Human Endogenous Retroviruses and Toll-Like Receptors

Abstract

Human endogenous retroviruses (HERVs) are estimated to comprise ∼8% of the entire human genome, but the vast majority of them remain transcriptionally silent in most normal tissues due to accumulated mutations. However, HERVs can be frequently activated and detected in various tissues under certain conditions. Nucleic acids or proteins produced by HERVs can bind to pattern recognition receptors of immune cells or other cells and initiate an innate immune response, which may be involved in some pathogenesis of diseases, especially cancer and autoimmune diseases. In this review, we collect studies of the interaction between HERV elements and Toll-like receptors and attempt to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases.

Introduction

As a subset of transposable elements, endogenous retroviruses (ERVs) appeared in the vertebrate genome millions of years ago and are remnants of germ cell infection by exogenous retrovirus during evolution (Bannert and Kurth, 2006). In the case of human endogenous retroviruses (HERVs), 98,000 ERV elements or fragments are inserted into the human genome, which is dispersed over 8% of the whole genome (Lander et al, 2001).

So far, there are at least 30 ERV families, named according to the transfer RNA used to prime reverse transcription, to be identified (Mayer et al, 2011). Nevertheless, it was generally accepted that HERVs are now silent due to mutations, such as deletions or nonsense mutations, and hypermethylation (Feschotte and Gilbert, 2012). Therefore, ERVs have always been considered “junk viruses”. However, some groups still contain open reading frames for one or more structural genes.

There is substantial evidence of HERVs reactivation, and its expression levels are closely related to several pathological conditions, especially autoimmune diseases and cancers (Bhardwaj and Coffin, 2014; Cegolon et al, 2013; Kassiotis, 2014; Mullins and Linnebacher, 2012).

Innate immunity is the first and most ancient line of defense against pathogens and host-derived molecules and plays an essential role in developing infections and tissue damage. Modulation of innate immunity has become a potential therapeutic strategy for several immune-related diseases due to its crucial role in these pathologies (Hennessy and McKernan, 2021). Innate immune cells are activated by binding to pathogens and their products through pattern recognition receptors (PRRs) recognition, leading to nonspecific anti-infection, immune regulation, and participation in the process of initiation and effect of adaptive immunity (Li and Wu, 2021).

There are different PRRs, including Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors, C-type lectin receptors, and absent in melanoma-2-like receptors (Takeuchi and Akira, 2010). Among these PRRs, TLRs are the first to be discovered and the most intensely studied in the innate immune system. Although innate immunity can maintain body homeostasis, under certain circumstances, overactivation of the natural immune system mediated by TLRs will lead to an imbalance of homeostasis. It will even trigger the occurrence of many autoimmune diseases (Yu, 2016).

Some studies have shown that viral nucleic acid or proteins produced by HERVs can act as ligands to activate TLR signaling pathways and participate in many diseases (Hurst and Magiorkinis, 2015). This review will focus on the interaction between HERVs and TLRs and will reveal the role of the innate immune response in the pathogenesis of multiple types of malignancies, autoimmune, and neurodegenerative diseases.

Overview of HERVs

Genetic structure of HERVs

A typical HERV genome is about 7–11 kb in size, and its structure is similar to that of exogenous retroviruses (such as HIV), consisting of three structural genes (gag, pol, and env) flanked by two long terminal repeats (LTRs) (Vargiu et al, 2016). The LTR region is the regulatory center for HERV expression, containing promoters, enhancers, and polyadenylation sites that regulate RNA transcription. The gag gene encodes three proteins: capsid, nucleocapsid, and matrix. The pol gene encodes mainly proteases, reverse transcriptases, ribonuclease H, and integrase. The env gene encodes an envelope glycoprotein, cleaved into two protein subunits, including the surface unit and the transmembrane unit.

Other typical features include the primer binding site (PBS) and the polypurine trait (PPT), the former located between the 5′LTR region and the gag gene, and the latter between the 3′LTR region and the env gene (Cullen and Schorn, 2020). PBS is the binding site of cellular tRNA during reverse transcription, and PPT is the PBS in positive-strand DNA production. The LTR region was recombined by homologous recombination, leaving only the solitary LTRs in the host genome.

Transactivation of HERVs

Due to the accumulation of point mutations and deletions, HERVs were gradually silenced throughout evolution. In addition, epigenetic mechanisms, particularly CpG methylation and cytosine deamination of LTR, the basal expression of HERVs in various cell types and tissues are tightly controlled, making it relatively stable in the host. However, there are still many external or internal factors that activate HERVs expression, such as radiation [e.g., ultraviolet (Schanab et al, 2011) and gamma-rays (Mikhalkevich et al, 2021)], viral infections [e.g., influenza A virus (Schmidt et al, 2019), HSV-1 (Bello-Morales et al, 2021), and HIV-1 (Li et al, 2021b)], drugs [e.g., caffeine and aspirin (Liu et al, 2013)], and cytokines [e.g., TNF-α (Manghera et al, 2016) and IL-1], which led to increased transcriptional activity and production of viral proteins.

Exogenous viral infection is vital in regulating HERVs reactivation among these inducers. Recent studies have shown that HERVs can also be activated by SARS-CoV-2 infection. The expression of HERV-W Env in leukocytes of COVID19 patients increased significantly compared with healthy controls (Balestrieri et al, 2021; Marston et al, 2021). In bronchoalveolar lavage fluid from COVID19 patients, multiple HERV families were detected to upregulate expression, particularly HERV-FRD (Kitsou et al, 2021).

Another study showed that the expression levels of some HERV families (HERV-H, HERV-K, and HERV-W) were significantly increased in peripheral blood samples from COVID19 children compared with healthy children; further, the expression level of HERVs in patients with mild symptoms was significantly higher than in a patient with severe complications (Tovo et al, 2021).

HERVs and human diseases

Although some HERVs have physiological functions, such as HERV-W (syncytin-1) and HERV-FRD (syncytin-2) involved in placentation (Dupressoir et al, 2012), most HERVs exhibit pathogenic potential after abnormal activation. So far, there has been substantial evidence that HERVs are associated with the occurrence and development of various diseases. Many studies have reported that HERV-derived RNA transcripts or proteins can be detected in a variety of tissues or humoral samples from cancer patients, such as breast cancer (Steiner et al, 2021; Zhou et al, 2016), ovarian cancer (Rycaj et al, 2015), prostate cancer (Rezaei et al, 2021; Steiner et al, 2021), and colon cancer (Dolci et al, 2020; Steiner et al, 2021).

