyond in auto-inflammatory diseases.

Source: Calvier L, Drelich A, Hsu J, Tseng CT, Mina Y, Nath A, Kounnas MZ, Herz J. Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases. Front Immunol. 2023 Jun 27;14:1185748. doi: 10.3389/fimmu.2023.1185748. PMID: 37441066; PMCID: PMC10333573. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333573/ (Full text)

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment

Abstract:

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients.

To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3T-MRI scans and signature inflammatory markers in n=120 participants comprising healthy never-infected controls, healthy COVID-19 survivors, and subgroups of long-COVID patients with and without cognitive impairment according to screening with Montreal Cognitive Assessment.

Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p<0.05, FWE-corrected).

Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNg, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment.

We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Source: Bianca Besteher, Tonia Rocktaeschel, Alejandra Patricia Garza, Marlene Machnik, Johanna Ballez, Dario Lucas Helbing, Katrhin Finke, Philipp Reuken, Daniel Guellmar, Christian Gaser, Martin Walter, Nils Opel, Ildiko Rita Dunay. Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment. medRxiv 2023.07.21.23292988; doi: https://doi.org/10.1101/2023.07.21.23292988 https://www.medrxiv.org/content/10.1101/2023.07.21.23292988v1v (Full text available as PDF file)

Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection

Abstract:

To understand the roles of acute phase viral dynamics and host immune responses in PASC, we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR. Participants self-collected nasal specimens up to 21 times within the first 28 days after symptom onset; Interviewer-administered clinical questionnaires and blood samples were collected at enrollment and days 9, 14, 21, 28, and month 4 and 8 post-symptom.

Defining PASC as the presence of any symptom new or worse since infection reported at their 4-month visit, we compared viral markers (quantity and duration of viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-a, IFN-a, IFN-g, MCP, IP-10, and Spike IgG) over the acute period.

In comparison to those who fully recovered, those who developed PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA, infectious virus, and N-antigen, longer duration of viral shedding, and lower Spike-specific IgG levels within the first 10 days of the acute phase of illness. No significant differences were identified among a panel of host immune markers, though there was a trend toward higher initial levels of certain markers (e.g., MCP-1, IFN-a, and IFN-g) in those who went on to develop PASC.

Early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC. These findings highlight the importance of understanding the early biological markers from acute SARS-CoV-2 infection in the natural history of PASC.

Source: Scott Lu, Michael J. Peluso, David V. Glidden, Michelle C. Davidson, Kara Lugtu, Jesus Pineda-Ramirez, Michel Tassetto, Miguel Garcia-Knight, Amethyst Zhang, Sarah A. Goldberg, Jessica Y. Chen, Maya Fortes-Cobby, Sara Park, Ana Martinez, Matthew So, Aidan Donovan, Badri Viswanathan, Rebecca Hoh, Kevin Donohue, David R. McIlwain, Brice Gaudiliere, Khamal Anglin, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos Petropoulos, Steven G. Deeks, Melissa Briggs-Hagen, Raul Andino, Claire M. Midgley, Jeffrey N. Martin, Sharon Saydah, J. Daniel Kelly. Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection. medRxiv 2023.07.14.23292649; doi: https://doi.org/10.1101/2023.07.14.23292649 https://www.medrxiv.org/content/10.1101/2023.07.14.23292649v1.full-text (Full text)

Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors

Abstract:

In general, an individual who experiences the symptoms of Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2 infection is declared as recovered after 2 weeks. However, approximately 10–20% of these survivors have been reported to encounter long-term health problems, defined as ‘long COVID-19’, e.g., blood coagulation which leads to stroke with an estimated incidence of 3%, and pulmonary embolism with 5% incidence.
At the time of infection, the immune response produces pro-inflammatory cytokines that stimulate stromal cells to produce pro-hepatocyte growth factor (pro-HGF) and eventually is activated into hepatocyte growth factor (HGF), which helps the coagulation process in endothelial and epithelial cells. HGF is a marker that appears as an inflammatory response that leads to coagulation.
Currently, there is no information on the effect of SARS-CoV-2 infection on serum HGF concentrations as a marker of the prognosis of coagulation in long COVID-19 survivors. This review discusses the pathophysiology between COVID-19 and HGF, IL-6, and D-dimer.
Source: Zaira B, Yulianti T, Levita J. Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors. Current Issues in Molecular Biology. 2023; 45(7):5725-5740. https://doi.org/10.3390/cimb45070361 https://www.mdpi.com/1467-3045/45/7/361 (Full text)

An understanding of the immune dysfunction in susceptible people who develop the post-viral fatigue syndromes Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

Viral infection in most people results in a transient immune/inflammatory response resulting in elimination of the virus and recovery where the immune system returns to that of the pre-infectious state. In susceptible people by contrast there is a transition from an acute immune response to a chronic state that can lead to an ongoing lifelong complex post-viral illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. This susceptibility is proposed to be genetic or be primed by prior health history. Complex abnormalities occur in immune cell functions, immune cell metabolism and energy production, and in cytokine immune modulator regulation. The immune system of the brain/central nervous system becomes activated leading to dysfunction in regulation of body physiology and the onset of many neurological symptoms.

