Distinct proteomic signatures in Ethiopians predict acute and long-term sequelae of COVID-19, 2025, Wolday et al.

[SNT Gatchaman]

Distinct proteomic signatures in Ethiopians predict acute and long-term sequelae of COVID-19
Wolday, Dawit; Gebrehiwot, Abrha G; Le Minh, An Nguyen; Rameto, Muhammed Ahmed; Abdella, Saro; Gebreegziabxier, Atsbeha; Amogne, Wondwossen; Rinke de Wit, Tobias F; Hailu, Messay; Tollera, Getachew; Tasew, Geremew; Tessema, Masresha; Miller, Matthew; Gillgrass, Amy; Bowdish, Dawn M E; Kaushic, Charu; Verschoor, Chris P

INTRODUCTION
Little is known about the acute and long-term sequelae of COVID-19 and its pathophysiology in African patients, who are known to have a distinct immunological profile compared to Caucasian populations. Here, we established protein signatures to define severe outcomes of acute COVID-19 and determined whether unique protein signatures during the first week of acute illness predict the risk of post-acute sequelae of COVID-19 (Long COVID) in a low-income country (LIC) setting.

METHOD
Using the Olink inflammatory panel, we measured the abundance of 92 proteins in the plasma of COVID-19 patients (n=55) and non-COVID-19 individuals (n=23). We investigated distinct inflammatory protein signatures in acute severe COVID-19 individuals (n=22) compared to asymptomatic or mild/moderate COVID-19 cases (n=33), and non-COVID-19 controls.

RESULTS
Levels of SLAMF1, CCL25, IL2RB, IL10RA, IL15RA, IL18 and CST5 were significantly upregulated in patients with critical COVID-19 illness compared to individuals negative for COVID-19. The cohort was followed for an average of 20 months, and 23 individuals developed Long COVID, based on the WHO’s case definition, while 32 COVID-19 patients recovered fully. Whereas upregulated levels of SLAMF1, TNF, TSLP, IL15RA, IL18, ADA, CXCL9, CXCL10, IL17C, and NT3 at the acute phase of the illness were associated with increased Long COVID risk, upregulated TRANCE was associated with a reduced risk of developing Long COVID. Protein levels of SLAMF1, IL15RA, and IL18 associated with critical illness during the acute phase of COVID-19 also predicted Long COVID risk.

DISCUSSION
Patients with severe COVID-19 and Long COVID outcomes exhibited distinct proteomic signatures. Unravelling the pathophysiology of severe acute COVID-19 and Long COVID before its advent may contribute to designing novel interventions for diagnosing, treating, and monitoring of SARS-CoV-2 infection and its associated acute and long-term consequences.

Link | PDF (Frontiers in Immunology) [Open Access]

 

[Hutan]

Little is known about the acute and long-term sequelae of COVID-19 and its pathophysiology in African patients, who are known to have a distinct immunological profile compared to Caucasian populations.

Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease, 2014:

Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity.

Studies in African populations are very welcome. But I thought it was a bit odd to imply that there is one African immunological profile. I would have thought, relative to any continent, the genetic diversity of the indigenous people would be highest in Africa.

 

[Hutan]

Levels of SLAMF1, CCL25, IL2RB, IL10RA, IL15RA, IL18 and CST5 were significantly upregulated in patients with critical COVID-19 illness compared to individuals negative for COVID-19. The cohort was followed for an average of 20 months, and 23 individuals developed Long COVID, based on the WHO’s case definition

Use of the WHO case definition for Long Covid and the high number of people with severe illness means it is hard to make much of this in relation to ME/CFS (at least from the abstract). Also small sample size.

Hopefully there are more publications about Long Covid in Ethiopia from this team.

The gene cards entries for the identified genes are interesting, although perhaps there is something of the horoscope effect going on.

Acute phase markers associated with persistent symptoms
SLAMF1

SLAMF1 (Signaling Lymphocytic Activation Molecule Family Member 1) is a Protein Coding gene. Diseases associated with SLAMF1 include Measles and Subacute Sclerosing Panencephalitis. Among its related pathways are Toll-like receptor signaling pathway and Hematopoietic Stem Cells and Lineage-specific Markers. Gene Ontology (GO) annotations related to this gene include signaling receptor activity and antigen binding.
Enables several functions, including SH2 domain binding activity; identical protein binding activity; and virus receptor activity. Involved in several processes, including negative regulation of CD40 signaling pathway; negative regulation of cytokine production; and positive regulation of MAPK cascade. Located in extracellular exosome. Is active in plasma membrane.

