THE TIR DOMAIN RECOGNIZES INVASIVE PATHOGENS AND INDUCES AN IMMUNE RESPONSE

Trubiani O, Mazzon E. The TIR domain recognizes invasive pathogens and induces an immune response. International Journal of Infection. 2025;9(2):39-41.

O. Trubiani^* and E. Mazzon

Department of Medical, Oral and Biotechnological Sciences, University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy.

*Correspondence to:
Prof. Oriana Trubiani,
Department of Medical, Oral and Biotechnological Sciences,
University “G. D’Annunzio” of Chieti-Pescara,
66100 Chieti, Italy,
e-mail: trubiani@unich.it

Received: 04 April, 2025 Accepted: 30 May, 2025

ISSN 1972-6945 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

The Toll-interleukin-1 receptor (TIR) is a conserved domain of the innate immune response and a signal transducer. TIR is a member of the pattern recognition receptors (PRRs) and is involved in the initiation of microbial-induced signals. Together with the TIR domain, Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs). TIR participates in the interaction between TLRs and adaptors such as MyD88 and TIR domain-containing adaptor protein inducing interferon beta (TRIF), complex reactions that culminate in the activation of NF-kB. To inhibit the immune response, bacteria and viruses can produce proteins that mimic the TIR domain to compete with endogenous adaptors. TLRs mediate the production of interferons (IFNs) which are antiviral immune proteins. TLR regulation is crucial in the inflammatory process.

KEYWORDS: Toll-interleukin-1 receptor, domain, signal transducer, innate immune response, infection

INTRODUCTION

Toll-interleukin-1 receptor (TIR) is a 150-amino acid immune system transducer (1). The TIR domain is a component of pattern recognition immune proteins (PRIPs) which is a conserved domain critical in the innate immune response. This domain is part of pattern recognition receptors (PRRs) that play a key role in signaling during infections.

The TIR domain is a structural region found in Toll-like receptors (TLRs). TLRs recognize components of pathogens such as bacteria, viruses, fungi, and parasites and are also involved in the synthesis of pro-inflammatory cytokines. With the TIR domain, TLRs recognize pathogen-associated molecular patterns (PAMPs), including lipopolysaccharides (LPS) from Gram-negative bacteria and viral RNAs (2). The TIR domain mediates the interaction between TLRs and adaptors such as MyD88 and TIR domain-containing adaptor protein inducing interferon beta (TRIF), activating NF-κB and MAPK. The TIR domain is a conserved cytoplasmic component of TLRs and IL-1R receptors. TIR domains generate nicotinamide adenine nucleotide (NAD+)-derived small signaling molecules that could induce the regulated death of infected cells.

DISCUSSION

The TIR domain plays a key role in infections. It is a highly conserved portion present in both TLRs and IL-1 receptors (IL-1Rs). The TIR domain is crucial for activating the innate immune response, where macrophages are activated by TLRs and IL-1R ligands.

TIR shares structural regions such as BOX1, BOX2, and BOX3, which are important for protein-protein interactions. Adaptor proteins such as MyD88 interact with the TIR domain and activate pro-inflammatory genes (3). In addition to reacting with cellular adaptors such as MyD88, the TIR domain interacts with TIRAP, TRIF, and TRAM. These are essential for activating the NF-kB and MAPK cascades, which lead to the synthesis of pro-inflammatory cytokines (Fig.1). During infection, TLRs recognize conserved structures in pathogens such as PAMPs, including Gram-negative bacterial products that bind to TLR4 and viral RNA, which in turn binds to TLR-3, TLR-7, and TLR-8; while bacterial DNA binds to TLR-9 (4). Once the TIR domain binds to the pathogen, signal transduction occurs with the recruitment of adaptor proteins, including MyD88, and the production of IL-1β, TNF, and interferons (IFNs).

Fig. 1. Viral RNA activates Toll-like receptor (TLR)-7 which activates the Toll-interleukin-1 receptor (TIR) domain and results in a signaling cascade involving MyD88 that modulates immune cells mediating the immune response. Additionally, TIR domain-containing adaptor protein inducing interferon beta (TRIF) leads to the induction of cytokines.

However, pathogens have developed strategies to evade the TIR. Some bacteria, such as Salmonella, produce proteins that mimic the TIR domain, competing with endogenous adaptors and inhibiting the immune response. For example, Brucella melitensis produces TIR domain-containing protein B (TcpB), which mimics the TIR and binds to the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP/MAL), preventing the activation of TLR-2 and TLR-4.

Mutations in the TIR domain can lead to immunodeficiency with susceptibility to bacterial infections. Immune deficiency can also lead to chronic inflammation or autoimmunity. The intracytoplasmic TIR protein is important for immune signal transduction and plays a key role in the innate immune response, particularly during viral infections. The TLR resists viral attack by activating the interferons IFN-a and IFN-b (5).

Some viruses have developed evasion mechanisms to interfere with TIR signaling. Viruses can inhibit TLR dimerization and degrade the MyD88 and TRIF adaptors. Furthermore, some viruses can block signal transduction in adaptors. In the antiviral response, influenza viruses activate TLRs 7/8 and MyD88, which are required for the production of IFNs that trigger an immune response (6).

In coronavirus disease 2019 (COVID-19) induced by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), TLR-7 is activated, particularly in dendritic cells, causing an IFN response even though the virus can inhibit MyD88 and TRIF. Herpes viruses activate TLR-9 and subsequently, type I IFN. TLR inhibitors limit inflammation, while stimulators act as immunomodulators and increase antiviral activity.

CONCLUSIONS

TIR is an immune signal transducer and is part of the PRRs that recognize microorganisms. TIR participates in the action of TLRs that bind microorganisms and activate MyD88, TRIF, and NF-kB, resulting in the production of immunoregulatory cytokines. Some bacteria and viruses produce proteins that mimic the TIR domain and inhibit the immune response. TLR regulation by TIR is essential for modulating acute and chronic inflammation and inflammatory diseases.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Martin MU, Wesche H. Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2002;1592(3):265-280. doi:https://doi.org/10.1016/s0167-4889(02)00320-8
2. Shirey KA, Lai W, Brown LJ, et al. Select targeting of intracellular Toll-interleukin-1 receptor resistance domains for protection against influenza-induced disease. Innate Immunity. 2020;26(1):26-34. doi:https://doi.org/10.1177/1753425919846281
3. Nimma S, Gu W, Manik MK, Ve T, Nanson JD, Kobe B. Crystal structure of the Toll/interleukin-1 receptor (TIR) domain of IL-1R10 provides structural insights into TIR domain signalling. FEBS letters. 2022;596(7):886-897. doi:https://doi.org/10.1002/1873-3468.14288
4. Coban C, Ishii KJ, Kawai T, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. Journal of Experimental Medicine. 2005;201(1):19-25. doi:https://doi.org/10.1084/jem.20041836
5. Flür K, Allam R, Zecher D, et al. Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5. The American Journal of Pathology. 2009;175(5):2014-2022. doi:https://doi.org/10.2353/ajpath.2009.080585
6. Shang J, Zheng Y, Mo J, et al. Sox4 represses host innate immunity to facilitate pathogen infection by hijacking the TLR signaling networks. Virulence. 2021;12(1):704-722. doi:https://doi.org/10.1080/21505594.2021.1882775