The mammalian immune system has evolved complex methods for addressing and adapting to foreign antigens. At the same time, viruses have co-evolved evasion machinery to address the many ways that host organisms attempt to eradicate them. DNA and RNA viruses use complex methods to evade immune cell detection through disruption of the Interferon Signaling Pathway, remodeling of cellular architecture, targeted gene silencing, and recognition protein cleavage. [1]
The human immune system relies on a plethora of cell-cell signaling pathways to transmit information about a cell's health and microenvironment. Many of these pathways are mediated by soluble ligands, cytokines, that fit like a lock-and-key into adjacent cell surface receptors. This language of cell communication imparts both specificity and spatiotemporal control for the transmission of data. [2]
The Interferon System is composed of a family of cytokines. Type-I Interferons, IFN-α/β, and Type-III Interferons, IFN-λ play key roles in adaptive immunity, acting as communication highways between cells infected with foreign double stranded DNA or double stranded RNA. Mammalian cells utilize specialized receptors known as Pattern Recognition Receptors(PRRs) to detect viral infection; these receptors are able to recognize pathogen-associated molecular patterns (PAMPs) inscribed in viral DNA and RNA. These pattern recognition receptors, often localized to either the cytosol or the nucleus, are responsible for notifying infected cells and initiating the secretion of interferon cytokines. [3]
The precise role of double-stranded (ds)RNA is still widely investigated as a central player in the Interferon System. Groups have found that positive-strand RNA viruses and dsRNA viruses produced significant amounts of dsRNA, but the precise methods mammalian cells leverage to distinguish between self vs. non-self dsRNA have yet to be uncovered. Studies suggest that recognition must extend beyond simple identification of dsRNA structure and likely relies on other epigenetic markers. [4]
dsRNA has been implicated in the activation of the interferon system through the activation of Protein Kinase R, PKR. Cytoplasmic PKR is often associated with the ribosome in mammalian cells where it is able to recognize double-stranded and single-stranded RNA and subsequently phosphorylate varies substrates, arresting protein synthesis. [5] The activation of PKR subsequently triggers interferon signaling, initiating cell death in response to viral dsRNA recognition. While the PKR The roles of PKR activation have been deeply studied with groups finding that it is insensitive to the presence of short dsRNA and siRNA but showing significant affinity for dsRNA and ssRNA with secondary structure. [4]
Groups have found that the Interferon Signaling promotes the activation of a 2'-5'-oligoadenylate synthetase, sensitive to the presence of dsRNA longer than 15 base pairs. Because this mechanism is not sensitive to self vs. non-self dsRNA binding, results indicate overall reduction in protein synthesis but indicated no specificity for a sole reduction of viral protein synthesis. [6]
In recent years, studies have focused on how viruses evade Pattern Recognition Receptors, target adaptor proteins and their kinases, inhibit transcription factors for Interferon induction, and evade Interferon Stimulated Genes. [3]
Viruses of the flaviviridae Family, such as hepatitis C virus, have developed complex viral mechanisms to rearrange the cell membrane, creating a membranaceous web designed to house viral replication machinery. These viruses utilize endogenous host cell nuclear pore complex proteins to shield viral RNA from Pattern Recognition Receptors by excluding PRRs from the interior of the viral membrane compartment. By utilizing architectural rearrangement of the membrane, viruses have developed a method to evade cytoplasm localized pattern recognition proteins such as RIG-I. In order to evade pattern recognition, other viruses such as Enterovirus have evolved multi-functional proteins that not only help in viral protein processing but also cleave cytoplasmic recognition proteins MDA5 and RIG-I, further demonstrating the extent to which viruses can reduce Interferon Signaling through various pathways. Other viruses have been reported to target upstream activators of pattern recognition proteins, antagonizing upstream proteins that removed inhibitory post-translational modifications. [3]
Other viruses utilize host cell proteins to shield viral DNA until it has reached the nucleus. Upon entry into the host cell cytoplasm, the HIV-1 capsid is recognized and bound by cyclophilin A (CypA); this affinity interaction stabilizes the capsid and prevents exposure of the HIV-1 cDNA to pattern recognition receptors in the cytoplasm. This shielding allows the HIV-1 cDNA to translocate to the nucleus where it may begin replication. [7]
Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.
Lassa mammarenavirus (LASV) is an arenavirus that causes Lassa hemorrhagic fever, a type of viral hemorrhagic fever (VHF), in humans and other primates. Lassa mammarenavirus is an emerging virus and a select agent, requiring Biosafety Level 4-equivalent containment. It is endemic in West African countries, especially Sierra Leone, the Republic of Guinea, Nigeria, and Liberia, where the annual incidence of infection is between 300,000 and 500,000 cases, resulting in 5,000 deaths per year.
Toll-like receptor 3 (TLR3) also known as CD283 is a protein that in humans is encoded by the TLR3 gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system. TLR3 recognizes double-stranded RNA in endosomes, which is a common feature of viral genomes internalised by macrophages and dendritic cells.
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.
The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.
Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν, referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.
Orthoreovirus is a genus of viruses, in the family Reoviridae, in the subfamily Spinareovirinae. Vertebrates serve as natural hosts. There are ten species in this genus. Diseases associated with this genus include mild upper respiratory tract disease, gastroenteritis, and biliary atresia. Mammalian orthoreovirus 3 induces cell death preferentially in transformed cells and therefore displays inherent oncolytic properties.
A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. A viral envelope protein or E protein is a protein in the envelope, which may be acquired by the capsid from an infected host cell.
Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.
Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.
RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.
The double-stranded RNA-specific adenosine deaminase enzyme family are encoded by the ADAR family genes. ADAR stands for adenosine deaminase acting on RNA. This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.
Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.
MDA5 is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor capable of detecting viruses. It is generally believed that MDA5 recognizes double stranded RNA (dsRNA) over 2000nts in length, however it has been shown that whilst MDA5 can detect and bind to cytoplasmic dsRNA, it is also activated by a high molecular weight RNA complex composed of ssRNA and dsRNA. For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. The signaling cascades in MDA5 is initiated via CARD domain. Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response.
Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.
RIG-I-like receptors are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system. RIG-I is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 and LGP2, this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection. The RLR receptors provide frontline defence against viral infections in most tissues.
An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon. Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to the expression of a subset of genes involved in the innate immune system response. ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites. It's currently estimated that 10% of the human genome is regulated by interferons (IFNs). Interferon stimulated genes can act as an initial response to pathogen invasion, slowing down viral replication and increasing expression of immune signaling complexes. There are three known types of interferon. With approximately 450 genes highly expressed in response to interferon type I. Type I interferon consists of INF-α, INF-β, INF-ω and is expressed in response to viral infection. ISGs induced by type I interferon are associated with viral replication suppression and increase expression of immune signaling proteins. Type II interferon consists only of INF-γ and is associated with controlling intracellular pathogens and tumor suppressor genes. Type III interferon consists of INF-λ and is associated with viral immune response and is key in anti-fungal neutrophil response.
The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.
HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.