The potential molecular mechanisms by which HERVs induce tumors may involve activating proto-oncogenes, inhibiting tumor suppressor genes, promoting cell transformation, influencing chromosomal stability, and suppressing antitumor immunity (Kassiotis, 2014). The HERVs are also involved in the development of autoimmune diseases, such as multiple sclerosis (MS) (Lezhnyova et al, 2020), rheumatoid arthritis (Mameli et al, 2017), systemic lupus erythematosus (Stearrett et al, 2021), and type 1 diabetes (T1D) (Levet et al, 2019).

In addition, HERVs are closely associated with the development of neurological disorders, such as Alzheimer's disease (AD) (Licastro and Porcellini, 2021), schizophrenia (Frank et al, 2005; Yan et al, 2022), and bipolar disorders (Frank et al, 2005). The underlying pathogenesis behind these diseases often involves aberrant activation of innate immune cells, which may be associated with their PRRs recognition of HERV expression products, particularly HERV-derived nucleic acids. It is foreseeable that an increasing number of diseases will be associated with the abnormal activation of HERVs. The HERV elements may also become candidate biomarkers for diagnosis, treatment monitoring, or prognostic evaluation.

General Characteristics of TLRs

The TLRs are a family of innate immune receptors highly conserved and ancient in evolution. It is one of the critical members of the PRRs family in the innate immune system. The TLR exerts a natural immune defense role by recognizing pathogen-associated molecular pattern (PAMP), initiating intracellular signal transduction, inducing the release of pro-inflammatory cytokines, type Ⅰ interferon (IFN), and costimulatory molecules, promoting dendritic cell (DC) maturation and generating adaptive immunity (Asami and Shimizu, 2021; Fitzgerald and Kagan, 2020).

The toll was first found in Drosophila in genes that control the dorsal-ventral polarity of the Drosophila embryo (Nusslein-Volhard et al, 1980). However, it was later found to be involved in antifungal immunity (Lemaitre et al, 1996). In 1997, the human homolog of the Drosophila Toll protein (now called TLR4) was cloned, and it was shown that the Toll/NF-κB signaling pathway is conserved in humans. Toll signaling stimulates the adaptive immune response (Medzhitov et al, 1997).

To date, at least 13 TLRs (TLR1–TLR13) have been found in mammals, of which TLR1–TLR9 is more conservative and expressed in both humans and mice, TLR10 is only expressed in humans, and TLR11–TLR13 is only expressed in mice (Kawasaki and Kawai, 2014). In the following, we will discuss only TLRs expressed in humans.

Molecular structure of TLRs

The TLRs belong to the type I transmembrane receptor, and all members have similar structural domain arrangements, including an extracellular domain, a transmembrane domain, and an intracellular domain (Kawai and Akira, 2007). The extracellular region is a pathogen-binding domain, a leucine domain formed by 19–25 tandem leucine-rich repeating motifs (LRR), and 2–4 conserved cysteine structures (Gong and Wei, 2014). In terms of spatial arrangement, the entire LRR forms a highly conservative horseshoe-shaped spatial structure, which participates in identifying and combining ligands (Bell et al, 2003).

Studies have found that the LRR region has poor homology in different TLRs, suggesting that TLR molecules' ligands have other structures (Botos et al, 2011). The transmembrane region is a cysteine-rich region that is often thought to be associated with the subcellular localization of TLR (Botos et al, 2011). The intracellular part contains about 200 amino acids. It is highly homologous to the IL-1 receptor, called the Toll/IL-1 receptor (TIR) domain, responsible for interacting with intracellular adaptor proteins containing TIR domains to initiate downstream signal transduction (Nimma et al, 2021).

Therefore, the TIR domain is a binding site for interaction with downstream protein kinases and is the core element of TLR signal transduction (Fornarino et al, 2011). Given that the TIR domain is highly conserved in evolution, the TLR signaling pathways are similar between different species (Kang and Lee, 2011).

Tissue distribution and localization of TLRs

The TLR is widely distributed in a variety of tissues and cells, not only expressed in various immune cells but also in a large number of epithelial cells, endothelial cells, such as gastrointestinal epithelium (Burgueno and Abreu, 2020; Semin et al, 2021), the respiratory epithelium (Baral et al, 2014; Iwamura and Nakayama, 2008), genitourinary tract epithelium (Amjadi et al, 2018; Habib, 2021), and vascular endothelium (Goulopoulou et al, 2016). Monocyte-macrophages are the immune cells that express the most TLRs, and all but TLR3 can be expressed (Grassin-Delyle et al, 2020; Gulati et al, 2019).

Eosinophils can express TLR1, TLR4, TLR7, TLR9, and TLR10 (Nagase et al, 2003). The basophil constitutively expressed TLR2, TLR4, TLR9, and TLR10 (Komiya et al, 2006). B cells also express TLR in large quantities but do not express TLR3 and TLR8, whereas T cells only express TLR1 and TLR4 (Kumar, 2021). The expression of TLRs in DCs is more complex and related to the corresponding functional state of different subpopulations (Sato et al, 2020).

The TLR is expressed in the form of homodimers or heterodimers on the cell surface (TLRs 1, 2, 5, 6, and 10), endosomal surface (TLRs 3, 7, 8, and 9), or both (TLR4) (Shekarian et al, 2017). However, it has also been found that TLR3 can be expressed on the cell membrane of epithelial cells (Erdinest et al, 2014) and fibroblasts (Erdinest et al, 2014; Matsumoto et al, 2002). In addition to TLR3, in some instances, TLR7 and TLR9 can also be expressed on the cell surface depending on the cell type. The subcellular location of TLR depends on cell species, suggesting that different cells depend on TLR to induce different IFN production pathways after pathogen infection (Matsumoto et al, 2003).

Ligands and signaling pathways of TLRs

Due to the different subcellular localizations and the molecular structure of the extracellular region, TLRs recognized different ligands, including PAMPs and damage-associated molecular patterns (DAMPs) (Behzadi et al, 2021). The PAMPs are present in all pathogens, including bacteria, viruses, fungi, and parasites. Cell-surface TLRs mainly bind to proteins, lipids, and lipoproteins (TLR1, TLR2, TLR4–TLR6, and TLR10), whereas the endosomal TLRs recognize nucleic acids (TLR3, TLR7–TLR9) (Takeuchi and Akira, 2010).

TLR2 can form heterodimers with TLR1 or TLR6, recognizing a variety of PAMPs from bacteria or fungi, such as bacterial peptidoglycans, lipoteichoic acid lipopeptides, and yeast polysaccharides (Mullaly and Kubes, 2006; Takeuchi et al, 2002; Takeuchi et al, 2001); TLR4 in complex with MD2 mainly recognizes bacterial lipopolysaccharides (LPS) (Park et al, 2009), viral capsid proteins (Lv et al, 2018); TLR3 mainly recognizes viral dsRNA, whereas TLR7 and TLR8 mainly recognize ssRNA of viruses (Shimizu, 2017); and TLR9 mainly recognizes nonmethylated CpG motifs in bacterial and viral DNA (Shimizu, 2017). On recognizing PAMPs and DAMPs, TLRs subsequently trigger intracellular signal transduction and induce an innate immune response (Fig. 1).

FIG. 1.

HERVs elements interact with TLRs. The TLRs are expressed to either on the cell surface or within endosomes. Nucleic acids or proteins derived from HERV can bind to TLRs as ligands and activate downstream MyD88-dependent or -independent signaling pathways to produce a large number of transcription factors, including NF-κB, AP-1, and IRF, which ultimately lead to the release of pro-inflammatory cytokines and type I IFN. HERV, human endogenous retrovirus; IFN, interferon; TLR, Toll-like receptor.

Currently, it is believed that TLR-mediated signaling pathways can be mainly divided into the MyD88-dependent pathway and the TIR domain-containing adaptor inducing IFN-β (TRIF)-dependent pathway, according to the different adaptor molecules (Kawasaki and Kawai, 2014). After most of the TLRs (except TLR3) bind to a specific ligand, the TIR domain of MyD88 is recruited through its TIR domain. Then, the interleukin-1 receptor-associated kinase (IRAK) family protein molecule is attached to the signal transduction complex through the death domain of MyD88, and the complex continues to recruit and activate the downstream TRAF6 molecules (Fitzgerald and Kagan, 2020).

In addition, TLR3 and TLR4 recruit TRAF3 and TRAF6 through the nondependent MyD88 pathway, that is, through the TRIF or TRIF-related adaptor molecule (TRAM) (Fitzgerald and Kagan, 2020). Both two pathways finally activate transcription factors (such as NF-κB, AP-1, and IRF) to regulate the secretion and expression of type I IFN, pro-inflammatory cytokines, and chemokines.

Interaction Between HERVs and TLRs

Most studies on the interaction between HERVs and TLRs come from animal models. Until now, some accumulated evidence indicates that the relationship between HERVs and TLR-mediated innate immunity is very complex. On the one hand, the TLR signal plays a vital role in controlling the HERVs. The TLR deficiency can lead to ERV reactivation in mice. On the other hand, HERV-derived proteins or RNA can act as ligands to bind specific TLRs, initiate the innate immune response, and play an essential role in the pathogenesis of various immune-related diseases (Table 1).

Table 1.

Effects of Interaction Between Endogenous Retroviruses Elements and Toll-Like Receptors

HERV elements	TLR pathways	Observations	References
MSRV-Env-SU	CD14/TLR4 pathway	Induces PBMCs to secret major pro-inflammatory cytokines Triggers the maturation of human DCs Stimulates murine DCs produce pro-inflammatory cytokines Induces EAE in mice	Rolland et al (2006) Perron et al (2013)
MSRV-Env	TLR4 pathway	Induces HCMEC/D3 cells to overexpress ICAM-1 and secrete IL-6 and IL-8 Induces the expression of pro-inflammatory cytokines and iNOS, as well as the formation of nitrotyrosine groups, and decreases the expression of myelin proteins in cultured OPCs Impairs the differentiation of OPCs to mature myelinating oligodendrocytes Rescues MSRV-Env-mediated myelin deficits by modulating TLR4 expression and activation	Duperray et al (2015) Kremer et al (2013) Madeira et al (2016) Gottle et al (2021)
HERV-W-Env	TLR4 pathway	Facilitates the production of TNF-α and IL-10 in glial cells Impairs the insulin secretion of pancreatic β cells in vitro through the NF-κB signaling pathway	Wang et al (2021) Levet et al (2017)
Syncytin-1	TLR3 pathway	Triggers the activation of CRP in human microglia and astrocytes	Wang et al (2018)
HERV-K HML-2 env dsRNA	TLR3 pathway	Increases the expression of IFN-I and inflammation-related genes and affects macrophage polarization after gamma irradiation	Mikhalkevich et al (2021)
HERV-K HML-2 env ssRNA	mTLR7/hTLR8 pathway	Induces neuronal apoptosis via TLR/SARM1 signaling	Dembny et al (2020)

CRP, C-reactive protein; DC, dendritic cell; EAE, experimental allergic encephalomyelitis; hTLR8, human TLR8; HERV, human endogenous retrovirus; IFN, interferon; iNOS, inducible nitric oxide synthase; MSRV, multiple sclerosis-associated retrovirus; mTLR7, mouse TLR7; OPC, oligodendrocyte precursor cell; PBMC, peripheral blood mononuclear cell; TLR, Toll-like receptor.

TLR3

TLR3 is widely expressed in immune cells and the central nervous system, including neurons, astrocytes, and microglia, indicating the particular function of TLR3 in the nervous system (Gao et al, 2021; Kumar, 2019; Li et al, 2021a). Syncytin-1 is the envelope protein of HERV-W. The levels of syncytin-1 and C-reactive protein (CRP) were significantly increased in patients with schizophrenia, and their expressions were positively correlated and relatively consistent.

Overexpression of syncytin-1 significantly increased the levels of CRP, TLR3, and IL-6 in both human microglia and astrocytes, but the expression of CRP and IL-6 decreased after TLR3 knocking down (Wang et al, 2018). Further studies have confirmed that syncytin-1 can act as a ligand to interact directly with TLR3, activate IRF3 (a downstream molecule of TLR3) through phosphorylation, and trigger the signaling pathway (Wang et al, 2018). These findings imply that syncytin-1 can induce neuroinflammation via the TLR3 signaling pathway.

Further, studies have found that TLRs are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Abnormal expression of HERV dsRNA triggers excessive activation of TLR3. This induces the transport of IRF3, IRF7, and NF-κB to the nucleus and activates the transcription of IFN-α/β, which binds to the I-IFN receptor that promotes the IFN response. Therefore, the ERVs-TLR3 axis may play an essential role in establishing one of the most significant features in MDS-erythropoiesis (de Oliveira et al, 2021).

Another study also confirmed that the ERVs-TLR3 axis could affect the phenotype of macrophages differentiated from monocytes after gamma radiation (Mikhalkevich et al, 2021). They confirmed that gamma radiation could trigger ERV transcription, especially HERV-K (HML-2). At the same time, the expression of dsRNA receptors MDA-5 and TLR3 also increased and bound with the equivalent copies of HML-2 RNA, triggering downstream signaling pathways, resulting in increased expression of IFN-I and inflammation-related genes, ultimately affecting the polarization of macrophages.

Finally, the activation of TLR3 signaling by a panel of HERV-derived dsRNA transcripts has been observed after the treatment with DNA methyltransferase (DNMT) inhibitors in serval ovarian cancer cell lines. DNMT inhibitors can induce transcription of HERV env genes through demethylation of its promoter regions, causing upregulation of cytosolic dsRNA and subsequently triggering a type I IFN response and apoptosis via the TLR3 pathway (Chiappinelli et al, 2015).

TLR4

The TLR4-mediated innate immune response is well known to be critical in controlling Gram-negative bacterial infections. In 2000, Kurt-Jones et al (2000) confirmed that TLR4 and CD14 could recognize the fusion protein of respiratory syncytial virus to trigger the innate immune response, which is the first reported TLR to respond to viral proteins. Many studies have shown that CD14/TLR4 can also recognize HERV-derived proteins to trigger inflammatory responses.

Most of the interaction between HERVs and TLR4 comes from studying the immunopathological mechanism of MS. MS is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults. HERV-W, one of the members of HERV, was initially found in MS patients and was also named MS-associated retrovirus (MSRV) (Li and Karlsson, 2016). MSRV-Env is a functional envelope glycoprotein repeatedly detected in most MS patients (Perron et al, 2012).

This protein is a highly potent endogenous TLR4 agonist and thus has pro-inflammatory properties in several types of immune cells, such as circulating monocytes, DCs, and macrophages. Rolland et al (2006) reported that the surface unit of MSRV-Env, like LPS, stimulates human peripheral blood mononuclear cell cultures through the CD14/TLR4 pathway to induce the secretion of major pro-inflammatory cytokines such as IL-1β, IL-6, or TNF-α.

Further, it can also trigger the maturation of human DCs in a TLR4-dependent manner and has been shown to induce experimental allergic encephalomyelitis in mice (Perron et al, 2013). In addition to immune cells, MSRV-Env can activate other types of cells (e.g., endothelial cells, epithelial cells, oligodendrocytes, glial cells) through the TLR4 pathway to induce an inflammatory response or tissue damage. Wang et al (2021) reported that MSRV-Env could facilitate the production of TNF‑α and IL-10 by activating TLR4 in glial cells.

Duperray et al (2015) reported that recombinant MSRV-Env could induce HCMEC/D3 cells to overexpress ICAM-1 and secrete the cytokines IL-6 and IL-8 in a dose-dependent manner. The HCMEC/D3 cell line, as a human blood-brain barrier in vitro model, has been extensively characterized for the brain endothelial phenotype. ICAM-1 is the primary mediator of leukocyte-endothelial cell adhesion. Therefore, overexpression of ICAM-1 contributes to the adhesion and migration of activated immune cells through a monolayer of endothelial cells.

Kremer et al (2013) confirmed that TLR4 could be expressed in human brain tissues and cultured oligodendrocyte precursor cells (OPCs). MSRV-Env can induce the expression of pro-inflammatory cytokines and inducible NO synthase as well as the formation of nitrotyrosine groups and decrease myelin protein expression in cultured OPCs through activating TLR4. They believe that nitrosative stress mediated by MSRV-Env/TLR4 will reduce the ability of oligodendrocytes to differentiate, failing remyelination.

Madeira et al (2016) confirmed that MSRV-Env alters the differentiation of OPCs to mature myelinating oligodendrocytes through TLR4 activation. GNbAC1, a humanized monoclonal antibody against MSRV-Env, may reverse the process of remyelination impaired by MSRV-Env expressed in MS lesions. More recently, Gottle et al (2021) reported that several small molecules had demonstrated the ability to rescue MSRV-Env-mediated myelin deficits by modulating TLR4 expression and activation. These findings strongly support the hypothesis that MSRV is involved in the pathogenesis of MS through its Env protein activates TLR4 to induce chronic inflammation and inhibit remyelination.

Further, HERV-W Env will likely be involved in T1D pathogenesis by activating TLR4. There is already a large amount of evidence that TLR4 and HERV-W Env are closely related to the development of T1D, respectively. First, LPS directly damages insulin secretion of pancreatic β cells in vitro through the CD14/TLR4 and NF-κB pathway (Amyot et al, 2012; Garay-Malpartida et al, 2011). TLR4 knockout significantly reduces MyD88 and IRAK-1 protein phosphorylation levels in the diabetic mouse model (Devaraj et al, 2011). Further, TLR4 and MyD88 were increased dramatically in patients with T1D compared with the normoglycemic subjects (de Melo et al, 2022).

Second, ERV activation has been observed in β cells from the T1D mouse model (Suenaga and Yoon, 1988; Tsumura et al, 1998), and viral proteins were involved in inflammatory and autoreactive T cell responses (Bashratyan et al, 2017). What is more, HERV-W-Env protein can be detected in sera (70%) and islet acinar cells (75%) in T1D patients and has been shown to directly impair insulin secretion by primary pancreatic β cells in vitro, which was confirmed in HERV-W-env transgenic mice (Levet et al, 2017). However, it remains uncertain whether direct damage to islet β cells or induction of autoimmune responses involved in the pathogenesis of T1D through the HERV-W-Env/TLR4 axis remains uncertain and needs to be clarified by further studies.

TLR7, TLR8, and TLR9

Like TLR3, TLR7/TLR8/TLR9 is also localized on the membrane of intracellular compartments. Single-stranded RNA (ssRNA) has been identified as the natural ligand of TLR7 and TLR8, but TLR9 only recognizes specific unmethylated CpG DNA. TLR7 is a retroviral sensor receptor expressed in plasmacytoid DCs, CD11b⁺ DC, and B cells. TLR7-dependent recognition is necessary for an effective immune response against retroviruses in the body (Kane et al, 2011). Viral RNA stimulation of TLR7 can directly regulate the expression of a set of transcription factors or genes.

These transcription factors or genes can promote the germinal center response and the initiation of immunoglobulin conversion, such as activation-induced cytidine deaminase. It can also regulate the expression of cytokines that are autocrine effects of B cells. Alternatively, it is also possible to control the maintenance of germinal center responses by stimulating germinal center B cells' continued proliferation or survival. Interestingly, TLR7 has overlap effects with TLR8 and TLR9 and often participates in the onset and development of a disease.

Many studies have shown that HERV-K (HML-2) is related to various diseases, such as neurological diseases (Li et al, 2015; Manghera et al, 2014). However, a few studies have demonstrated the direct signaling role of HERV RNA in cell activation. A study has shown that extracellular HERV-K (HML-2) RNA is an effective activator of human TLR8 (hTLR8) and mouse TLR7 (mTLR7). Studies have shown that HSP60 triggers neuronal damage by activating microglia in a TLR4 and MyD88-dependent manner (Lehnardt et al, 2008), and the received neurons can release HERV-K transcripts to trigger neurodegeneration (Dembny et al, 2020).

Some HERV-K proviruses contain sequences similar to ssRNA40, especially the GUUGUGU motif in the env gene (Heil et al, 2004). HERV-K can act as a ligand for mTLR7 and hTLR8 and activate mTLR7 and hTLR8. Its derived oligoribonucleotides activate microglia and macrophages through mTLR7 and hTLR8, thus inducing innate immunity.

Besides, the study also found that unmodified HERV-K RNA can cause TLR7-dependent neurotoxicity. On this basis, the activation of the innate immune system may contribute to neurodegenerative diseases (Dembny et al, 2020). In some studies, the frequency of detecting HERV-K RNA containing TLR7/8 recognition motifs in cerebrospinal fluid of AD patients by RT-PCR was higher than in control individuals. The occurrence of AD may be related to the mechanism mentioned earlier.

Neurons are exposed to HERV-K RNA with GU-enriched sequences, and HERV-K RNA induces neurodegeneration through intrinsic mTLR7 and hTLR8 signaling. The essential feature of this signal is that endogenous RNA is dislocated in the extracellular space (Lehmann et al, 2012), and it may be released during the cell damage process caused by pathogenic factors. This pathogenic factor contacts the TLR located in the endosome of neurons, which leads to the release of endogenous HERV-K transcripts from damaged neurons, causing further neurodegeneration.

Under physiological conditions, the interaction between these HERV-K RNA transcripts and neuronal TLR7/TLR8 can be prevented by positioning these components in separate cell compartments. However, the precise local concentration of extracellular functional HERV-K RNA in the brain parenchyma at the injury or pathological site of neurodegenerative disease is unknown and difficult to estimate.

Studies have shown that ERVs are expressed and cannot be effectively controlled by the immune system lacking TLR3, TLR7, and TLR9. The three TLRs combined with maintaining ERV-induced tumors and germline genome integrity. In the absence of these TLRs, damage to the ERV-specific antibody response in vivo and the decrease in DCs on the initiation of NK cells in vitro indicate that nucleic acids that recognize TLRs play an essential role in the loss of anti-ERV defense to late-onset T-cell acute lymphoblastic leukemia formation (Yu et al, 2012).

Conclusions and Perspectives

Although ERVs are the products of primate ancestors infected with exogenous viruses, they still play an indispensable role in physiology and pathology. More and more evidence shows that inflammatory and immune-related diseases are associated with abnormal activation of HERVs, in which the interaction between HERV-derived elements and TLRs plays an important role. On the one hand, the expression products of HERVs can initiate the inflammatory response and shape innate immunity by activating a variety of TLRs.

On the other hand, TLR signals can, in turn, control HERV expression via the binding of downstream transcription factors (such as NF-κB) to its LTRs. So, HERVs have become an essential endogenous regulator of innate immunity, used to elucidate the pathogenesis of certain diseases. We predict that interference with HERVs-TLRs interactions could become a new therapeutic strategy.

Footnotes

Acknowledgments

The authors thank Dr. Dawei Cui (The First Affiliated Hospital of Zhejiang University School of Medicine, China) for his valuable suggestions.

Authors' Contributions

J.Z. and X.J.: Conceptualization and article design; X.J., X.L., and F.G.: Collection of data and visualization; X.J.: Writing—original draft; J.Z.: Writing—review and editing. All authors read and approved the final version of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by grants from the Shaoxing Science and Technology Program of Zhejiang Province (Grant No. 2018C30028).

References

Amjadi

, Zandieh

, Salehi

, et al. Variable localization of Toll-like receptors in human fallopian tube epithelial cells. Clin Exp Reprod Med, 2018; 45(1):1–9; doi: 10.5653/cerm.2018.45.1.1

Amyot

, Semache

, Ferdaoussi

, et al. Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-kappaB signalling. PLoS One, 2012; 7(4):e36200; doi: 10.1371/journal.pone.0036200

Asami

, Shimizu

. Structural and functional understanding of the toll-like receptors. Protein Sci, 2021; 30(4):761–772; doi: 10.1002/pro.4043

Balestrieri

, Minutolo

, Petrone

, et al. Evidence of the pathogenic HERV-W envelope expression in T lymphocytes in association with the respiratory outcome of COVID-19 patients. EBioMedicine, 2021; 66:103341; doi: 10.1016/j.ebiom.2021.103341

Bannert

, Kurth

. The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genomics Hum Genet, 2006; 7:149–173; doi: 10.1146/annurev.genom.7.080505.115700

Baral

, Batra

, Zemans

, et al. Divergent functions of Toll-like receptors during bacterial lung infections. Am J Respir Crit Care Med, 2014; 190(7):722–732; doi: 10.1164/rccm.201406-1101PP

Bashratyan

, Regn

, Rahman

, et al. Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice. Eur J Immunol, 2017; 47(3):575–584; doi: 10.1002/eji.201646755

Behzadi

, Garcia-Perdomo

, Karpinski

. Toll-like receptors: General molecular and structural biology. J Immunol Res, 2021; 2021:9914854; doi: 10.1155/2021/9914854

Bell

, Mullen

, Leifer

, et al. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol, 2003; 24(10):528–533; doi: 10.1016/s1471-4906(03)00242-4

10.

Bello-Morales

, Andreu

, Ripa

, et al. HSV-1 and endogenous retroviruses as risk factors in demyelination. Int J Mol Sci, 2021; 22(11):5738; doi: 10.3390/ijms22115738

11.

Bhardwaj

, Coffin

. Endogenous retroviruses and human cancer: Is there anything to the rumors?. Cell Host Microbe, 2014; 15(3):255–259; doi: 10.1016/j.chom.2014.02.013

12.

Botos

, Segal

, Davies

. The structural biology of Toll-like receptors. Structure, 2011; 19(4):447–459; doi: 10.1016/j.str.2011.02.004

13.

Burgueno

, Abreu

. Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol, 2020; 17(5):263–278; doi: 10.1038/s41575-019-0261-4

14.

