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The Critical Role of Tetraspanins in Bacterial Infections

Tetraspanins help bacteria attach to cells, influencing infection mechanisms.

PA Wolverson, I Fernandes Parreira, MO Collins, JG Shaw, LR Green

― 5 min read


Tetraspanins: Bacteria's Tetraspanins: Bacteria's Entryway attachment and infection. Tetraspanins are key for bacterial
Table of Contents

Tetraspanins are a family of proteins found in the cell membranes of many organisms, including humans. They are like the social butterflies of the cell, with 33 known members that each play unique roles. These proteins have a characteristic shape with four sections that stretch across the cell membrane and loops that extend outside the cell. Think of them as tiny bridges connecting various proteins and structures within a cell.

One of the key features of tetraspanins is their ability to form clusters with other proteins, creating specialized areas known as tetraspanin-enriched microdomains. These microdomains are busy places, involved in activities like helping cells stick together, moving around, and sending signals within and outside the cell. They are also the frontlines during Infections from various bacteria and viruses.

Tetraspanins and Bacterial Infections

Recent research reveals that tetraspanins contribute to how certain bacteria can cling to and invade cells. Several notorious bacterial pathogens, including Neisseria meningitidis (the one responsible for meningitis), Staphylococcus aureus (the one that can cause skin infections), and Escherichia coli (a common gut bacterium), have been shown to use tetraspanins to gain entry into cells. These bacteria don’t just waltz in; they rely on tetraspanins to arrange the right environment for their intrusion.

The general idea is that tetraspanins help other receptors on the cell surface come together, making it easier for bacteria to attach. For instance, in the case of Staphylococcus aureus, a tetraspanin called CD9 helps create a stage where fibronectin, a protein that acts like a glue, can bind to the bacteria, allowing them to adhere and infect the cells.

The Mechanics of Bacterial Adherence

Understanding how bacteria use tetraspanins is like piecing together a mystery. For example, Neisseria meningitidis has a specific way of sticking to cells. It starts by using tiny hair-like structures called pili to latch onto the human cell receptors, like CD147 or CD46. This initial handshake is crucial for the later stages of infection. Once attached, the bacteria enter a more intimate relationship with the host cells through interactions with other proteins.

Staphylococcus aureus uses a different approach, employing a range of receptors to attach to host cells. CD9 has been shown to work with various proteins, helping the bacteria stick to cells by organizing an optimal attachment site, which is essential for their survival.

Research Highlights

In a study exploring the role of tetraspanins, researchers used a technique called proximity labelling to understand how CD9 interacts with other proteins on epithelial cells. By tagging CD9 with a special marker, they could track which proteins it was hanging out with during bacterial infections.

This approach allowed scientists to observe changes in the interactions between proteins when cells were infected. It turns out that CD9 promotes the attachment of bacteria to cells by organizing other proteins necessary for this process. Researchers found that different bacteria could trigger different sets of interactions, suggesting that the tetraspanin microdomains are quite dynamic and responsive to their environment.

Results of the Study

The findings showed that when CD9 was knocked out or disrupted, the bacteria had a tougher time sticking to cells. This emphasized the tetraspanin's importance in bacterial adherence. For Neisseria meningitidis, it was discovered that removing CD9 significantly reduced the bacteria's ability to attach to the host cells. Meanwhile, for Staphylococcus aureus, the results were similar, showcasing CD9's critical role in facilitating this process.

Interestingly, researchers also tested a peptide derived from CD9, which could reduce bacterial adherence when applied to cells. This suggests that disrupting CD9’s function could potentially serve as a novel way to combat bacterial infections, especially given the growing concern around antibiotic resistance.

The Importance of CD9 Interactions

The study identified several proteins known to be involved in bacterial adherence and other cellular functions. Among the proteins that interact with CD9 were CD46 and CD147, both linked to Neisseria meningitidis, and CD44, associated with Staphylococcus aureus. The fact that these interactions differed based on the bacterial type highlights how specific proteins are recruited depending on which bacteria are trying to invade. It’s like having a custom VIP list for each type of bacteria.

What Does This All Mean?

Understanding the role of tetraspanins in bacterial adherence helps us grasp how infections occur at a cellular level. It opens doors to potential treatment strategies that could prevent bacteria from grabbing onto our cells and causing trouble.

There’s a silver lining in the fight against antibiotic resistance, as targeting CD9 and its interactions could lead to new therapeutic approaches that don’t rely on traditional antibiotics.

Future Directions and Conclusion

The ongoing research into tetraspanins and their interactions with bacteria could lead to exciting new developments in infection control and treatment. Scientists are keen to uncover the full range of proteins involved in these processes and how they could be manipulated for therapeutic purposes.

As we delve deeper into the complexity of cellular interactions, we learn that there is much more to bacteria and our immune responses than meets the eye. The dance between bacteria and host cells is intricate, and tetraspanins like CD9 are key players in this performance. By better understanding these interactions, we can work towards more effective strategies to keep bacteria at bay and maintain our health.

In conclusion, the world of tetraspanins and their role in bacterial infections is full of surprises. Who knew that tiny proteins could have such a significant impact on whether bacteria get a foothold in our bodies? It's a reminder that in the microscopic world, even the smallest players can have an outsized influence on our health.

Original Source

Title: Dynamics of the CD9 interactome during bacterial infection of epithelial cells by proximity labelling proteomics

Abstract: Epithelial colonisation is often a critical first step in bacterial pathogenesis, however, different bacterial species utilise several different receptors at the cell membrane to adhere to cells. We have previously demonstrated that interference of the human tetraspanin, CD9, can reduce adherence of multiple species of bacteria to epithelial cells by approximately 50%. However, CD9 does not act as a receptor and is responsible for organising and clustering partner proteins commandeered by bacteria for efficient adherence. CD9 can organise numerous host proteins at the cell membrane but the full interactome has not been delineated. Here, using a novel CD9 proximity-labelling model, we demonstrate a vast and diverse CD9 interactome with 845 significantly enriched proteins associated with CD9 over four hours. These putative proximal proteins were associated with various cellular pathways including cell adhesion, ECM-receptor interactions, endocytosis, SNARE interactions and adherens and tight junctions. Significant and known interactors of CD9 were enriched including {beta}1 integrins and major immunoglobulin superfamily members but also included several known bacterial adherence receptors including CD44, CD46 and CD147. We further demonstrate dynamism of the interactome during infection at three separate time points with two different bacterial species, Neisseria meningitidis and Staphylococcus aureus. During meningococcal infection, 13 unique proximal proteins associated with CD9 were significantly enriched across four hours compared to uninfected cells. However, upon staphylococcal infection far fewer enriched proximal proteins were identified demonstrating that different bacteria require different host factors during CD9-mediated bacterial adherence. Transient knockdown of CD44 and CD147, candidate receptor proteins identified in our screen, significantly reduced staphylococcal and meningococcal adherence respectively. This effect was ablated in the absence of CD9 or if epithelial cells were treated with a CD9-derived peptide demonstrating the association of these proteins during staphylococcal and meningococcal adherence. We demonstrate for the first time the CD9 interactome of epithelial cells and that bacteria hijack these interactions to efficiently adhere to epithelial cells. This process is bacterial species specific, recruiting several different proteins during infection but a host-derived peptide is able to interfere with this process. We have therefore developed a tool that can measure changes within the CD9 interactome after cellular challenge, established a mechanism in which CD9 is used as a universal organiser of bacterial adhesion platforms and demonstrated that this process can be stopped using a CD9-derived peptide.

Authors: PA Wolverson, I Fernandes Parreira, MO Collins, JG Shaw, LR Green

Last Update: Dec 14, 2024

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.12.13.628358

Source PDF: https://www.biorxiv.org/content/10.1101/2024.12.13.628358.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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