Introductory Chapter: Peroxisome-Virus Interaction from SARS-CoV-2 Perspective

1. Introduction

Shannon Butalla and Melissa Gamble, parents of children affected by the peroxisomal disorder, took concrete steps in 2010 to establish the “Global Peroxisomal Disorders Foundation (GFPD).” The foundation has become an effective and complementary center providing research and family support for patients and their relatives struggling with rare peroxisomal diseases in the community. Peroxisomes, which are active in almost all our cells under normal conditions, are organelles that take an active role in lipid metabolism and render specific biochemical toxins harmless. Sabotaging the peroxisomes, which have supercritical initiatives for cell homeostasis, has irreparable consequences. Peroxisomal disorders include single-enzyme defects that affect a specific biochemical pathway and/or biogenesis defects that affect the entire peroxisome and therefore the organism. Many patients with peroxisome biogenesis defect (PBD) simultaneously lack the multiple functions of the peroxisome. These patients show a clinical gradient termed peroxisome biogenesis disorders-Zellweger Spectrum Disorders (PBD-ZSD). PBD-ZSD symptoms manifest in a wide range of patients. The disease symptoms can vary from mild as progressive hearing and vision problems after childhood to moderate-/high-level diseases including feeding problems, low muscle tone, and brain and liver disorders since infancy. Many patients with severely affected PBD-ZSD present with multiple medical problems, persistent seizures, developmental abnormalities, and even death in the neonatal period [1].

In patients with PBD-ZSD, autosomal recessive mutations have been found in a group of peroxisomal genes called peroxin (PEX), which plays a role in peroxisome biogenesis. In a typical PBD-ZSD family, each of the parents may be a carrier of a mutation in a gene such as PEX1. For example, the mutant PEX1 gene in both carrier parents does not affect the health of the carrier and does not produce severe disease for them. This is because there are two copies (diploidy) of each gene in each individual’s genome, including PEX1. A healthy second copy can protect a carrier from the disease, but two carrier parents for the same gene have a 25% chance of transmitting the mutation to their children in each pregnancy. Because of their importance for peroxisome, the functions of PEX genes and their products, of which 37 have been discovered so far, are being studied intensively [2].

2. Peroxisome virus interaction

2.1 Pandemic declaration and SARS-CoV-2

On March 11, 2020, it was recognized by the World Health Organization (WHO) that the epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (later named COVID-19) has become a pandemic. As of July 10, 2022, around 553 million confirmed cases and more than 6.3 million deaths have been reported worldwide due to COVID-19 [3, 4].

SARS-CoV-2 is a new strain of the coronavirus family that triggers and deepens health, social, and economic crises worldwide. Considering the effects of this virus on the organism, its interaction with the peroxisome is critical. SARS-CoV-2 infection in some human cell lines (Huh-7 and SK-N-SH) causes striking changes in peroxisome morphology. Since the peroxisomal membrane integrity is affected by the virus, peroxisomal matrix proteins leak into the cytosol and a marked reduction in the number of mature peroxisomes in the infected cells. Some proteins encoded by ORF14 of SARS-CoV-2 interact physically with human PEX14, which act as a membrane protein during matrix protein import and peroxisome biogenesis. Given the role of peroxisomes in innate immunity, the argument is getting stronger that SARS-CoV-2 can either directly target peroxisomes or is dangerous because it targets them. Therefore, a viral attack can cause the loss of function in the structural integrity, matrix protein content, and antiviral signaling of the peroxisome [5].

