Modulation of Human Macrophages by Plasma from COVID-19 Patients Following BCG Vaccination: BATTLE Trial

Abstract

Keini Buosi,1,* Mehrsa Jalalizadeh,1,* Aline Rosa Maia,2 Joseane Morari,2 Licio Augusto Velloso,2 Leonardo Oliveira Reis1,3 1Uroscience, School of Medical Sciences, University of Campinas, UNICAMP, Campinas, Sao Paulo, 13083-872, Brazil; 2Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 13083-864, Brazil; 3Immunoncology, Pontifical Catholic University of Campinas, PUC-Campinas, Campinas, Sao Paulo, 13087-571, Brazil*These authors contributed equally to this workCorrespondence: Leonardo Oliveira Reis, PUC-Campinas, Pontifical Catholic University of Campinas, ImmunOncology, Av. John Boyd Dunlop - Jardim Ipaussurama, Campinas, Sao Paulo, 13034-685, Brazil, Tel/Fax [phone], Email [email protected]: To analyze the interfering effect of plasma from COVID-19 convalescent adults vaccinated or not with intradermal Bacillus Calmette-Guérin (BCG) on human macrophages.Methods: The BATTLE clinical trial (NCT04369794) was initiated in the 2020 SARS-CoV-2 pandemic to study the safety and efficacy of BCG revaccination of COVID-19 convalescent adults. We measured the expression induction of eleven COVID-19-related genes in human macrophages cultured in plasma taken from 22 BCG vaccinated and 17 placebo patients at baseline and 45 days post-intervention. Subgroup analysis was based on gender, age, job type (healthcare worker [HCW] vs non-HCW), and the presence of anosmia/dysgeusia.Results: Compared to plasma from placebo counterparts, the plasma of BCG vaccinated patients increased the expression induction of interferon (IFN)β-1b (p = 0.042) in human macrophages. This increase was more pronounced in females and in healthcare workers (HCW) (p = 0.007 and 0.001, respectively). Interferon-induced transmembrane protein 3 (IFITM3) expression induction was increased by plasma from BCG vaccinated females, young age group, and HCWs (p = 0.004, 0.011, and 0.040, respectively). Interleukin (IL)-10 induction increased by the plasma of young BCG recipients (p = 0.008). Induction of IL-6 expression increased by non-HCW BCG recipients plasma but decreased by HCW BCG recipients plasma (p = 0.005). Baseline plasma of patients who presented with anosmia/dysgeusia at the time of admission induced lower angiotensin-converting enzyme 2 (ACE2) compared to those without the symptom (0.76 vs 0.97, p = 0.004). ACE2 expression induction significantly increased by plasma of BCG recipients if they had anosmia/dysgeusia on admission (p = 0.028).Conclusion: The expressions of IFNβ-1b, IFITM3, IL-6, and IL-10 in human macrophages incubated with the plasma of COVID-19 convalescent patients were modulated by BCG. These modulations depended on subject-specific characteristics, including gender, age, clinical presentation (anosmia/dysgeusia), job type, and previous exposure to mycobacteria.Keywords: COVID, BCG, trained immunity, gender, age, healthcare worker, IFNs, ACE2

Keywords

• covid
• bcg
• trained immunity
• gender
• age
• healthcare worker
• ifns
• ace2.