Cegolon

, Salata

, Weiderpass

, et al. Human endogenous retroviruses and cancer prevention: Evidence and prospects. BMC Cancer, 2013; 13:4; doi: 10.1186/1471-2407-13-4

15.

Chiappinelli

, Strissel

, Desrichard

, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell, 2015; 162(5):974–986; doi: 10.1016/j.cell.2015.07.011

16.

Cullen

, Schorn

. Endogenous retroviruses walk a fine line between priming and silencing. Viruses, 2020; 12(8):792; doi: 10.3390/v12080792

17.

de Melo

, de Souza

KSC

, Ururahy

MAG

, et al. Toll-like receptor inflammatory cascade and the development of diabetic kidney disease in children and adolescents with type 1 diabetes. J Paediatr Child Health, 2022; 58(6):996–1000; doi: 10.1111/jpc.15884

18.

de Oliveira

RTG

, Cordeiro

JVA

, Vitoriano

, et al. ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis. Med Oncol, 2021; 38(3):27; doi: 10.1007/s12032-021-01466-1

19.

Dembny

, Newman

, Singh

, et al. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight, 2020; 5(7):e131093; doi: 10.1172/jci.insight.131093

20.

Devaraj

, Tobias

, Jialal

. Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine, 2011; 55(3):441–445; doi: 10.1016/j.cyto.2011.03.023

21.

Dolci

, Favero

, Toumi

, et al. Human endogenous retroviruses long terminal repeat methylation, transcription, and protein expression in human colon cancer. Front Oncol, 2020; 10:569015; doi: 10.3389/fonc.2020.569015

22.

Duperray

, Barbe

, Raguenez

, et al. Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4. Int Immunol, 2015; 27(11):545–553; doi: 10.1093/intimm/dxv025

23.

Dupressoir

, Lavialle

, Heidmann

. From ancestral infectious retroviruses to bona fide cellular genes: Role of the captured syncytins in placentation. Placenta, 2012; 33(9):663–671; doi: 10.1016/j.placenta.2012.05.005

24.

Erdinest

, Aviel

, Moallem

, et al. Expression and activation of toll-like receptor 3 and toll-like receptor 4 on human corneal epithelial and conjunctival fibroblasts. J Inflamm (Lond), 2014; 11(1):3; doi: 10.1186/1476-9255-11-3

25.

Feschotte

, Gilbert

. Endogenous viruses: Insights into viral evolution and impact on host biology. Nat Rev Genet, 2012; 13(4):283–296; doi: 10.1038/nrg3199

26.

Fitzgerald

, Kagan

. Toll-like receptors and the control of immunity. Cell, 2020; 180(6):1044–1066; doi: 10.1016/j.cell.2020.02.041

27.

Fornarino

, Laval

, Barreiro

, et al. Evolution of the TIR domain-containing adaptors in humans: Swinging between constraint and adaptation. Mol Biol Evol, 2011; 28(11):3087–3097; doi: 10.1093/molbev/msr137

28.

Frank

, Giehl

, Zheng

, et al. Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders. J Virol, 2005; 79(17):10890–10901; doi: 10.1128/JVI.79.17.10890-10901.2005

29.

Gao

, Ciancanelli

, Zhang

, et al. TLR3 controls constitutive IFN-beta antiviral immunity in human fibroblasts and cortical neurons. J Clin Invest, 2021; 131(1):e134529; doi: 10.1172/JCI134529

30.

Garay-Malpartida

, Mourao

, Mantovani

, et al. Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis. BMC Immunol, 2011; 12:18; doi: 10.1186/1471-2172-12-18

31.

Gong

, Wei

. Structure modeling of Toll-like receptors. Methods Mol Biol, 2014; 1169:45–53; doi: 10.1007/978-1-4939-0882-0_5

32.

Gottle

, Schichel

, Reiche

, et al. TLR4 associated signaling disrupters as a new means to overcome HERV-W envelope-mediated myelination deficits. Front Cell Neurosci, 2021; 15:777542; doi: 10.3389/fncel.2021.777542

33.

Goulopoulou

, McCarthy

, Webb

. Toll-like receptors in the vascular system: Sensing the dangers within. Pharmacol Rev, 2016; 68(1):142–167; doi: 10.1124/pr.114.010090

34.

Grassin-Delyle

, Abrial

, Salvator

, et al. The role of Toll-like receptors in the production of cytokines by human lung macrophages. J Innate Immun, 2020; 12(1):63–73; doi: 10.1159/000494463

35.

Gulati

, Kumar

, Mukhopadhaya

. Differential recognition of Vibrio parahaemolyticus OmpU by toll-like receptors in monocytes and macrophages for the induction of proinflammatory responses. Infect Immun, 2019; 87(5):e00809-18; doi: 10.1128/IAI.00809-18

36.

Habib

. Multifaceted roles of Toll-like receptors in acute kidney injury. Heliyon, 2021; 7(3):e06441; doi: 10.1016/j.heliyon.2021.e06441

37.

Heil

, Hemmi

, Hochrein

, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 2004; 303(5663):1526–1529; doi: 10.1126/science.1093620

38.

Hennessy

, McKernan

. Anti-viral pattern recognition receptors as therapeutic targets. Cells, 2021; 10(9):2258; doi: 10.3390/cells10092258

39.

Hurst

, Magiorkinis

. Activation of the innate immune response by endogenous retroviruses. J Gen Virol, 2015; 96(Pt 6):1207–1218; doi: 10.1099/jgv.0.000017

40.

Iwamura

, Nakayama

. Toll-like receptors in the respiratory system: Their roles in inflammation. Curr Allergy Asthma Rep, 2008; 8(1):7–13; doi: 10.1007/s11882-008-0003-0

41.

Kane

, Case

, Wang

, et al. Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry. Immunity, 2011; 35(1):135–145; doi: 10.1016/j.immuni.2011.05.011

42.

Kang

, Lee

. Structural biology of the Toll-like receptor family. Annu Rev Biochem, 2011; 80:917–941; doi: 10.1146/annurev-biochem-052909-141507

43.

Kassiotis

. Endogenous retroviruses and the development of cancer. J Immunol, 2014; 192(4):1343–1349; doi: 10.4049/jimmunol.1302972

44.

Kawai

, Akira

. TLR signaling. Semin Immunol, 2007; 19(1):24–32; doi: 10.1016/j.smim.2006.12.004

45.

Kawasaki

, Kawai

. Toll-like receptor signaling pathways. Front Immunol, 2014; 5:461; doi: 10.3389/fimmu.2014.00461

46.

