With the advent of child rearing, more and more people are raising fur babies, and more and more pet restaurants are opening. I don’t know if you’ve ever had the experience of going into a pet restaurant happily, only to find that within a few minutes, your whole body starts to itch, sneeze, runny nose and swollen eyes? If so, then unfortunately, you may be allergic to fur children, not suitable for small pets at home.
But did you know? A study conducted in the UK found that most people are actually allergic to cats not because of their fur, but a specific protein. The study found that the salivary glands and cortical lines of cats secrete a special protein that binds to an immune receptor in humans and triggers an allergic reaction.
In order to better understand which immune receptor is responsible, the researchers conducted a further analysis and found that the reaction is caused by binding to TLR4, a pathogen recognition receptor in humans. The researchers tried to inhibit this receptor with chemical molecules, causing the cat protein to be unable to bind to this receptor, and found that the human immune response was no longer occurring, thus confirming that it was this TLR4 receptor that was causing the human allergy to cats.
Interestingly, a recent study also found that TLR4 is associated with a new coronavirus (SARS-CoV-2)! What exactly is the correlation? Let’s read on ……
Introduction to TLR4
Toll-Like Receptor 4(TLR4) is a member of the TLR family and can be found on macrophages, dendritic cells and monocytes, as well as on the surface of some tissues. TLRs play an important role in the human body as they recognize exogenous pathogens and initiate the innate immune response in the body.
The TLR normally operates as follows: when it binds to an antigen outside the body, it triggers a series of responses downstream in the body, which in turn cause cells to produce immune hormones to achieve an immune response that helps humans fight against pathogens. Clinically, TLR has been associated with a variety of conditions such as sepsis, insulin resistance, atherosclerosis, hypertension, cancer, neurodegenerative diseases, and pregnancy, among others.
TLR4 Transmission
For a more detailed explanation of the downstream response of TLR after antigen contact, we can start by looking at this flow chart:
TLR4 is immunized using Pathogen-associated Molecular Patterns (PAMPs). First, an antigen like Lipopolysaccharide (LPS), an endotoxin produced by Gram-negative bacteria, binds to TLR4 extracellularly. However, this binding depends on the helper protein MD2, which helps TLR4 to recognize LPS, so MD2 needs to bind to TLR4 first. Another important molecule is CD14, which, like MD2, is another important molecule that helps LPS bind to TLR4, and TLR4 can only recognize it when these two molecules bind to TLR4.
When TLR4 recognizes LPS, it starts the proliferation of downstream transcription factors NF-κB, which leads to the production of cytokines and cytotoxic factors TNF-α, IL-1β and IL-6, initiating the Canonical pathway.
In addition to antigens, TLR4 also binds to specific Damage-associated Molecular Patterns (DAMPs) for recognition. Viruses such as Respiratory syncytial virus (RSV), Ebola virus and Dengue virus are known to bind to TLR4.
TLR4 and SARS-CoV-2
The evidence shows that TLR4 has the strongest protein-protein interaction with the spike protein of SARS-CoV-2 compared to other TLRs. That is, TLR4 binds more readily to the spike protein of SARS-CoV-2.
In SARS-CoV-2 patients, the excessive inflammatory response caused by TLR4 has been identified as a key cause of acute lung injury, which can also lead to pulmonary fibrosis. In contrast, in the cardiovascular setting, activation of TLR4 on platelets, either by PAMP or DAMP, induces thrombosis and inflammatory responses, increasing the risk of myocardial infarction in patients.
Reasons for SARS-CoV-2 tends to bind to TLR4
The study summarizes the following reasons:
I. Viruses use TLR4 to enter cells and increase ACE2 expression
ACE2 is a receptor on the surface of the cell membrane, and the virus must penetrate the receptor to reach the interior of the cell. Therefore, activation of TLR4 can increase the expression of ACE2 and promote the entry of virus into cells.
II. Viral activation of PI3K (Phosphatidylinositol 3-Kinase) using TLR4
PI3K is an enzyme required for cell survival and is involved in cell growth, proliferation, differentiation, mobility, survival and intracellular transport, etc. PI3K prevents abnormal cell death and phagocytosis, so if the virus activates PI3K, it will certainly prolong cell survival and indirectly increase the time for the virus itself to replicate in human cells.
Nevertheless, the question arises whether the activation of TLR4 during acute viral infection is beneficial or harmful to the body? In actuality, the answer is probably both. For one thing, the body needs an immune response to fight the virus, so the transmission of TLR4 signals is important for virus defense. Yet, if it is over-activated, it can lead to a very serious inflammatory response, or even a cytokine storm, which in severe cases can lead to death.
Mechanism of SARS-CoV-2 treatment by TLR4
With the understanding of TLR4, scientists are actively developing a promising treatment for SARS-CoV-2. At present (2022/04/20), the clinical development direction includes:
- TLR4 Receptor inhibitor: Eritoran和Resatorvid
- Glycyrrhizin: Antagonizes TLR4 receptors and prevents viral replication.
- Nifuroxazide: Blocking the TLR4-NLRP3/IL-1β communication pathway.
Despite the fact that there is still no correct treatment for NCCP, the scientific community’s discoveries are still a source of admiration. No matter the improvement in research efficiency or the advancement in the development of new drugs, we should be grateful to the people who have worked so hard on NCCP and stay healthy so that we can continue to live our daily lives and live with the virus in the midst of the severe epidemic.
The next article will introduce the basic human immune system and is well worth reading if you are interested, the link is as follows:
References:
Aboudounya MM, Heads RJ. COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation. Mediators Inflamm. 2021;2021:8874339. Published 2021 Jan 14. doi:10.1155/2021/8874339 🔗
TLR4 toll like receptor 4 [ Homo sapiens (human) ] Full report: 🔗
Zhao, Y., Kuang, M., Li, J. et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res 31, 818–820 (2021). https://doi.org/10.1038/s41422-021-00495-9 🔗
Sciencedirect: TLR4 🔗
