Outcome of Epstein-Barr Virus Infection Followed by Acute Toxoplasmosis: Protection or Exacerbation?

Abstract

Background: Toxoplasma gondii (T. gondii) and Epstein-Barr virus (EBV) are common pathogenic infections with a high incidence reaching 30% and 90% of the worldwide population respectively. T. gondii is an obligate intracellular parasite responsible for a spectrum of diseases grouped under toxoplasmosis. The outcome of these diseases highly depends on the host immune system. In immunocompetent patients, acute toxoplasmosis is often asymptomatic, and rapidly transforms, after the onset of the host immune response, to a persistent chronic toxoplasmosis (CT) for a lifetime. CT can reactivate and lead to a life-threatening condition in immunocompromised patients, and associates with primary neuropathies and behavioral disorders in immunocompetent patients. EBV, or human herpes virus 4 (HHV-4), is an enveloped linear double stranded DNA virus that belongs to the family Herpesviridae. EBV undergoes latency in infected memory B cells for the lifetime of an individual. EBV is the most common cause of infectious mononucleosis, a self-limiting disease in healthy individuals. EBV also associates with a number of tumors and autoimmune diseases. Both pathogens interact with and activate common Toll Like Receptors (TLR), namely TLR-3, -7, and -9, triggering a strong Th-1 response, and releasing proinflammatory cytokines such as IL17 and IFN-γ. Despite their high prevalence, the outcome of the co-occurrence of EBV and T. gondii, remains underexplored. Aim: A comprehensive bigger project by our team is investigating the outcome of acute and chronic toxoplasmosis on EBV infection and vice-versa. As part of this project, we investigated the molecular and cellular effects of an EBV infection followed by acute toxoplasmosis in vitro and in vivo. As part of a broader project investigating the outcome of AT and CT on EBV infection and vice-versa, this study assessed the molecular and cellular effects and consequences of EBV infection followed by AT in vitro and in vivo. Methods: In vitro, we infected the P3HR1 B cell line harboring EBV, with T. gondii parasites and examined the replication of the parasite and the expression of lytic and latent viral markers. In vivo, BALB/c mice were infected with EBV DNA, followed by T. gondii parasites. The parasite burden in spleen and peritoneum as well as the expression of select TLR namely 3, 7 and 9, and the proinflammatory cytokines (IFN-γ and IL-17) were evaluated. Results: We demonstrated that infection of P3HR1 with T. gondii impacts the lytic and latent cycle of EBV. We also unveiled an effect of EBV followed by T. gondii infection on AT in vivo. Indeed, mice injected with EBV DNA followed by T. gondii tachyzoites exhibited a higher burden of tachyzoites in both the peritoneum and spleens, revealing an exacerbation of AT. This higher burden of tachyzoites was concurrent with significantly increased transcript levels of TLR-3, -7 and -9 in the spleens of these mice, and a significant increase in the transcript levels of IFN-γ and IL-17A, further highlighting an exacerbation of AT when it follows EBV. Conclusion: Our study provides insights on the outcome of co-occurrence of two highly prevalent pathogenic infections and enhances our understanding on whether one infection exacerbates or protects from the other, shedding light on the involved cellular and molecular players.