Abstract

1. Introduction

Transactive response DNA binding protein 43 kDa (TDP-43), encoded by the TARDBP gene, belongs to the family of heterogeneous nuclear ribonucleoproteins (hnRNPs) that serve multiple roles in the generation and processing of RNA. Its critical role in RNA processing occurs through its interaction with many ribonucleoprotein complexes (spliceosome, Drosha, poly-adenylation, stress granule, and translational complexes) in the nucleus and cytoplasm. Through all these interactions, TDP-43 is now known to regulate many cellular processes that include all aspects of gene expression, from transcription to RNA maturation (both coding and non-coding), transport, stability, and eventual translation [1,2,3,4,5,6,7].

This ubiquitously expressed RNA-binding protein predominantly resides in the nucleus although a minor proportion is always shuttling back and forth to the cytoplasm together with its bound RNAs. However, cellular stresses are known to transiently increase the amount of TDP-43 into the cytoplasm and assemble in stress granules [8]. As a result, many cellular alterations that lead to disruption of nucleocytoplasmic trafficking, prolonged stress, and changes in liquid–liquid phase separation can lead to TDP-43 accumulation in insoluble aggregates that are located mostly in the cytoplasm of glia and degenerating neurons in the central nervous system (CNS) [9]. The TDP-43 in these aggregates is variably modified and subjected to cleavage, ubiquitination, and several other post-translational modifications that include phosphorylation, acetylation, and sumoylation [10,11,12]. All these modifications represent pathological hallmarks of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) as well as other types of conditions such as traumatic brain injury [10,13]. In general, however, aberrant cleavage and cytoplasmic aggregation of TDP-43 are identified as molecular signatures for most forms of ALS and FTLD and have been shown to contribute significantly to disease progression [10]. Following aggregation in insoluble forms, the loss of “active” TDP-43 in the cellular pool is thought to lead to abnormalities of splicing and RNA metabolism with subsequent neuronal dysfunction [14]. Very recently, this has been clearly observed in patients by the detection of “cryptic” exons inclusion in important genes, such as UNC13A and STMN2, where the absence of TDP-43 during the splicing process induces the spliceosome to include pre-mRNA sequences in the mature mRNA which in normal conditions would never have been included (with consequential loss of function effects) [15,16].

The cellular toxicity that results from TDP-43 aggregation pathology is thought to initiate a cascade of downstream toxic effects that not only occur within the initiating cell but also can be spread between vulnerable cell types and to other regions of the nervous system [17]. This transmission through the tissue may involve prion-like properties of TDP-43, in which pathologically misfolded protein templates the propagation of aggregation pathology [17,18,19].

From a historical point of view, it is interesting to note that the first identification of TDP-43 occurred in the mid-nineties when it was hypothesized to bind the DNA transactivation–responsive (TAR) sequence of the human immunodeficiency virus type 1 (HIV-1) and inhibit viral transcription; hence, the name of TDP-43, where 43 refers to the molecular weight of the wild-type protein based on its primary amino acid sequence [1]. However, this transcriptional inhibitory activity was not confirmed in later studies [20], although more recent studies have reported the capability of TDP-43 to influence cell permittivity to HIV-1 infection [21] and latency [22].

In parallel and interestingly, enterovirus-induced pathology has also been widely studied in the context of ALS and TDP-43 [23]. However, despite great efforts in this direction, the clinical data are controversial, probably due to the inconsistency and differences in viral detection techniques, disease stage of sample collection, as well as the potential virus-triggered “prion-like mechanism”. Most importantly, however, although a causal relationship between chronic viral infection and ALS development remains to be established, many recent observations have reported that TDP-43 can play a role in many viral infections. Therefore, this review article aimed to describe the novel potential relationship between TDP-43 and enteroviruses (EVs), Theiler’s murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV).

2. Viral Infections and TDP-43

3. The Role of Neuroinflammation in Viral Infection and Neurodegeneration: A Potential Link with TDP-43 Dysfunction

Research interest in investigating the relationship between neuronal inflammation and neurodegeneration has been exponentially increased through the pass years. The establishment of neuronal dysfunctions frequently involve the release of numerous pro-inflammatory cytokines and the activation of apoptotic pathways leading to cell death [76]. Specifically, abnormal accumulation of pro-inflammatory cytokines, such as interleukins (IL)-1β [77], IL-6 [78], and transforming growth factor beta (TGF-β) [79], has been described surrounding the amyloid plaques of Alzheimer’s disease (AD) patients, as well as in serum and plasma of patients affected by neuropsychiatric disorder [80]. In addition, increasing levels of IL-4, IL-5, IL-10, IL-6, and tumor necrosis factor alpha (TNF-α) were detected in serum of ALS patients comparing to healthy subjects [81], and some of those factors were also linked to neuroinflammation in FTD [82,83,84]. Finally, it is important to note that an imbalance between pro- and anti-inflammatory molecules has been described during different viral infections that are occasionally associated with the Induction of neurological manifestations. For example, it has been widely demonstrated that the injection of pro-inflammatory cytokine TNF-α induces neuropathic pain in humans [85,86]. TNF-α is normally expressed at low levels in CNS, although microglia and astrocytes can release high amount of this factor during injury, neurodegenerative disorders, and infections [87]. For example, studies performed in mice have highlighted that injection of HIV envelope glycoprotein gp120 induced the activation of microglia and astrocytes with the consequent production of TNF-α at the spinal cord levels. This, in turn, triggered neuropathy symptoms similar to those seen in HIV-1 patients with neuropathic pain [88]. Another example of immunological neuropathy has been described in TMEV infection. TMEV is an RNA virus with tropism for nervous system where it establishes chronical demyelinating disorder in susceptible mouse strains similar to that observed in multiple sclerosis. During TMEV infection, it has been demonstrated that both microglia and macrophages stimulate the production and release of numerous interleukins, TNF-α, and Interferon gamma (IFN-γ) [89]. Neurological symptoms were also associated with the activation of endogenous retroviruses and more recently observed in patients affected by prolonged SARS-CoV-2 pathology. In these cases, the mechanisms behind those symptoms are linked to autoimmunity or chronic inflammation [90,91].

With this in mind, it is important to highlight that several immunoproteins are spatially and temporally modulated in the nervous system, as well as expressed in specific subsets of neuronal cells [92,93]. Moreover, the impairment of the cross-talk between neurons and glia has been described as a further consequence of neuroinflammatory cascades. In this respect, astrocytes (macroglia) play a fundamental role in maintaining neuronal milieu due to their neuroprotective and metabolic functions, such as controlling blood–brain barrier (BBB) integrity, modulating the extracellular amount of neurotransmitter and ions, the elimination of toxins from cerebrospinal fluid and providing trophic sources for neuron’s energy metabolism [94]. Notably, reactive astrocytes were found to be involved in the production of several neuronal mediators during viral infections. This process is also supported by microglia through the expression of IL-1, IL-6, TNF-α, and IFN-γ that in turn stimulates astrocyte proliferation throughout a defense mechanism namely astrogliosis [95].

In addition to these connections, defects in RBP functions due to mutations, post-translational modifications, and aggregation, may contribute to exacerbate and sustained this unhealthy process. In fact, it is well-known that RBPs are key players in the RNA metabolism especially in neurons where they are particularly expressed [96]. Recently, it has been demonstrated that pro-inflammatory mediators, such as IFN-γ and TNF-α, are able to trigger hnRNP A1 mislocalization and stress granule formation in murine primary neuron culture, with consequently neurite damage [97]. Specifically, SAFA (also known as hnRNP U) was found to be involve in protecting cells from viral infections, since it acts at a nuclear sensor for viral dsRNA and is able to trigger the activation of super-enhancer of anti-viral gene expression, such as IFNB1 [98]. Interestingly, the ability of hnRNPs to commonly regulate mRNA targets implicated in both brain functions and inflammatory pathways is recently emerged. siRNA mediated the depletion of hnRNP U, hnRNP D, hnRNP K, DAZAP1, hnRNP Q, hnRNP R, and TDP-43 in human neuroblastoma SH-SY5Y cell line pointed out the importance of RBP homeostasis in modulating both processes and providing further evidence of their connection [99,100]. Among the genes commonly regulated by TDP-43 and other hnRNPs is important to mention TNF-α (described above) and intercellular adhesion molecule 1 (ICAM-1, or CD54). Although TNF-α mRNA was found to be upregulated in SH-SY5Y treated with siRNA against TDP-43 [99], in monocytes TNF-α was downregulated after siTDP-43 treatment [101], indicating that the mechanism occurring during TDP-43-mediated TNF-α regulation is dependent on cell types, and likely involved the participation of other cellular factors. Indeed, these results highlight the importance of cell-specific differences in the shaping of TDP-43 functional properties [102].

On the other hand, ICAM-1 is an adhesion molecule that participates together with vascular cell adhesion molecule 1 (VCAM-1) at both interaction and extravasation of leukocytes at the BBB. ICAM-1 is also expressed in microglial cells and astrocytes of white and grey matter and its overexpression on CNS vascular endothelium is one of the hallmarks of brain inflammation [103]. In particular, it has been demonstrated that TDP-43 silencing is capable of upregulating ICAM-1 mRNA expression in neuronal-like cells, as well as that the knockout of ICAM-1 in mice can confer resistance of encephalitis related to WNV infection, by diminishing viral load, leukocyte infiltration, and neuronal damage with respect to control animals [99,104]. Increasing levels of ICAM-1 were also reported in aging, bipolar disorder, and even dementia [105,106].

Notably, downregulation of TDP-43 was also associated with strongly suppression of IL-6 production after IL-1β and TGF-β1 stimulation in cultured primary human brain pericytes. Scotter and collaborators have hypothesized that this could be due to the TDP-43 dependent splicing regulation of hnRNP D [107]. These results have been supported by two recent publications regarding the role of Protein tyrosine phosphatase 1B (PTP1B) inhibition in attenuating astrocytes cell death as a consequence of TDP-43 mediated suppression of IL-6 [108], as well as the role of TDP-43 as a scaffold protein of the interleukin-6 and -10 splicing activating compartment (InSAC) [109].

Regarding the network TDP-43/virus/neurodegeneration, it is important to notice that IL-6 is an interleukin produced by several types of brain cells in way that is dependent on cell ages and in response to injury, such as tissue damage and infection [110]. Furthermore, IL-6 expression was found to be linked to both pro- and anti-inflammatory effects, highlighting its importance in the regulation of immune response. In keeping with these effects, IL-6 was also described to inhibit the replication of HBV via several mechanisms, including downregulation of human liver bile acid transporter Na(+)/taurocholate cotransporting polypeptide (NTCP) receptor [111], repression of viral transcripts by targeting the epigenetic modification (histone acetylation) of the HBV covalently closed circular DNA (cccDNA) [112] and by blocking the expression of both hepatocyte nuclear transcription factors (HNF) 1 and 4 alpha [113]. Circulating levels of IL-6 have also been used as predictive biomarker to identify severe SARS-CoV-2 pathology [114] and the increased levels of IL-6 were found to correlate with several abnormalities in blood tests observed in patients suffering from COVID-19 [115], as well as in HIV patients developing autoimmune disease [116].

Regarding neurodegeneration, increased levels of IL-6 expression were detected in the astrocyte-derived extracellular vesicles of sporadic ALS patients [117], in nigrostriatal region and in the cerebrospinal fluid of PD patients [118] and within and nearby amyloid plaques in AD patients [119]. On the contrary, the knockout of IL-6 in a mice transgenic model of Huntington’s disease (HD) was reported to worsen the phenotype associated to HD leading to dysregulation of genes essential for synaptic functions and relevant for the pathogenesis of HD [120].