TNF - not also associated with severe acute illness

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation.

TSLP - not also associated with severe acute illness

TSLP (Thymic Stromal Lymphopoietin) is a Protein Coding gene. Diseases associated with TSLP include Cryoglobulinemic Vasculitis and Allergic Asthma. Among its related pathways are Cytokine Signaling in Immune system and Innate Immune System.
This gene encodes a hemopoietic cytokine proposed to signal through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor and the IL-7R alpha chain. It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells. The protein promotes T helper type 2 (TH2) cell responses that are associated with immunity in various inflammatory diseases, including asthma, allergic inflammation and chronic obstructive pulmonary disease.

IL15RA

IL15RA (Interleukin 15 Receptor Subunit Alpha) is a Protein Coding gene. Diseases associated with IL15RA include Capillary Disease and Capillary Leak Syndrome. Among its related pathways are Akt Signaling and Cytokine Signaling in Immune system.

IL18

The protein encoded by this gene is a proinflammatory cytokine of the IL-1 family that is constitutively found as a precursor within the cytoplasm of a variety of cells including macrophages and keratinocytes. The inactive IL-18 precursor is processed to its active form by caspase-1, and is capable of stimulating interferon gamma production, and of regulating both T helper (Th) 1 and Th2 responses. This cytokine has been implicated in the injury of different organs, and in potentially fatal conditions characterized by a cytokine storm.

ADA - not also associated with severe acute illness

ADA (Adenosine Deaminase) is a Protein Coding gene. This gene encodes an enzyme that catalyzes the hydrolysis of adenosine to inosine in the purine catabolic pathway. Various mutations have been described for this gene and have been linked to human diseases related to impaired immune function such as severe combined immunodeficiency disease (SCID) which is the result of a deficiency in the ADA enzyme. In ADA-deficient individuals there is a marked depletion of T, B, and NK lymphocytes, and consequently, a lack of both humoral and cellular immunity. Conversely, elevated levels of this enzyme are associated with congenital hemolytic anemia.

CXCL9 - not also associated with severe acute illness

CXCL9 (C-X-C Motif Chemokine Ligand 9).
This antimicrobial gene is part of a chemokine superfamily that encodes secreted proteins involved in immunoregulatory and inflammatory processes. The protein encoded is thought to be involved in T cell trafficking. The encoded protein binds to C-X-C motif chemokine 3 and is a chemoattractant for lymphocytes but not for neutrophils.

CXCL10 - not also associated with severe acute illness

Interferon-Inducible Cytokine IP-10, 10 KDa Interferon Gamma-Induced Protein
This antimicrobial gene encodes a chemokine of the CXC subfamily and ligand for the receptor CXCR3. Binding of this protein to CXCR3 results in pleiotropic effects, including stimulation of monocytes, natural killer and T-cell migration, and modulation of adhesion molecule expression. This gene may also be a key regulator of the 'cytokine storm' immune response to SARS-CoV-2 infection

IL17C - not also associated with severe acute illness

The protein encoded by this gene is a T cell-derived cytokine that shares the sequence similarity with IL17. This cytokine was reported to stimulate the release of tumor necrosis factor alpha and interleukin 1 beta from a monocytic cell line. The expression of this cytokine was found to be restricted to activated T cells.

NT3 - not also associated with severe acute illness

Neurotrophin 3. The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system.
NTF3 (Neurotrophin 3) is a Protein Coding gene. Diseases associated with NTF3 include Hypochondriasis and Diabetic Neuropathy.

(Yes, that is hypochondriasis - hypochondria. Just what we need - not.

Malacard entry: Hypochondriasis, also known as hypochondria, is a condition where individuals excessively worry about having a serious illness. This somatoform disorder involves persistent preoccupation or fear of having life-threatening illnesses, leading to distress and impairment in various areas of life. Hypochondriacs exhibit repetitive health-related behaviors or maladaptive avoidance behaviors related to health. They may fluctuate in their ability to accept alternative explanations for their beliefs, with some being able to entertain doubts while others remain convinced of their illness despite evidence to the contrary.

It seems to me likely that people labelled with hypochondria may indeed be experiencing troublesome symptoms caused by undiagnosed issues with neurons. All diseases are physical.


Acute phase markers associated with no persistent symptoms
TRANCE - TNFSF11

This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis.