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.