2.2 Interactions of some viruses with peroxisomes

A newly discovered mechanism in human immunodeficiency virus (HIV) patients (AIDS) has offered hope as a different approach for treating COVID-19. More recently, the steps of HIV attack on peroxisomes, which regulate many cellular mechanisms, including the immune system, have been demonstrated. It has been demonstrated that some viruses, including West Nile virus (WNV) and ZIKA virus (ZIKV), have different instruments to inhibit the host-cell interferon response, such as reducing peroxisomes. In fact, all viruses have ways of blocking the host-interferon response. This situation is consistent with the concept that peroxisomes are an important target for viral infections. At this point, researchers evaluated that SARS-CoV-2 could also attack peroxisomes and started testing drugs that increase peroxisome activity against the virus in cell cultures. Recently, a group of scientists reported the mechanistic basis for why many HIV patients suffer from premature aging, lipodystrophy (change in the body fat metabolism cascade), and several diseases. The team identified four microRNAs with increased expression in the brains of HIV patients with dementia. All four microRNAs increased in the brains of these patients appeared to target the peroxisome biogenesis pathway. These increased expression molecules downregulate protein expression required to form peroxisomes. On the other hand, it has been shown that increased peroxisomes by manipulating appropriate genes can inhibit ZIKV replication. Tests of drugs that increase peroxisomes are ongoing to evaluate the success against SARS-CoV-2 and HIV. Many of the agents that researchers have tried have been approved as cancer drugs. During these investigations, it was discovered that a pathway that inhibits peroxisome formation was targeted. Despite possible indications for drug use, it is noted that some peroxisome boosters can be taken orally and have low side effects [6].

3. The plasmalogen importance for viral defense

The cellular functions of plasmalogens, which are abundant in many mammalian tissues, have not yet been fully elucidated. However, it is evaluated that they can protect cells against the harmful effects of endogenous reactive oxygen species. It is also thought to act as signaling molecules and modulators in the membrane [7, 8, 9]. Plasmalogen biosynthesis requires functional peroxisomes that are oxidative organelles in the cell. Peroxisomes are important host organelles where certain viral replication can take place [10]. Plasmalogen deficiency observed in cardiometabolic and multiple neurodegenerative diseases may predispose humans to SARS-CoV-2 and other similar viral infections. On the other hand, increased plasmalogen levels were detected in humans infected with some viruses (ZIKV, HBV, and HIV) and in the virion lipidome of cytomegalovirus [11, 12, 13, 14]. Increased plasmalogen levels revealed a strong association between the ZIKV lifecycle and host peroxisomes. This finding scientifically explains the upregulation of resident plasmalogens and peroxisome-mediated lipidome changes in the serum of patients infected with ZIKV [14, 15]. Meanwhile, it has been reported that the plasmalogen phosphatidylcholine molecule plays an important role in influenza virus infection [16].

The infection response of the host cell can be used as the basic determinant in the pathogenesis of any infectious disease, including the COVID-19 pandemic. The lipid composition of the host cell plasma membrane has a decisive role in the life cycle of a virus, because the first step of the infection process is the entry of the virus into the cell by crossing the membrane. In viral infections in a cell, peroxisomes act as vital immune signaling foci and assist the host by regulating antiviral signaling [10]. Peroxisomes are critical organelles that act as a double-edged sword in the viral infection process. Since this cellular organelle, which both harbors and kills the pathogen, has a primary role in host antiviral defense, it can transform into a useful apparatus that serves viral replication through critical manipulations [17]. This interaction in favor of the virus brings to mind the famous aphorism of nineteenth-century German philosopher Friedrich Nietzsche “What doesn’t kill me, makes me stronger.”