Finally, neuroinflammatory pathways linked to TDP-43 dependent modulation of IL-1β and nuclear factor-κB (NF-κB) can also be observed during neurodegenerative disorders and viral illness. In 2020, Lee and collaborators demonstrated that overexpression of TDP-43 was able to induce IL-1β and NF-κB upregulation in primary mouse astrocytes. In this report, the signaling cascade TDP-43-PTP1B-NF-κB was found to be responsible for the TDP-43 mediated neuronal death and mitochondrial dysfunction observed in those cells [108].

In this respect, it is interesting to note that IL-1β is an immune mediator involved in pro-inflammatory signaling in astrocytes and glia cells [121,122], while NF-κB is a transcriptional factor of several cytokines, chemokines and is important in the functional activity of inflammasome [123].

Accordingly, increased levels of IL-1β were described in brain of AD patients [77] and it has been described to drive ALS pathogenesis in mice [124], as well as to promote SARS-CoV2 viral entry in A549 human lung cell line [125].

Furthermore, NF-κB resulted to be activated in ALS patients and mouse models [126,127] in a mouse model of progranulin (GRN)-deficient FTD [128], in PD patients [129], in HD patients and mouse models [130]. Moreover, a role of NF-κB signaling was detected in SARS-CoV-2 [131], HBV [132], HIV-1/2 [133,134], CVB3 [135], and HSV-1 [136] infection.

Last but not the least, it is important to mention the link between several long noncoding RNAs (lncRNAs), RBPs activity, and the role this can play in the maintenance of immune homeostasis [137,138]. In this context, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) are two lncRNAs implicated in neurodegenerative process and viral infection, also in association with TDP-43 [139,140,141,142,143]. For example, upregulation of MALAT1 was reported in response of flavivirus and human papilloma virus (HPV) infection [141,142]. Additionally, a role of MALAT1 and TDP-43 in regulating the expression of antiviral type I IFN (IFN-I) has been recently proposed [143]. Specifically, in this work it has been demonstrated that different viruses were able to induce downregulation of MALAT1 leading to TDP-43 release, activation, and consequently IFN-I production [143].

In addition, altered expression of NEAT1 was described during HIV-1 and HSV-1 infection [144,145], as well as during several neurological disorders linked to TDP-43 disorders such as ALS and FTLD [140]. Moreover, upregulation of constitutive NEAT1 isoform (NEAT1_1) was reported to ameliorate TDP-43 induced toxicity in models of TDP-43 proteinopathy [139].

Taken together, all this information provides clear evidence of the importance of maintaining a healthy brain homeostasis, as well as supporting the role of TDP-43 and, more, in general, of RBPs in controlling transcripts implicated in neuronal inflammation and brain dysfunctions (Figure 1).

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Figure 1

Relationship between TDP-43-controlled immune mediators and neuronal dysfunctions/viral infection. Regulation of TDP-43 levels contributes to increase or reduce the expression of different immune mediators, such as IL-1β, NF-κB, IL-6, ICAM-1, and TNF-α. Up- and downregulated effects are indicated with upward and downward arrows, respectively. Neurodegenerative and viral implications are also reported in the table.

