Introduction
Understanding the delicate dance between hosts and pathogens is vital for developing strategies to combat infectious diseases. Central to this interplay are SMAD transcription factors, which mediate signaling for the transforming growth factor-β (TGF-β) superfamily. These transcription factors manage a wide array of cellular processes, including embryogenesis, immunity, inflammation, and cancer. Remarkably, the functions of SMADs can sometimes be contradictory. For instance, while SMAD3 has been cited as a tumor suppressor due to its role in arresting cell cycle progression, it paradoxically promotes cancer metastasis in other contexts. Recent research has uncovered that SMAD proteins are crucial targets for pathogens aiming to modulate host signaling, thereby enhancing their infectivity and spread.
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Canonical TGF-β Superfamily Signaling
To appreciate how pathogens manipulate SMAD signaling, it's essential first to understand the TGF-β pathway under normal cellular conditions. The TGF-β superfamily, includes TGF-βs, BMPs, activins, inhibins, growth differentiation factors (GDFs), and nodal, signals through SMAD proteins. Canonical TGF-β signaling involves three stages: ligand expression and activation, receptor phosphorylation, and SMAD-mediated signal transduction.
Expression and Activation: TGF-β ligands are synthesized as inactive complexes bound to latency-associated peptides. These complexes are stored in the extracellular matrix and require activation mechanisms to become biologically active.
Receptor Binding and Phosphorylation: The active ligands bind to type II receptors, which then recruit and phosphorylate type I receptors, also known as activin receptor-like kinases (ALKs). This receptor complex then recruits SMAD anchor proteins that facilitate the phosphorylation of receptor-associated SMADs (R-SMADs).
SMAD Signaling: Upon phosphorylation, R-SMADs form complexes with common SMAD (Co-SMAD) SMAD4. These complexes translocate to the nucleus to regulate target gene expression. Inhibitory SMADs (I-SMADs) like SMAD6 and SMAD7 can antagonize this process by preventing R-SMAD phosphorylation and promoting their degradation.
Fig. 1 Schematic of TGF-β and BMP signaling pathway with SMAD complexes (Lai L. Y. S., et al. 2022).
Pathogen Modulation of SMAD Signaling
Pathogens can hijack SMAD signaling at multiple levels. They may alter the activity of ligands, receptors, or the SMAD proteins themselves to create a cellular environment conducive to infection. Below are notable examples of how different pathogens modulate SMAD2, SMAD3, and other SMAD proteins during infection.
Pathogen Dissemination and Spread
Pathogens often exploit SMAD signaling to enhance their dissemination and spread by regulating genes encoding tight junctions and extracellular matrix (ECM) glycoproteins. For example, ebolavirus (EBOV) infection upregulates TGF-β secretion and increases SMAD3 phosphorylation, leading to changes in epithelial-to-mesenchymal transition (EMT) markers like N-cadherin and fibronectin. These changes facilitate viral dissemination via intravasation. Similarly, vaccinia virus (VACV) infection promotes SMAD2, SMAD3, and SMAD4 signaling to enhance cell migration, through receptor-independent mechanisms.
Pathogens can also modulate SMAD signals to penetrate the central nervous system (CNS). Streptococcus pneumoniae secretes neuraminidase A (NanA), which activates TGF-β, downregulates the tight junction protein ZO-1, and disrupts the blood-brain barrier. This enables the bacterial pathogen to invade the CNS, leading to meningitis. Influenza A virus (IAV) exploits a similar mechanism, with its neuraminidase enzyme cleaving latent TGF-β, enhancing adhesion molecule expression, and predisposing the host to bacterial co-infections.
Immune Modulation
SMAD2 and SMAD3 are central to both the innate and adaptive immune responses. TGF-β influences IgA class switching, upregulates Th17 lymphocytes, and mediates the transition from inflammation to fibrotic tissue healing via regulatory T cells (Tregs). Pathogens can manipulate SMAD signaling to either enhance or attenuate immune responses.