With the discovery of mitochondrial antiviral signaling (MAVS), an innate host immune response, mitochondria were recognized as an important subcellular signaling center. Initially, MAVS, which produced a rapid antiviral reaction, was thought to be specific to mitochondria only. However, considering the known roles of peroxisomes in detoxification, the identification of peroxisomal MAVS (or PAVS) has revealed the importance of peroxisome in host defense as an antiviral signaling organelle. This finding was supported by the discovery of increased host peroxisome biogenesis during human cytomegalovirus (HCMV) and herpes simplex type 1 (HSV-1) infections [18]. The synthesis of some vital molecules, which are essential for viral penetration and the success of the virus life cycle, only in the peroxisome is the most important link in the chain. These molecules are plasmalogens and some cellular lipids such as docosahexaenoic acid, a very long chain omega-3 fatty acid. The units that synthesize plasmalogen and some lipids are peroxisomes, which are indispensable for the construction of viral envelopes, modulation of host cholesterol homeostasis, and maintenance of virus-host balance during infection. It is therefore not surprising that peroxisomes are an attractive candidate for cellular remodeling during some viral infections. Consistent with this proposition, it has been suggested that increased plasmalogen in HCMV virions [12] and alterations in peroxisomal lipid metabolism may be a general characteristic of enveloped virus infections. Plasmalogen and some lipids are essential components of many enveloped viruses, including HCMV and influenza. Therefore, it is considered that this argument may also be valid for SARS-CoV-2. However, further lipidomic analysis is required in COVID-19 samples for a more detailed projection [19].

Macrophages, professional phagocytes of the host immune system, can detect and clear invading pathogens such as viruses and damaged cells. Plasmalogen deficiency in macrophages is associated with a reduced ability to phagocytosis. This situation is significantly reversed when cells are exposed to lysophosphatidylethanolamine plasmalogen [20]. Similarly, restoration of plasmalogen levels leads to increases in the number and size of lipid microdomains in the membranes of macrophages. Therefore, exogenous plasmalogen administration is likely to be adopted as an innovative strategy for optimizing macrophage function [19]. According to the results of a comprehensive bioinformatics study on macrophage differentiation, the plasmalogen phosphatidylethanolamine (PE) molecule is a biomarker of immune system activation. As an interesting finding, a significant decrease in plasmalogen levels was observed in obese subjects [21]. In light of these findings, the potential link between host plasmalogen dysregulation and the high morbidity and mortality levels observed in COVID-19 patients is considered significant. Again, a strong correlation is observed between decreased plasmalogen levels and a number of pathological conditions, including neurodegenerative and cardiometabolic disorders, as well as severe COVID due to coronavirus infection. In coronavirus-induced lipidome patterns, irregular plasmalogen levels in the infected patients are of interest. This finding indicates that the plasmalogen molecule is among the key lipids in potentially modulating viral infection [19].

4. The host cell reprogramming by SARS-CoV-2

SARS-CoV-2 replication alters the morphology, number, and function of many cellular structures. Peroxisome accumulation was observed in regions containing double-membrane vesicle (DMV) clusters formed by the endoplasmic reticulum (ER). This finding was confirmed by detecting a marked increase in peroxisome-associated protein, PMP70, in infected cells by confocal microscopy and Western blot analysis. The convergence between the peroxisome and the viral RNA replication site serves to protect viral RNA from oxidative damage [10] or to establish a signaling platform that generates a cytokine response [22].

It has been discovered that many cellular components other than the ER and peroxisomes are also remodeled in cells infected with SARS-CoV-2. It is noteworthy that this transformation is accompanied by decreased mitochondrial ATP synthase, swollen cristae, and matrix condensation. The related observation is consistent with reduced oxidative phosphorylation in cells infected with SARS-CoV-2 and transcriptional changes pointing to virus-induced metabolic reprogramming [23]. The virus in the infected cell manages dynamic changes in the biosynthesis and utilization of macromolecules such as glucose, nucleotides, fatty acids, and amino acids to expand the maneuvering space. These changes are directly related to the success of viral infection [24].

5. Inference

As can be seen from the results of the studies discussed above, there is a multilayered, dynamic, and complex interaction between peroxisome health and the virus life cycle. The coincidental and rapid evolution of viruses in the direction of manipulating the peroxisomal pathway at any stage during the infection process may lead to dead ends or irreparable damage to the host cell defense system. In general, the possibility that extraordinary viruses such as SARS-CoV-2 may favor people with fragile peroxisomes for genetic or environmental reasons should be seriously considered. In this context, handling new insights such as peroxisome health in the control of viral pandemics will provide an important achievement in the fight against the disease.