A dysfunctional immune system is core to the development of the post-viral condition as shown with diverse strategies of immune profiling.  Many studies have shown changes in numbers and activity of immune cells of different phenotypes and their metabolism. Immune regulating cytokines show complex altered patterns and vary with the stage of the disease, and there are elements of associated autoimmunity.  These complex changes are accompanied by an altered molecular homeostasis with immune cell transcripts and proteins no longer produced in a tightly regulated manner, reflected in the instability of the epigenetic code that controls gene expression.

Potential key elements of the altered immune function in this disease needing further exploration are changes to the gut-brain-immune axis as a result of changes in the microbiome of the gut, and viral reactivation from latent elements of the triggering virus or from a prior viral infection. Long COVID, an Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-like illness, is the post-viral condition that has arisen in large numbers solely from the pandemic virus Severe Acute Respiratory Syndrome Coronovirus-2.

With over 760 million cases worldwide, an estimated ~100 million cases of Long COVID have occurred within a short period. This now provides an unprecedented opportunity to understand the progression of these post-viral diseases, and to progress from a research phase mainly documenting the immune changes to considering potential immunotherapies that might improve the overall symptom profile of affected patients, and provide them with a better quality of life.

Source: WALKER, Max O.M. et al. An understanding of the immune dysfunction in susceptible people who develop the post-viral fatigue syndromes Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4083>. Date accessed: 15 july 2023. doi: https://doi.org/10.18103/mra.v11i7.1.4083. https://esmed.org/MRA/mra/article/view/4083/99193547075 (Full text as PDF file)

The immunology of long COVID

Abstract:

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge.

Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities.

Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Source: Altmann, D.M., Whettlock, E.M., Liu, S. et al. The immunology of long COVID. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00904-7 https://www.nature.com/articles/s41577-023-00904-7 (Full text)

A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms

Abstract:

Approximately 30% of COVID-19 cases may experience chronic symptoms, known as post-COVID-19 syndrome (PCS). Common PCS symptoms can include fatigue, cognitive impairment, and persistent physical, neurological, and neuropsychiatric complaints.

To improve healthcare and management of the current and future pandemics, we highlight the need for establishing interdisciplinary post-viral outpatient clinics comprised of specialists in fields such as psychiatry, psychotherapy, neurology, cardiology, pneumology, and immunology. In this way, PCS patients with a high health burden can receive modern diagnostics and targeted therapeutic recommendations. A key objective is to distinguish the “sick recovered” from the “healthy recovered.”

Our hypothesis is that there is a PCS subgroup with autoimmune-mediated systemic and brain-vascular dysregulation, which may lead to circulatory disorders, fatigue, cognitive impairment, depression, and anxiety. This can be clarified using a combination of specific antibody diagnostics and precise clinical, psychological, and apparative testing.

Source: Guest PC, Neyazi A, Braun-Dullaeus RC, Müller P, Schreiber J, Haghikia A, Vasilevska V, Steiner J. A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms. Adv Exp Med Biol. 2023;1412:97-115. doi: 10.1007/978-3-031-28012-2_5. PMID: 37378763. https://pubmed.ncbi.nlm.nih.gov/37378763/

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

Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy

Background: The negative impact of long COVID on social life and human health is increasingly prominent, and the elevated risk of cardiovascular disease in patients recovering from COVID-19 has also been fully confirmed. However, the pathogenesis of long COVID-related inflammatory cardiomyopathy is still unclear. Here, we explore potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy.

Methods: Datasets that met the study requirements were identified in Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were obtained by the algorithm. Then, functional enrichment analysis was performed to explore the basic molecular mechanisms and biological processes associated with DEGs. A protein–protein interaction (PPI) network was constructed and analyzed to identify hub genes among the common DEGs. Finally, a third dataset was introduced for validation.

Results: Ultimately, 3,098 upregulated DEGs and 1965 downregulated DEGs were extracted from the inflammatory cardiomyopathy dataset. A total of 89 upregulated DEGs and 217 downregulated DEGs were extracted from the dataset of convalescent COVID patients. Enrichment analysis and construction of the PPI network confirmed VEGFA, FOXO1, CXCR4, and SMAD4 as upregulated hub genes and KRAS and TXN as downregulated hub genes. The separate dataset of patients with COVID-19 infection used for verification led to speculation that long COVID-associated inflammatory cardiomyopathy is mainly attributable to the immune-mediated response and inflammation rather than to direct infection of cells by the virus.

Conclusion: Screening of potential biomarkers and therapeutic targets sheds new light on the pathogenesis of long COVID-associated inflammatory cardiomyopathy as well as potential therapeutic approaches. Further clinical studies are needed to explore these possibilities in light of the increasingly severe negative impacts of long COVID.

Source: Peng Qi, Mengjie Huang and Haiyan Zhu. Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy. Front. Med., 29 June 2023. Sec. Infectious Diseases: Pathogenesis and Therapy. Volume 10 – 2023 | https://doi.org/10.3389/fmed.2023.1191354 https://www.frontiersin.org/articles/10.3389/fmed.2023.1191354/full (Full text)

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

Abstract:

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed.

We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls.

In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis.

Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Source: Paniskaki K, Konik MJ, Anft M, Heidecke H, Meister TL, Pfaender S, Krawczyk A, Zettler M, Jäger J, Gaeckler A, Dolff S, Westhoff TH, Rohn H, Stervbo U, Scheibenbogen C, Witzke O, Babel N. Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19. Front Microbiol. 2023 Jun 2;14:1196721. doi: 10.3389/fmicb.2023.1196721. PMID: 37333646; PMCID: PMC10272838. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272838/ (Full text)