Tag: cytokines

The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the “Cytokine Storm”, which is a dramatic increase in inflammatory cytokines in the blood.
In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or “Long COVID”. Therefore, there is an urgent need to better understand the mechanisms of the virus.
The spike protein on the surface of the virus is composed of joined S1–S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm.
In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC.
Source: Forsyth CB, Zhang L, Bhushan A, Swanson B, Zhang L, Mamede JI, Voigt RM, Shaikh M, Engen PA, Keshavarzian A. The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells. Microorganisms. 2022; 10(10):1996. https://doi.org/10.3390/microorganisms10101996 https://www.mdpi.com/2076-2607/10/10/1996/htm (Full text)

Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood.

We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of interferon gamma (IFNγ) and interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ESCP, Martins TB, Hill HR, Coiras M, Shah KS, Planelles V, Spivak AM. Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID. medRxiv [Preprint]. 2022 Oct 5:2022.10.03.22280661. doi: 10.1101/2022.10.03.22280661. PMID: 36238724; PMCID: PMC9558442. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558442/ (Full text)

Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Abstract:

The epipharynx, located behind the nasal cavity, is responsible for upper respiratory tract immunity; however, it is also the site of frequent acute and chronic inflammation. Previous reports have suggested that chronic epipharyngitis is involved not only in local symptoms such as cough and postnasal drip, but also in systemic inflammatory diseases such as IgA nephropathy and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID.

Epipharyngeal Abrasive Therapy (EAT), which is an effective treatment for chronic epipharyngitis in Japan, is reported to be effective for these intractable diseases. The sedation of chronic epipharyngitis by EAT induces suppression of the inflammatory cytokines and improves systemic symptoms, which is considered to be one of the mechanisms, but there is no report that has proved this hypothesis. The purpose of this study was to clarify the anti-inflammatory effect of EAT histologically.

The study subjects were 8 patients who were not treated with EAT and 11 patients who were treated with EAT for chronic epipharyngitis for 1 month or more. For immunohistochemical assessment, the expression pattern of IL-6 mRNA, which plays a central role in the human cytokine network, was analyzed using in situ hybridization. The expression of IL-6 in the EAT-treated group was significantly lower than those in the EAT nontreated group (p = 0.0015). In addition, EAT suppressed the expression of tumor necrosis factor alpha (TNFα), a crucial proinflammatory cytokine. As a result, continuous EAT suppressed submucosal cell aggregation and reduced inflammatory cytokines. Thus, EAT may contribute to the improvement of systemic inflammatory diseases through the suppression of IL-6 expression.

Source: Nishi K, Yoshimoto S, Nishi S, Nishi T, Nishi R, Tanaka T, Tsunoda T, Imai K, Tanaka H, Hotta O, Tanaka A, Hiromatsu K, Shirasawa S, Nakagawa T, Yamano T. Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis. Int J Mol Sci. 2022 Aug 16;23(16):9205. doi: 10.3390/ijms23169205. PMID: 36012469; PMCID: PMC9409341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409341/ (Full text)

Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

Abstract:

While significant attention has been paid to the immunologic determinants of disease states associated with COVID-19, their contributions to post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, it is critical to understand if specific features of the disease are associated with discrete immune processes, and whether those processes may be therapeutically targeted. To this end, we performed wide immunologic and serological characterization of patients in the early recovery phase of COVID-19 across a breadth of symptomatic presentations.

Using high-parameter proteomics screening and applied machine learning (ML), we identify clear signatures of immunologic activity between PASC patients and uncomplicated recovery, dominated by inflammatory cytokine signaling, neutrophil activity, and markers of cell death. Consistent with disease complexity, heterogeneity in plasma profiling reveals distinct PASC subsets with striking divergence in these ongoing inflammatory processes, here termed plasma quiescent (plaq) and inflammatory (infl) PASC.

In addition to elevated inflammatory blood proteomics, inflPASC patients display positive clinical tests of acute inflammation including C-reactive protein and fibrinogen, increased B cell activity with extrafollicular involvement coupled with elevated targeting of viral nucleocapsid protein and clinical autoreactivity. Further, the unique plasma signatures of PASC patients allowed for the creation of refined models with high sensitivity and specificity for the positive identification of inflPASC with a streamlined assessment of 12 blood markers. Additionally, refined ML modeling highlights the unexpected significance of several markers of potential diagnostic or therapeutic use for PASC in general, including the peptide hormone, epiregulin.

In all, this work identifies clear biological signatures of PASC with potential diagnostic and therapeutic potential and establishes clear disease subtypes that are both easily identifiable and highly relevant to ongoing efforts in both therapeutic targeting and epidemiological investigation of this highly complex disease.

Source: Matthew Woodruff, Kevin S Bonham, Fabliha A Anam, Tiffany Walker, Yusho Ishii, Candice Y Kaminski, Martin Runnstrom, Alexander Truong, Adviteeya Dixit, Jenny Han, Richard Ramonell, Natalie S. Haddad, Mark Rudoloph, Arezou Khosroshahi, Scott A Jenks, F. Eun-Hyung Lee, Ignacio Sanz. Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID. medRxiv 2021.09.21.21263845; doi: https://doi.org/10.1101/2021.09.21.21263845.  (Full text available as PDF file)

Current knowledge about Chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) causes – summary

Abstract:

Chronic Fatigue Syndrome (CFE) is a severe and disabling disease whose etiology has not yet been elucidated. This implies the lack of a specific biomarker for the diagnosis of PE, and no causal treatment.

