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Cooperation of innate immune cells during Hepatitis C virus infection
Induction of an innate immune response requires recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). However, pathogens like the Hepatitis C virus (HCV) have evolved mechanisms to evade innate immune responses in infected host cells. HCV specifically infects hepatocytes, thus specialized immune cells are not affected by the immune modulatory mechanisms exerted by HCV. Indeed, it was observed that plasmacytoid dendritic cells (pDCs) recognize HCV infected cells and respond with IFNα secretion. In this study the response of innate immune cells against HCV was further analyzed in a co-culture of HCV subgenomic replicon (SGR) cells and peripheral blood mononuclear cells (PBMCs). It was confirmed that IFNα is produced by pDCs in this co-culture and it was shown that the secreted IFNα inhibits viral replication. Subsequently, it was demonstrated that pDC activation is triggered by viral RNA and that recognition of viral RNA in pDCs is dependent on TLR7. The transfer of viral RNA from infected cells into pDCs required cell-cell contacts. Following the characterization of the pDC response, a Luminex assay was performed to detect further cytokines and chemokines secreted by PBMCs in response to HCV SGR cells. As secretion of IFNγ was detected, NK cells were assumed to be activated. NK cell depletion from PBMCs resulted in loss of IFNγ, proving that NK cells are the source of IFNγ. Moreover, it was observed that also monocytes play a role in the anti-viral response. Flow cytometry and ImageStream analysis revealed an uptake of particles from HCV SGR cells by monocytes. The particles were found to be apoptotic vesicles, as PBMCs induced apoptosis in HCV SGR cells via tumor necrosis factor-related apoptosis inducing ligand (TRAIL) expression on NK cells. However, interactions between pDCs, NK cells and monocytes were required for efficient clearance of HCV SGR cells, as purified immune cells alone did not kill HCV SGR cells. Although expression of TRAIL receptors was comparable in HCV SGR cells and Huh-7 control cells, HCV activated PBMCs specifically targeted HCV SGR cells without killing Huh-7 control cells. The specific kill of HCV SGR cells was finally explained by the observation that HCV SGR cells are sensitive towards TRAIL induced apoptosis. In summary it was shown that next to pDCs also NK cells and monocytes contribute to the response against HCV. Most importantly, the results underline the necessity of the interplay and mutual activation of different innate immune cells to initiate an efficient, rapid and specific response against HCV infected cells.
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570 Biowissenschaften, Biologie
570 Life sciences