M1 macrophage polarization prevails in EBV infected children in an immuneregulatory environment

Macrophages can be polarized toward a proinflammatory phenotype (M1) (CD68+) or to an anti-inflammatory one (M2) (CD163+). Polarization can be triggered by cytokines such as IFN-γ for M1, or IL-10 and TGF-β, for M2. In the context of pediatric EBV infection, little is known about macrophage polarization in EBV primary or persistent infection. When studying tonsils of patients undergoing primary infection (PI), healthy carrier (HC), reactivation (R) and not infected (NI), M1 profile prevailed in all infection status. However, an increase in M2 cells was observed in those patients with broader expression of latency antigens, in particular EBNA2. Tonsils from primary infected patients showed an increased IL-10 expression, whereas, unexpectedly, TGF-β expression correlated with M1 marker. Furthermore, an inverse correlation was demonstrated between CD68 and IFN-γ. Therefore, in the context of asymptomatic infection in children, M1 macrophage polarization prevails, even in the presence of IL-10 and TGF-ꞵ immunomodulatory cytokines, and it might be independent from lymphomagenesis process. Our finding indicates that macrophages may have a significant plasticity in response to different types of extrinsic stimuli, and further studies are required to investigate M1 polarization under anti-inflammatory stimuli. Importance Most studies on EBV primary infection have been performed in adolescents and young adult populations with Infectious Mononucleosis (IM) in developed countries. Furthermore, studies related to macrophage polarization were assessed in EBV-associated lymphomas, but little is known about macrophage polarization in the context of primary infection at the site of viral entry and replication, the tonsils. Therefore, the aim of this study was to characterize macrophage response in children undergoing EBV primary or persistent infection, in order to enlighten the role of macrophages in viral pathogenesis, in a population with a high incidence of EBV-associated lymphomas in children younger than 10 years old. This study may contribute to explain, at least in part, the asymptomatic viral infection in children from an underdeveloped region, since M1 polarization pattern prevails, but in a regulatory environment.