Kitsou

, Kotanidou

, Paraskevis

, et al. Upregulation of human endogenous retroviruses in bronchoalveolar lavage fluid of COVID-19 patients. Microbiol Spectr, 2021; 9(2):e0126021; doi: 10.1128/Spectrum.01260-21

47.

Komiya

, Nagase

, Okugawa

, et al. Expression and function of toll-like receptors in human basophils. Int Arch Allergy Immunol, 2006; 140(Suppl 1):23–27; doi: 10.1159/000092707

48.

Kremer

, Schichel

, Forster

, et al. Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol, 2013; 74(5):721–732; doi: 10.1002/ana.23970

49.

Kumar

. Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol, 2019; 332:16–30; doi: 10.1016/j.jneuroim.2019.03.012

50.

Kumar

. Toll-like receptors in adaptive immunity. Handb Exp Pharmacol, 2022; 276:95–131; doi: 10.1007/164_2021_543

51.

Kurt-Jones

, Popova

, Kwinn

, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol, 2000; 1(5):398–401; doi: 10.1038/80833

52.

Lander

, Linton

, Birren

, et al. Initial sequencing and analysis of the human genome. Nature, 2001; 409(6822):860–921; doi: 10.1038/35057062

53.

Lehmann

, Kruger

, Park

, et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci, 2012; 15(6):827–835; doi: 10.1038/nn.3113

54.

Lehnardt

, Schott

, Trimbuch

, et al. A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci, 2008; 28(10):2320–2331; doi: 10.1523/JNEUROSCI.4760-07.2008

55.

Lemaitre

, Nicolas

, Michaut

, et al. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell, 1996; 86(6):973–983; doi: 10.1016/s0092-8674(00)80172-5

56.

Levet

, Charvet

, Bertin

, et al. Human endogenous retroviruses and type 1 diabetes. Curr Diab Rep, 2019; 19(12):141; doi: 10.1007/s11892-019-1256-9

57.

Levet

, Medina

, Joanou

, et al. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. JCI Insight, 2017; 2(17):e94387; doi: 10.1172/jci.insight.94387

58.

Lezhnyova

, Martynova

, Khaiboullin

, et al. The relationship of the mechanisms of the pathogenesis of multiple sclerosis and the expression of endogenous retroviruses. Biology (Basel), 2020; 9(12):464; doi: 10.3390/biology9120464

59.

, Wu

. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther, 2021; 6(1):291; doi: 10.1038/s41392-021-00687-0

60.

, Karlsson

. Expression and regulation of human endogenous retrovirus W elements. APMIS, 2016; 124(1–2):52–66; doi: 10.1111/apm.12478

61.

, Acioglu

, Heary

, et al. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun, 2021a;91:740–755; doi: 10.1016/j.bbi.2020.10.007

62.

, Lee

, Henderson

, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med, 2015; 7(307):307ra153; doi: 10.1126/scitranslmed.aac8201

63.

, Guo

, Li

, et al. Infection by diverse HIV-1 subtypes leads to different elevations in HERV-K transcriptional levels in human T cell lines. Front Microbiol, 2021b;12:662573; doi: 10.3389/fmicb.2021.662573

64.

Licastro

, Porcellini

. Activation of endogenous retrovirus, brain infections and environmental insults in neurodegeneration and Alzheimer's disease. Int J Mol Sci, 2021; 22(14):7263; doi: 10.3390/ijms22147263

65.

Liu

, Chen

, Li

, et al. Activation of elements in HERV-W family by caffeine and aspirin. Virus Genes, 2013; 47(2):219–227; doi: 10.1007/s11262-013-0939-6

66.

, Wang

, Su

, et al. Herpes simplex virus type 2 infection triggers AP-1 transcription activity through TLR4 signaling in genital epithelial cells. Virol J, 2018; 15(1):173; doi: 10.1186/s12985-018-1087-3

67.

Madeira

, Burgelin

, Perron

, et al. MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment. J Neuroimmunol, 2016; 291:29–38; doi: 10.1016/j.jneuroim.2015.12.006

68.

Mameli

, Erre

, Caggiu

, et al. Identification of a HERV-K env surface peptide highly recognized in rheumatoid arthritis (RA) patients: A cross-sectional case-control study. Clin Exp Immunol, 2017; 189(1):127–131; doi: 10.1111/cei.12964

69.

Manghera

, Ferguson

, Douville

. Endogenous retrovirus-K and nervous system diseases. Curr Neurol Neurosci Rep, 2014; 14(10):488; doi: 10.1007/s11910-014-0488-y

70.

Manghera

, Ferguson-Parry

, Lin

, et al. NF-kappaB and IRF1 induce endogenous retrovirus K expression via interferon-stimulated response elements in its 5’ long terminal repeat. J Virol, 2016; 90(20):9338–9349; doi: 10.1128/JVI.01503-16

71.

Marston

, Greenig

, Singh

, et al. SARS-CoV-2 infection mediates differential expression of human endogenous retroviruses and long interspersed nuclear elements. JCI Insight, 2021; 6(24):e147170; doi: 10.1172/jci.insight.147170

72.

Matsumoto

, Funami

, Tanabe

, et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol, 2003; 171(6):3154–3162; doi: 10.4049/jimmunol.171.6.3154

73.

Matsumoto

, Kikkawa

, Kohase

, et al. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun, 2002; 293(5):1364–1369; doi: 10.1016/S0006-291X(02)00380-7

74.

Mayer

, Blomberg

, Seal

. A revised nomenclature for transcribed human endogenous retroviral loci. Mob DNA, 2011; 2(1):7; doi: 10.1186/1759-8753-2-7

75.

Medzhitov

, Preston-Hurlburt

, Janeway

Jr . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 1997; 388(6640):394–397; doi: 10.1038/41131

76.

Mikhalkevich

, O'Carroll

, Tkavc

, et al. Response of human macrophages to gamma radiation is mediated via expression of endogenous retroviruses. PLoS Pathog, 2021; 17(2):e1009305; doi: 10.1371/journal.ppat.1009305

77.

Mullaly

, Kubes

. The role of TLR2 in vivo following challenge with Staphylococcus aureus and prototypic ligands. J Immunol, 2006; 177(11):8154–8163; doi: 10.4049/jimmunol.177.11.8154

78.

Mullins

, Linnebacher

. Human endogenous retroviruses and cancer: Causality and therapeutic possibilities. World J Gastroenterol, 2012; 18(42):6027–6035; doi: 10.3748/wjg.v18.i42.6027

79.

