New insights into how the Monkeypox (Mpox) virus evades the immune system

Medical News: The monkeypox virus (Mpox), a zoonotic pathogen that belongs to the Orthopoxvirus genus, has been the focus of global concern due to its rising cases and, more notably, its sophisticated mechanisms for evading the host immune system. As scientists continue to study the virus, new insights are being gained into how Mpox disrupts key immune processes, allowing it to thrive despite the body’s natural defenses.


New insights into how the Monkeypox (Mpox) virus evades the immune system

Recent research, conducted by a team of scientists from Kerman University of Medical Sciences and other institutions in Iran, delves into the complex ways the virus evades the immune system. This Medical News report provides an overview of these findings, detailing the roles of innate immune cells and the immune-dodging proteins Mpox employs. By understanding these mechanisms, researchers hope to develop more targeted and effective treatments and vaccines.
 
The Crucial Role of the Innate Immune System
The innate immune system is the body's first line of defense against invading pathogens, including viruses like Mpox. Key players in this defense include natural killer (NK) cells, dendritic cells (DCs), and granulocytes. These cells help to control viral infections early on and are essential for coordinating the body’s broader immune response.
 
NK cells, in particular, play a vital role in the initial response to viral infections. They target and destroy infected cells by releasing cytotoxic molecules, and they also secrete cytokines such as interferon-gamma (IFN-γ), which further stimulates the immune response. However, the monkeypox virus has developed mechanisms to counter NK cell activity. Research shows that during the first week of Mpox infection, the virus significantly reduces the expression of receptors that NK cells need to function properly, diminishing their ability to fight the infection.
 
Dendritic cells (DCs) also play an essential role in the body’s defense against Mpox. They are responsible for producing antiviral cytokines and presenting viral antigens to T-cells, which initiates the adaptive immune response. DCs are particularly important because they serve as a bridge between the innate and adaptive immune systems. Granulocytes, which include neutrophils and eosinophils, further support immune defense by engulfing infected cells and secreting cytokines that recruit additional immune cells to the infection site.

Despite these powerful immune responses, Mpox has evolved several strategies to evade them, allowing it to replicate and spread within the host. This article will explore these immune evasion tactics in detail, with a focus on the role of specific viral proteins in disrupting immune functions.
 
Mpox Evasion of the Immune System: The Role of the F3 Protein
One of the key strategies Mpox uses to evade the immune system is through its F3 protein, a homolog of the E3L protein found in Vaccinia virus. The F3 protein plays a critical role in inhibiting the host's Pro tein Kinase R (PKR) pathway, which is a major antiviral defense mechanism.
 
PKR is activated in response to the presence of double-stranded RNA (dsRNA), a byproduct of viral replication. Once activated, PKR shuts down protein synthesis in infected cells by phosphorylating eukaryotic initiation factor 2 alpha (eIF2α), effectively halting the virus's ability to replicate. PKR also triggers the production of interferons and activates other immune pathways that work to eliminate the virus.
 
However, Mpox counters this response by using the F3 protein to bind dsRNA, thereby preventing PKR activation. Without PKR, the virus can continue to replicate without interference. In addition to blocking PKR, the F3 protein also interferes with the production of interferons, which are critical for activating a broader immune response. By neutralizing these key defenses, Mpox gains a significant advantage early in the infection, allowing it to spread more efficiently.
 
Immune Disrupting Proteins: BR-203, A44L, B19R, BR-05/BR-226, BR-207, and F17
The F3 protein is not the only tool Mpox uses to evade the immune system. The virus employs several other proteins that disrupt various components of the immune response, allowing it to persist in the host. These proteins target different pathways and immune cells, weakening the host’s ability to mount an effective defense.
 
-BR-203: Preventing Lymphocyte Apoptosis
The BR-203 protein is crucial for preventing lymphocyte apoptosis, or programmed cell death. Normally, apoptosis is a mechanism the immune system uses to remove infected or damaged cells. By inhibiting this process, BR-203 ensures that virus-infected lymphocytes remain alive and continue to support viral replication. This allows the virus to maintain a reservoir of infected cells, prolonging the infection and making it more difficult for the immune system to eliminate the virus.
 