4. Conclusions

Over the years, the role of TDP-43 in the onset and progression of several disease have been extensively study. Despite the well-known involvement in brain pathologies, including, ALS, FTLD, Alzheimer’s, and Parkinson’s disease, TDP-43 has also been associated with cancer and viral infection [146]. Here, we summarized all the novelty regarding the interaction of TDP-43 and various DNA and RNA viruses (Figure 2). Overall, TDP-43 was found to actively contribute to viral entry, replication, and latency by binding several viral transcripts, as well as to participate in the establishment or at least significant contributions to neuropathic symptoms similar to those observed in neuronal disorders. Not by chance, some of the viruses presented in this review have also been described to be associated with brain dysfunction, as reported in Table 1. In keeping with this, during viral infections TDP-43 expression results to be frequently dysregulated, and it can also be post-translationally modified and translocated in the cytoplasm in a way that is similar to its modifications in neurodegeneration. All these alterations could therefore determine to the loss of TDP-43 endogenous functions, leading to cellular impairment and even cell death. It is interestingly to mention that TDP-43 collaborates with other RBPs in the maintenance of cell homeostasis and, presumably not by chance, some of these factors are also implicated in the same viral infection and in brain dysfunctions. For example, mutations in FUS encoding gene can exacerbate the sensibility to HIV-1 infection, and vice versa HIV-1 can increase the cytoplasmic localization of Fused in sarcoma (FUS) [147]. Furthermore, depletion of hnRNP K was described to reduce the HBV viral load in human hepatoma HepG2 cells, as well as hnRNP A1 was found to stimulate EV viral translation [27,60]. Finding new viral TDP-43 interactors could therefore be useful not only for a deeper characterization of the importance of TDP-43 pathology in viral disease, but also to provide deeper insight in the way this protein can establish unhealthy neurological conditions and inflammatory symptoms. As a consequence, the modulation of TDP-43 through chemical compounds, peptides, small interfering RNA (siRNAs), circular RNAs (circRNAs), and CRISPR/Cas9 based approaches may potentially represent novel therapeutic strategies for treating these virus-related disorders. Regarding TDP-43, in fact, several compounds have already been tested by employing different cellular/animal models and aspects of TDP-43 pathology, which includes its expression, nucleo-cytoplasmic balance and aggregation propensity [148]. For example, a small molecule called nTRD22, able to interact with the N-terminal domain of TDP-43 and to ameliorate the climbing defects, was observed in a Drosophila model of TDP-43 overexpression [149]. In the future, some of these compounds could be tested in cellular/animal models of viral infections to test their therapeutic functionality. In parallel, siRNA molecules and CRISPR/Cas9 therapeutic approaches aimed against specific TDP-43-viral protein interactors could also be tested to assess their ability to revert aberrant TDP-43 pathology during viral infections, as has been tried for neurodegenerative processes [150,151]. Finally, different antisense oligonucleotides (ASOs) have also been designed to target RBPs or their modifiers looking at neurodegenerative disorders and cancer. Among these, it is interesting to mention a study of 2017 performed on TDP-43 transgenic mice using ASOs targeting Ataxin-2 (Atxn-2) [152]. Basically, the reduction of Atxn-2 levels obtained by a single administration of ASOs into the CNS was successful in prolonging mice lifespan and improving their motor functions [152]. It would be therefore interesting to see, in the future, if some of these modulating factors of TDP-43 toxicity could also have a modifier effect on specific viral infections.

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Figure 2

Overview of several viruses linked to TDP-43 proteinopathy. TDP-43 is involved in several infections by DNA and RNA viruses, including Coxsackievirus B3 (CVB3), Theiler’s murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). This picture was created with Biorender.com. Predicted TDP-43 ternary-structure was created using AlphaFold algorithm and reprinted with the permission from Refs. [153,154].

In conclusion, all the evidence that has been accumulating with regards to the increasing connection between TDP-43 and viral infections could represent a novel and potentially interesting area to better understand the role played by this protein in cellular metabolism, its possible connections with neurodegeneration, but also a novel area to explore to develop novel anti-viral therapeutic approaches.

Funding Statement

This work was supported by Fondazione Italiana di Ricerca per la SLA—AriSLA (project NOSRESCUEALS) and Temerty Foundation and Western Ontario University.

Author Contributions

Conceptualization, E.B.; writing—review and editing, Z.R., E.B. and S.C.; supervision, E.B. and S.C.; project administration, E.B.; funding acquisition, E.B. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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