Nagase

, Okugawa

, Ota

, et al. Expression and function of Toll-like receptors in eosinophils: Activation by Toll-like receptor 7 ligand. J Immunol, 2003; 171(8):3977–3982; doi: 10.4049/jimmunol.171.8.3977

80.

Nimma

, Gu

, Maruta

, et al. Structural evolution of TIR-domain signalosomes. Front Immunol, 2021; 12:784484; doi: 10.3389/fimmu.2021.784484

81.

Nusslein-Volhard

, Lohs-Schardin

, Sander

, et al. A dorso-ventral shift of embryonic primordia in a new maternal-effect mutant of Drosophila . Nature, 1980; 283(5746):474–476; doi: 10.1038/283474a0

82.

Park

, Song

, Kim

, et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, 2009; 458(7242):1191–1195; doi: 10.1038/nature07830

83.

Perron

, Dougier-Reynaud

, Lomparski

, et al. Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice. PLoS One, 2013; 8(12):e80128; doi: 10.1371/journal.pone.0080128

84.

Perron

, Germi

, Bernard

, et al. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler, 2012; 18(12):1721–1736; doi: 10.1177/1352458512441381

85.

Rezaei

, Hayward

, Norden

, et al. HERV-K Gag RNA and protein levels are elevated in malignant regions of the prostate in males with prostate cancer. Viruses, 2021; 13(3):449; doi: 10.3390/v13030449

86.

Rolland

, Jouvin-Marche

, Viret

, et al. The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol, 2006; 176(12):7636–7644; doi: 10.4049/jimmunol.176.12.7636

87.

Rycaj

, Plummer

, Yin

, et al. Cytotoxicity of human endogenous retrovirus K-specific T cells toward autologous ovarian cancer cells. Clin Cancer Res, 2015; 21(2):471–483; doi: 10.1158/1078-0432.CCR-14-0388

88.

Sato

, Reuter

, Hiranuma

, et al. The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages. Int Immunol, 2020; 32(12):785–798; doi: 10.1093/intimm/dxaa055

89.

Schanab

, Humer

, Gleiss

, et al. Expression of human endogenous retrovirus K is stimulated by ultraviolet radiation in melanoma. Pigment Cell Melanoma Res, 2011; 24(4):656–665; doi: 10.1111/j.1755-148X.2011.00860.x

90.

Schmidt

, Domingues

, Golebiowski

, et al. An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity. Proc Natl Acad Sci U S A, 2019; 116(35):17399–17408; doi: 10.1073/pnas.1907031116

91.

Semin

, Ninnemann

, Bondareva

, et al. Interplay between microbiota, Toll-like receptors and cytokines for the maintenance of epithelial barrier integrity. Front Med (Lausanne), 2021; 8:644333; doi: 10.3389/fmed.2021.644333

92.

Shekarian

, Valsesia-Wittmann

, Brody

, et al. Pattern recognition receptors: Immune targets to enhance cancer immunotherapy. Ann Oncol, 2017; 28(8):1756–1766; doi: 10.1093/annonc/mdx179

93.

Shimizu

. Structural insights into ligand recognition and regulation of nucleic acid-sensing Toll-like receptors. Curr Opin Struct Biol, 2017; 47:52–59; doi: 10.1016/j.sbi.2017.05.010

94.

Stearrett

, Dawson

, Rahnavard

, et al. Expression of human endogenous retroviruses in systemic lupus erythematosus: Multiomic integration with gene expression. Front Immunol, 2021; 12:661437; doi: 10.3389/fimmu.2021.661437

95.

Steiner

, Marston

, Iniguez

, et al. Locus-specific characterization of human endogenous retrovirus expression in prostate, breast, and colon cancers. Cancer Res, 2021; 81(13):3449–3460; doi: 10.1158/0008-5472.CAN-20-3975

96.

Suenaga

, Yoon

. Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse. Diabetes, 1988; 37(12):1722–1726; doi: 10.2337/diab.37.12.1722

97.

Takeuchi

, Akira

. Pattern recognition receptors and inflammation. Cell, 2010; 140(6):805–820; doi: 10.1016/j.cell.2010.01.022

98.

Takeuchi

, Kawai

, Muhlradt

, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol, 2001; 13(7):933–940; doi: 10.1093/intimm/13.7.933

99.

Takeuchi

, Sato

, Horiuchi

, et al. Cutting edge: Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol, 2002; 169(1):10–14; doi: 10.4049/jimmunol.169.1.10

100.

Tovo

, Garazzino

, Dapra

, et al. COVID-19 in children: Expressions of type I/II/III interferons, TRIM28, SETDB1, and endogenous retroviruses in mild and severe cases. Int J Mol Sci, 2021; 22(14):7481; doi: 10.3390/ijms22147481

101.

Tsumura

, Miyazawa

, Ogawa

, et al. Detection of endogenous retrovirus antigens in NOD mouse pancreatic beta-cells. Lab Anim, 1998; 32(1):86–94; doi: 10.1258/002367798780559464

102.

Vargiu

, Rodriguez-Tome

, Sperber

, et al. Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology, 2016; 13:7; doi: 10.1186/s12977-015-0232-y

103.

Wang

, Liu

, Wang

, et al. Syncytin-1, an endogenous retroviral protein, triggers the activation of CRP via TLR3 signal cascade in glial cells. Brain Behav Immun, 2018; 67:324–334; doi: 10.1016/j.bbi.2017.09.009

104.

Wang

, Wu

, Huang

, et al. Human endogenous retrovirus W family envelope protein (HERV-W env) facilitates the production of TNF-alpha and IL-10 by inhibiting MyD88s in glial cells. Arch Virol, 2021; 166(4):1035–1045; doi: 10.1007/s00705-020-04933-8

105.

Yan

, Wu

, Zhou

, et al. HERV-W envelope triggers abnormal dopaminergic neuron process through DRD2/PP2A/AKT1/GSK3 for schizophrenia risk. Viruses, 2022; 14(1):145; doi: 10.3390/v14010145

106.

. The potential role of retroviruses in autoimmunity. Immunol Rev, 2016; 269(1):85–99; doi: 10.1111/imr.12371

107.

, Lubben

, Slomka

, et al. Nucleic acid-sensing Toll-like receptors are essential for the control of endogenous retrovirus viremia and ERV-induced tumors. Immunity, 2012; 37(5):867–879; doi: 10.1016/j.immuni.2012.07.018

108.

Zhou

, Li

, Wei

, et al. Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells. Oncotarget, 2016; 7(51):84093–84117; doi: 10.18632/oncotarget.11455