Helminth-induced inflammation enhances cytotoxic T cell–mediated control of γ-herpesvirus infection

A number of studies have highlighted the impact of helminth infection on concurrent inflammatory processes such as allergic asthma but also coinfection with viruses. In particular, the tightly regulated Th2 response induced during parasitic worm infection has recently been shown to favour reactivation from latency during murid γ-herpesvirus (MuHV-4) infection in mice. In our study, we aimed to determine how acute γ-herpesvirus infection and host colonization could be affected by preliminary helminth infection. Following Sm live infection or the Sm egg-induced inflammation in the lung to induce Th2-type responses, mice were subsequently infected intranasally with a MuHV-4-luciferase+ recombinant virus in order to track viral infection by bioluminescence. We observed that the parasite egg-induced inflammation caused a significant reduction of MuHV-4 infection levels in the lung at day 7 p.i. using in vivo imaging and viral titration. Additionally, the egg-induced inflammation in the lung protected from the weight loss caused by the acute viral infection. Using a MuHV-4-eGFP virus, we further observed that exposure to Sm eggs was associated with significantly reduced numbers of alveolar macrophages supporting viral infection. At 7 days following MuHV-4 infection, flow cytometry analysis revealed that preexposure to Sm eggs was associated with an enhanced influx of Ly6C+ monocytes and significantly increased CD8+ T-cells, including increased proportions and numbers of virus-specific CD8+ T cells in the lung, draining LN and spleen. Given these findings we further explored the anti-viral CD8+ T cell response after Sm egg exposure. Firstly, depletion of CD8+ cells restored viral infection to high levels at day 7 p.i. irrespective of the exposure to Sm eggs. Secondly, stimulation with MuHV-4-specific H-2b-restricted peptides revealed an enhanced IFN-γ production and expression of the CD44 activation marker in Sm preexposed mice. Finally, we used an in vivo cytotoxic assay at 7 days p.i. with MuHV-4 and observed a more effective killing of virus peptide pulsed target cells in Sm exposed mice. These results indicate that exposure to helminths before viral infection can drive an enhanced anti-viral CD8+ T cell response that could potentially be long lived and result in enhanced control of viral persistent infection by γ-herpesviruses.