For example, Citrobacter rodentium downregulates SMAD2 and SMAD3 to induce pro-inflammatory cytokines, while Burkholderia pseudomallei induces TGF-β secretion to support intracellular bacterial growth by inhibiting macrophage antibacterial activities. Conversely, Mycobacterium tuberculosis localises TGF-β within granulomas to suppress T-cell function. HIV and human cytomegalovirus (HCMV) modulate SMAD signaling to evade or suppress the host's immune responses.
Furthermore, TGF-β/SMAD signaling intertwines with antiviral responses, such as interferon production. For instance, respiratory syncytial virus (RSV) infection requires SMAD2 activity for optimal IFN-β secretion, whereas influenza A virus infection in epTGFβKO mice shows a heightened innate antiviral response.
Fibrosis
One of the hallmarks of TGF-β signaling is its role in fibrosis. SMAD3/SMAD4 complexes increase the expression of pro-fibrotic genes, driving chronic fibrotic conditions. Hepatitis B virus (HBV) and Hepatitis C virus (HCV) trigger liver fibrosis through enhanced TGF-β/SMAD signaling. HBV pX protein directly interacts with SMAD proteins to promote fibrosis, while HCV core and NS3 proteins modulate SMAD3 activity to both promote and inhibit fibrotic pathways, demonstrating the complexity of these interactions.
Salmonella typhimurium triggers chronic fibrosis by upregulating TβRI and TβRII and subsequently increasing SMAD2/SMAD3 phosphorylation. Similarly, severe acute respiratory syndrome-related coronavirus (SARS-CoV) nucleocapsid (N) protein enhances SMAD3/SMAD4 signaling to mediate pulmonary fibrosis.
Cell Proliferation and Death
SMAD2 and SMAD3 also regulate cell cycle progression and apoptosis. Pathogens such as the Human T lymphotropic virus (HTLV) and Epstein-Barr virus (EBV) modulate SMAD signaling to inhibit apoptosis and promote cellular proliferation, aiding in viral persistence and pathogenesis. SARS-CoV N protein suppresses pro-apoptotic SMAD3/SMAD4 genes, contributing to viral dissemination and late-stage fibrosis.
Iron Regulation
Bone morphogenetic proteins (BMPs) like BMP6 play essential roles in iron regulation through SMAD1/5/8 signaling. Pathogens like Salmonella and E. coli exploit this pathway to upregulate hepcidin, an iron-regulatory hormone, facilitating their survival in an iron-deprived extracellular environment. HCV also manipulates this pathway, altering iron regulation, although conflicting studies suggest a dual role depending on the stage and context of infection.
Inflammation and Immunity
Helicobacter pylori infection showcases how different SMAD pathways can be manipulated in tandem. H. pylori upregulates inhibitory SMAD7 to counteract the anti-inflammatory effects of TGF-β while also enhancing the expression of SMAD1/5/8 through BMP signaling to drive inflammatory conditions and associated pathologies such as intestinal metaplasia and gastric carcinoma.
Therapeutic Implications
The nuanced interplay between SMAD signaling and pathogenic infection opens up avenues for therapeutic intervention. Targeting specific SMAD-regulated pathways could provide novel approaches to mitigating diseases associated with chronic infections and related pathologies such as cancer and fibrosis. For instance, TGF-β inhibitors like SB431542 have shown potential in experimental settings, like reducing the spread of EBOV and the pro-inflammatory response in co-infections.
Conclusion
Pathogen-induced modulation of SMAD signaling is a sophisticated mechanism that enhances infectivity and promotes disease progression. By understanding these interactions, researchers can develop novel therapeutic strategies that disrupt these pathways, potentially limiting the pathogenicity and spread of various infections. Future research should continue to explore the intricate dynamics of SMAD signaling during infection, with the aim of identifying new interventions and expanding our understanding of cellular regulation in health and disease.
Reference
- Lai L. Y. S., et al. SMAD proteins: Mediators of diverse outcomes during infection. European Journal of Cell Biology. 2022, 101(2): 151204.
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