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

Abstract

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 β (IL-1β) and interleukin 18 (IL-18). IL-1β 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-1β 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-1β, 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.

Keywords: Inflammasomes; Inflammation; NLRP3; Viroporins; Virus-immunity.

Fig. 1

The role of IL-1β in eliciting immune responses against infections. IL-1β up-regulates a broad range of proinflammatory activities in immune cells. It induces rapid recruitment of neutrophils to sites of infection, activation of the endothelial adhesion molecules and induction of chemokines. It also induces the release of many cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-γ, TNF, and PDGF. It also induces proliferation of T-helper and B cells and enhances antigen presentation.

Fig. 2

Signals required for activation and release of IL-1β and IL-18. The first signal can be triggered by various PAMPs or DAMPS recognized by Toll-like receptor (TLR), IL-1 receptor (IL-1R), IL-18 receptor (IL-18R) or tumor necrosis factor receptor (TNFR). The activation of such receptors leads to the activation of NF-κB which induces the synthesis of pro-IL-1β. The second signal is provided by the activation of the inflammasome complex and caspase-1 leading to IL-1β processing. NLRP3 inflammasome detects signs of metabolic stress, including elevated extracellular glucose, monosodium urate (MSU) crystals, ATP and changes in the intracellular ion composition caused by viral encoded ion channels; viroporins activity and certain bacterial toxins, such as nigericin and maitotoxi. NLRP3 oligomerization leads to PYD domain clustering and presentation for homotypic interaction with the PYD- and CARD-containing adaptor ASC, whose CARD domain in turn recruits the CARD of procaspase-1. Procaspase-1 clustering permits autocleavage and formation of the active caspase-1 p10/p20 tetramer. Caspase-1 is activated within the inflammasome multiprotein complex through interaction with ASC (apoptosis-associated speck-like protein containing a carboxy-terminal CARD), a bipartite adapter protein that bridges NLRs and caspase-1.

Fig. 3

Viroporins activity and activation of inflammasomes. Viroporins activities can be clustered into three main groups that have been linked to activation of NLRP3 inflammasomes. The first group of viroporins pumps protons and dissipates proton gradient across trans-golgi network, eg.M2 of influenza A virus. The second group manipulates Ca²⁺ homeostasis, stimulating Ca²⁺ flux from intracellular storages to the cytosol providing the second signal for NLRP3 activation and IL-1β production such as 2B of polio and rhino virus. The third group increases mitochondrial stress and affects ROS production such as 3a of corona virus.