Posted by Spanish researchers recently published on the mechanisms involved in antiviral activity of zebrafish C-reactive protein-like protein (CRP1-7) against the spring viraemia of carp rhabdovirus (SVCV) in fish [1]. The results showed that the antiviral protection conferred by CRP1-7 was mainly due to the inhibition of autophagic processes. Cholesterol plays an important role in autophagy, so the antiviral effect of CRP1-7 was compared to that of 25-OH-cholesterol (25-HOC), which had been shown to act synergistically with CRPs and to that of methyl-beta-cyclodextrin (MBCD) with cholesterol-binding properties. These effects were comparable suggesting similar mechanisms based on interaction with cholesterol.
Many viruses, including those of fish, activate/need autophagy to replicate. As intracellular parasites, during the course of an infection, viruses encounter autophagy and interact with the proteins that execute this process. Consistent with this anti-viral role of host autophagy, some viruses encode virulence factors that interact with the host autophagy machinery and block the execution of autophagy. In contrast, other viruses appear to utilize components of the autophagic machinery to foster their own intracellular growth or non-lytic cellular egress.[2]
According to the proposed model for the mechanism by which CRPs, 25-HOC and MBCD interact with autophagy and SVCV entry, these three compounds produce an imbalance in the membrane cholesterol of the lipid rafts, which induces the increase of intracellular reactive oxygen species (ROS). [1] In turn, ROS stimulate the increase in lysosomal pH, which reduces both the fusion of lysosomes and intermediate endosomes, and consequently the formation of late endosomes/ endolysosomes. Because of their low pH, SVCV requires the formation of endolysosomes to trigger the fusion conformation of the SVCV G protein for viral entry, and a blockade of endolysosomes thus impairs SVCV release into the host’s cytosol.
[1] Bello-Perez, M., Pereiro, P., Coll, J., (…), Perez, L., Falco, A. (2020) Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol. Scientific Reports 10(1), 566. https://doi.org/10.1038/s41598-020-57501-0
[2] Kudchodkar, S.B., Levine, B. (2009) Viruses and autophagy. Rev Med Virol. 19(6), 359–378. doi: https://doi.org/10.1002/rmv.630