Apoptosis is an important mediator of pathogenesis in animal coronavirus disease

Apoptosis is a type of programmed cell death, which occurs in cells that are instably damaged or in cells with some viruses. This conditioning is extremely important in limiting virus replication and its spread to other neighboring cells.

New paper in the magazine Life provides an early review of the viral factors involved in initiating and influencing apoptosis within infectious cells.

Corona-viruses

Coronaviruses are among the most identified ribonucleic acid (RNA) viruses to date. Their genome is about 30 kb long, with four structural proteins, and several unstructured proteins and accessory. They are classified into alpha, beta, gamma and delta coronaviruses.

Several animal and human coronaviruses have been kept isolated to date and usually cause respiratory or gastrointestinal diseases. Like other viruses, they take over the host cell apparatus at all stages of their reproduction. This involves modifying several host genes, including those that encode host protections to enable viral reproduction.

Apoptosis

Recent studies have shown that, early in infection, coronaviruses alter cell metabolism and increase cell death rate. This occurs before adaptive immunity is stimulated, and this may reflect its role in a congenital viral infection.

Two of the most important processes involved in this modeling are apoptosis and cell cycle modification. Apoptosis is induced by several signaling pathways. Apoptosis may reduce viral proliferation, but the other effect may be – release of the infectious viral particles extracted at the time of lytic disease.

The cell pathways that activate apoptosis can be stimulated directly by the viral infection itself or indirectly through other signaling pathways. The latter is affected by the presence of the virus and recruits immune cells to the site of infection. Apoptosis is the final event, causing severe damage to the livers in lytic disease.

Apoptotic device

The viral components inside the cell are called pathogen-linked molecular patterns (PAMPs) and are identified by pattern recognition receptors (PRRs). These respond by activating cytokines and other signaling molecules that proliferate in interferon gene expression.

Another method of protection involves the identification of viral nucleic acid by host proteins that bind, such as the PRRs, with adapter proteins to activate two key transcription factors, namely, NFĸB and regulatory factor 3 IFN (IRF3). These are transferred to the nucleus and increase the sensitivity of type I interferons (IFNs).

These bind to the IFN-α / β receptor (IFNAR), which, in turn, shuts down a system of signals including the Janus kinase pathway / signal transducers and transcriptional pathway activators (JAK). / STAT). This result is the increase in several IFN-induced genes (ISGn).

These genes activate the process involved in cell protein synthesis and thus promote cell death. Another ISG that is a player in this process of translational closure is the mixture of 2 ′, 5′-oligoadenylate synthetase (OAS) and RNase L.

Regulators of apoptosis

Apoptosis is regulated by several pro- and anti-apoptotic proteins in the host cell. One family of proteins is the Bcl-2 family (B cell lymphoma-2), which includes factors that cause poration of the mitochondrial membrane and ultimately caspase enzyme activation, initiating apoptosis. Others protect against apoptosis.

Another family is mitogen-activated protein kinases (MAPKs), which include kinase 1/2 (ERK1 / 2), ERK5, p38, and c-Jun N-terminal kinases (JNK). The former is regulated by growth factors and mitogens, the latter by cellular stress. The JNK pathway could lead to pro-apoptotic gene activation or it may interact with Bcl-2 genes to do so, or it may activate other transcription factors such as 53 and p73.

Pathways of apoptosis activation

Two pathways of apoptosis have been identified, the sexual and the sexual. The former is mediated by activation of death ligands (FasL, TNF) interacted with their death receptors (DRs). Caspase-8 is a major inducer of apoptosis in animal coronaviruses acting through DRs. This enzyme, when activated, clears Bid, a Bcl2 protein, leading to mitochondrial cytochrome c release. The latter is crucial in the formation of the apoptosome by cleavage and caspase activation 9.

The genital tract is based on peripheral mitochondrial membrane permeabilization and is particularly observed with animal coronaviruses. Bcl2 proteins such as Bax and Bak induce apoptosis and are essential for the stimulation of this process through the interstitial or mitochondrial tract, along with caspase-9.

Many animal coronaviruses induce activity of both extrinsic and intrinsic pathways, indicating the complex network of signaling pathways involved in apoptosis.

Interaction of coronavirus with apoptosis genes

Viral genomes often encode genes that are homologous to host anti-apoptotic proteins. This allows them to delay apoptosis in the early stages of the disease and thus generate an appropriate production of new viruses. Other viral proteins can inhibit the transcription of some apoptotic genes or cause alteration of their protein products, in order to suppress their activity.

Induction of apoptosis by viral proteins can lead to complete capillary translation in host cells, inducing apoptosis, as seen by the poliovirus. In the case of the hepatitis C virus, the viral protein NS3 interacts with caspase-8, to induce cell death.

The routine review aims to identify pro-apoptotic mechanisms induced by animal coronaviruses. For example, Pidecine Epidemic Diarrhea Virus (PEDV) induces changes in the expression of 14 genes involved in caspase-dependent apoptosis to promote its replication, as well as to elicit character traits disease.

Another way in which apoptosis is involved in viral reproduction is by activating caspase, which is essential for the clearance of the viral protein nucleocapsid (N) during this process. This is the case with the transmissible gastroenteritis virus (TGEV), which activates the MAPK family, as well as FasL- and mitochondria-induced apoptosis. This process also involves the degradation of host microRNAs that maintain the mitochondrial apoptotic pathway.

Betacoronaviruses, such as the hepatine murine virus (MHV), induce apoptosis. This virus exhibits apoptosis with protein (E) uptake, again through caspase activation. In this case, apoptosis appears to be immune to virion production.

With the hemagglutinating porcine encephalomyelitis virus (PHEV), cell death is mediated by DRs and the mitochondrial-mediated pathways, including caspase-8 and caspase-9, as initiators, and caspase-3, as an effector of apoptosis.

Similarly, the gamma- and delta-coronaviruses exhibit complex entry of cell signaling pathways into the host cell, leading to altered apoptosis. Thus, many viral proteins alter host cell pathways to promote viral reproduction and disease characteristics.

What is the impact?

The fact that apoptosis occurs after infection of several hosts with a range of coronaviruses leads to the conclusion that it is a common feature of diseases with human and animal coronaviruses and is aimed at multiplication.

With the earlier acute respiratory coronavirus syndrome (SARS-CoV), protein 7a is complexed with Bcl-XL protein or other pro-survival factors, activating them and thus allowing apoptosis to progress. proceed through caspase-3 activation. The 3CL-like protease (3CLpro) also activates both caspase-3 and caspase-9 to induce apoptosis in cell culture.

All SARS-CoV viruses and currently circulating SARS-CoV-2 viruses contain the protein ORF3a that induces cell death through caspase activation in the extrinsic pathway through DRs.

The same role has not yet been demonstrated for viral proteins in animal coronavirus diseases. However, with PEDV, the S1 subtype of the spike protein, and the unstructured protein 1 (NSP1), as a initiator and effect of cell death, respectively, have been shown to be based on recent experiments.

Further studies may help to understand how these pathways work in other coronaviruses. The current state of knowledge may reflect the convenience of targeting this pathway for the management of coronavirus diseases.