Viroporins and inflammasomes: A key to understand virus-induced inflammation.

Viroporins are virus encoded proteins that alter membrane permeability and can trigger subsequent cellular signals. Oligomerization of viroporin subunits results in formation of a hydrophilic pore which facilitates ion transport across host cell membranes. These viral channel proteins may be involved in different stages of the virus infection cycle. Inflammasomes are large multimolecular complexes best recognized for their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-1 ß (IL-1ß) and interleukin 18 (IL-18). IL-1ß was originally identified as a pro-inflammatory cytokine able to induce both local and systemic inflammation and a febrile reaction in response to infection or injury. Excessive production of IL-1ß is associated with autoimmune and inflammatory diseases. Microbial derivatives, bacterial pore-forming toxins, extracellular ATP and other pathogen-associated molecular patterns trigger activation of NLRP3 inflammasomes. Recent studies have reported that viroporin activity is capable of inducing inflammasome activity and production of IL-1ß, where NLRP3 is shown to be regulated by fluxes of K+, H+ and Ca2+ in addition to reactive oxygen species, autophagy and endoplasmic reticulum stress. The aim of this review is to present an overview of the key findings on viroporin activity with special emphasis on their role in virus immunity and as possible activators of inflammasomes.

The p7 viroporin of the hepatitis C virus contributes to liver inflammation by stimulating production of Interleukin-1ß.

Hepatitis C is one of the most widespread infectious diseases worldwide and hepatitis C virus (HCV)-induced chronic inflammation is highly associated with progredient liver damage. It was shown that HCV infection increases levels of pro-inflammatory cytokines via activation of NOD-like receptor (NLRP3) inflammasomes, yet the underlying mechanism is still under question. We propose modulation of intracellular pH by p7, a 63 residue ion channel produced by the hepatitis C virus as a possible pathomechanism for hepatitis C-associated inflammation. Recombinant constructs corresponding to HCV genotypes 1-4 were expressed in HEK 293 and RAW 264.7 cells and changes of intracellular pH were monitored using pH-sensitive fluorescent probes as well as production of inflammatory cytokines. Presence of p7 induced general loss of vesicular acidity as well as producing a significant increase in the levels of interleukin-1ß (IL-1ß). Effects showed a genotype-dependent pattern of IL-1ß production, in agreement with the pH-response profile of p7 channels corresponding to hepatitis C genotypes. Lowering the pH of the extracellular medium increased activity of p7 channels as well as production of IL-1ß for genotypes 1, 3, and 4, but less for genotype 2. Our data are in agreement with the hypothesis that p7 activity can trigger intracellular signaling cascades that are involved in HCV-associated cytopathy.