-A44L: Manipulating Glucocorticoid Production
Another immune evasion strategy involves the A44L protein, which increases the production of glucocorticoid hormones in the host. Glucocorticoids are known immunosuppressants, meaning they dampen the immune response. By enhancing the production of these hormones, the A44L protein weakens the host’s defenses, giving Mpox more time to replicate and spread without facing significant resistance from the immune system.
 
-B19R: Blocking Interferon Signaling
Interferons are one of the body’s most effective antiviral defenses, and the B19R protein is designed to block their activity. B19R binds to interferon-alpha (IFN-α) and interferon-beta (IFN-β), preventing them from binding to their receptors on the surface of immune cells. Without this binding, the interferons cannot initiate the antiviral state in neighboring cells, significantly weakening the body’s ability to fight off the infection.
 
-BR-05/BR-226: Disrupting Tumor Necrosis Factor Signaling
Tumor necrosis factor-alpha (TNF-α) plays a crucial role in activating inflammation and recruiting immune cells to infection sites. The BR-05 and BR-226 proteins bind to TNF-α, preventing it from interacting with its receptors. This inhibits the normal inflammatory response, reducing the recruitment of immune cells to the site of infection and allowing Mpox to evade detection and destruction.
 
-BR-207: Inhibiting Interleukin-1 Production
Interleukin-1 (IL-1) is another important cytokine in the immune response, responsible for promoting inflammation and recruiting immune cells to the site of infection. IL-1 is activated by caspase-1, an enzyme that processes its inactive form into an active state. The BR-207 protein inhibits caspase-1, thereby reducing the production of active IL-1. This suppression of IL-1 limits the body’s inflammatory response and further aids Mpox in avoiding immune detection.
 
F17: Targeting the mTORC and cGAS-STING Pathways
The F17 protein of Mpox targets two critical immune pathways: the mTORC1 and mTORC2 pathways, and the cGAS-STING axis. The cGAS-STING pathway is responsible for detecting viral DNA in the cytoplasm and triggering the production of interferons and other cytokines. By disrupting this pathway, the F17 protein prevents the immune system from recognizing viral DNA and mounting an appropriate response. This allows the virus to replicate undetected, further evading the immune system.
 
Implications for Treatment and Vaccine Development
Understanding how Mpox evades the immune system provides valuable insights for developing new treatments and vaccines. Current antiviral treatments, such as Tecovirimat, target the viral envelope protein VP37, but future therapies may need to focus on blocking the virus’s immune evasion mechanisms, such as the F3 protein or other immune-disrupting proteins like BR-203 and A44L.
 
Vaccines that stimulate a robust interferon response and enhance the activity of NK cells and dendritic cells may offer improved protection against Mpox. Researchers are currently exploring mRNA-based vaccines and multi-epitope vaccines that target multiple viral proteins. These novel approaches could play a crucial role in preventing future outbreaks.
 
Conclusion
Mpox employs a variety of sophisticated strategies to evade the host immune system. By inhibiting PKR with its F3 protein and using proteins like BR-203, A44L, B19R, BR-05/BR-226, BR-207, and F17 to disrupt key immune pathways, the virus is able to persist in the host and evade destruction. Understanding these immune evasion mechanisms is essential for developing new treatments and vaccines that can effectively combat this virus.
 
The study findings were published in the peer-reviewed journal: Cytokine.
https://www.sciencedirect.com/science/article/pii/S1043466624002540
 
For the latest Mpox News, keep on logging to Thailand Medical News.
 
Read Also:
https://www.thailandmedical.news/news/nuclear-signal-in-monkeypox-mpox-virus-protein-p2-is-key-to-immune-system-evasion
 
https://www.thailandmedical.news/news/scientists-warned-in-2009-that-vaccinia-virus-in-current-mpox-vaccines-impairs-critical-immune-functions
 
https://www.thailandmedical.news/articles/monkeypox