Distinct proteomic signatures in Ethiopians predict acute and longterm sequelae of COVID-19

Dawit Wolday^1,2,3*Abrha Gebrehiwot¹An Nguyen Le Minh¹Muhammed Ahmed Rameto⁴Saro Abdella⁴Atsbeha Gebreegziabxier Weldemariam⁴Wondwossen Amogne Degu⁵Tobias F. Rinke de Wit⁶Mesay Hailu Dangisso⁴Getachew Tollera⁴Geremew Tassew⁴Masresha Tessema⁴Mattew Miller^1,2,3Amy Gillgrass^2,3,7Dawn M.E. Bowdish^2,3,7,8Charu Kaushic^2,3,7Chris P Verschoor⁹

• ¹Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ²McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ³Michael G. DeGroote Institute for Infectious Disease Research, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ⁴Ethiopian Public Health Institute, Addis Ababa, Addis Ababa, Ethiopia
• ⁵College of Health Sciences, Addis Ababa University, Addis Ababa, Addis Ababa, Ethiopia
• ⁶Amsterdam Institute for Global Health and Development, University of Amsterdam, Amsterdam, Netherlands
• ⁷Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ⁸Firestone Institute for Respiratory Health, St. Joseph's Healthcare, Hamilton, Ontario, Canada
• ⁹Health Sciences North Research Institute, Northern Ontario School of Medicine University, Sudbury, Ontario, Canada

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. 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 identified 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. 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. 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.