There are a number of diagnostic criteria that facilitate the diagnosis of PE, but it is still a diagnosis with exclusion. This chapter reviews the scientific literature systematically, summarizing the available knowledge about the probable etiology of Chronic Fatigue Syndrome.

The current topic of the influence of SARS-Cov-2 virus infection on the development of symptoms of IPC was also taken into account in particular.

A clear explanation of the etiology of PE is necessary for the further development of scientific knowledge about the Chronic Fatigue Syndrome.

Source: PRYLIŃSKA-JAŚKOWIAK, Monika & KOŻUCHOWSKI, Marcin. Current knowledge about Chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) causes – summary. Journal of Education, Health and Sport [online]. 13 September 2022, T. 12, nr 9, s. 712–719. [accessed 26.9.2022]. DOI 10.12775/JEHS.2022.12.09.084.  https://apcz.umk.pl/JEHS/article/view/39954 https://apcz.umk.pl/JEHS/article/view/39954/33214 (Full text)

Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Cultured Microglia to Release IL-1β

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown and serum levels of potential biomarkers have been inconsistent. Here we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.

Source: Tsilioni I, Natelson B, Theoharides TC. Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Cultured Microglia to Release IL-1β. Eur J Neurosci. 2022 Sep 24. doi: 10.1111/ejn.15828. Epub ahead of print. PMID: 36153118. https://pubmed.ncbi.nlm.nih.gov/36153118/

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome

Abstract:

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort.

A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome).

In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05).

Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Source: Queiroz MAF, Neves PFMD, Lima SS, Lopes JDC, Torres MKDS, Vallinoto IMVC, Bichara CDA, Dos Santos EF, de Brito MTFM, da Silva ALS, Leite MM, da Costa FP, Viana MNDSA, Rodrigues FBB, de Sarges KML, Cantanhede MHD, da Silva R, Bichara CNC, van den Berg AVS, Veríssimo AOL, Carvalho MDS, Henriques DF, Dos Santos CP, Nunes JAL, Costa IB, Viana GMR, Carneiro FRO, Palacios VRDCM, Quaresma JAS, Brasil-Costa I, Dos Santos EJM, Falcão LFM, Vallinoto ACR. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol. 2022 Jun 30;12:922422. doi: 10.3389/fcimb.2022.922422. PMID: 35846757; PMCID: PMC9279918. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279918/ (Full text)

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID

Abstract:

Background: There is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative.

Methods: Given the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients.

Findings: We discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/-13%) and specific (88%+/-7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42-53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses.

Interpretation: Our study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID.

Funding: This work was funded by the Addenbrooke’s Charitable Trust (900276 to NS), NIHR award (G112259 to NS) and supported by the NIHR Cambridge Biomedical Research Centre. NJM is supported by the MRC (TSF MR/T032413/1) and NHSBT (WPA15-02). PJL is supported by the Wellcome Trust (PRF 210688/Z/18/Z, 084957/Z/08/Z), a Medical Research Council research grant MR/V011561/1 and the United Kingdom Research and a Innovation COVID Immunology Consortium grant (MR/V028448/1).

Source: Krishna BA, Lim EY, Mactavous L; NIHR BioResource Team, Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Wills MR, Sithole N. Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID. EBioMedicine. 2022 Jul;81:104129. doi: 10.1016/j.ebiom.2022.104129. Epub 2022 Jun 27. PMID: 35772216; PMCID: PMC9235296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235296/ (Full text)

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Abstract:

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms.

Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Source: Sun Y, Koyama Y, Shimada S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front Aging Neurosci. 2022 Jun 16;14:903455. doi: 10.3389/fnagi.2022.903455. PMID: 35783147; PMCID: PMC9244793. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244793/ (Full text)

Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions

Abstract:

Background: Post-acute sequelae of COVID-19 (PASC) is a growing healthcare and economic concern affecting as many as 10%-30% of those infected with COVID-19. Though the symptoms have been well-documented, they significantly overlap with other common chronic inflammatory conditions which could confound treatment and therapeutic trials.

Methods: A total of 236 patients including 64 with post-acute sequelae of COVID-19 (PASC), 50 with myalgic encephalomyelitis-chronic fatigue syndrome (ME-CFS), 29 with post-treatment Lyme disease (PTLD), and 42 post-vaccine individuals with PASC-like symptoms (POVIP) were enrolled in the study. We performed a 14-plex cytokine/chemokine panel previously described to generate raw data that was normalized and run in a decision tree model using a Classification and Regression Tree (CART) algorithm. The algorithm was used to classify these conditions in distinct groups despite their similar symptoms.

Results: PASC, ME-CSF, POVIP, and Acute COVID-19 disease categories were able to be classified by our cytokine hub based CART algorithm with an average F1 score of 0.61 and high specificity (94%).

Conclusions: Proper classification of these inflammatory conditions with very similar symptoms is critical for proper diagnosis and treatment.

Source: Bruce K. Patterson, Jose Guevara-Coto, Edgar B. Francisco et al. Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions, 27 April 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1598634/v1]  https://www.researchsquare.com/article/rs-1598634/v1 (Full text)