Navigating Mpox’s Immune Evasion and Its Impact on Public Health and Therapy

Milad Zandi, PhD (left) and Zahra Heydarifard, PhD (right)

The re-emergence of mpox in non-endemic countries since 2022 has raised significant global health concerns due to its high transmissibility and mortality. A key challenge in combating mpox is its ability to evade the host’s innate immune system, which is the initial defense against viral infections.¹

Mpox employs various proteins to disrupt crucial antiviral pathways and mechanisms. These disruptions include interference with nuclear factor kappa B (NF-κB) signaling, cytokine production, complement and inflammasome activation, and chemokine binding. By modulating the expression and function of innate immune mediators, such as interferons, interleukins, and toll-like receptors, mpox impairs the recruitment and activation of key innate immune cells, including natural killer cells. This results in enhanced mpox replication and infection within host tissues and organs, leading to systemic inflammation, tissue damage, and organ failure.¹

In a Q&A with Contagion, Milad Zandi, PhD, and Zahra Heydarifard, PhD in medical virology, both assistant professors at Lorestan University Medical Sciences, provide insights into the molecular and cellular interactions between mpox and the innate immune system, highlighting potential targets and strategies for developing antiviral interventions.

Contagion: The study highlights mpox’s ability to disrupt key antiviral pathways such as NF-κB signaling and interferon responses. How do these disruptions impact the progression and severity of mpox infections in non-endemic countries, and what are the implications for public health strategies and vaccine development during this ongoing global outbreak?

Zandi Mpox’s ability to disrupt key antiviral pathways, such as NF-κB signaling and interferon responses, significantly impacts the progression and severity of infections, particularly in non-endemic countries where populations may lack prior immunity. These disruptions allow the virus to evade early immune detection and response, leading to prolonged viral replication and more severe disease manifestations. In non-endemic regions, this can result in higher transmission rates, increased severity of symptoms, and greater challenges in containing outbreaks. The impairment of these critical immune pathways can also complicate the course of the disease, making it more difficult to manage with conventional therapies. For public health strategies, this necessitates a shift towards more aggressive containment and treatment approaches, including the rapid deployment of antiviral agents that can counteract these immune evasion tactics. Vaccine development efforts must also take these immune disruptions into account, focusing on creating vaccines that can stimulate robust immune responses even in the presence of viral immune-modulating proteins. Additionally, there is a need for continuous monitoring of viral evolution to detect any changes that might further enhance its ability to evade immune responses, which would inform the adaptation of both therapeutic and vaccine strategies during the ongoing global outbreak.^2,3

Contagion: What are the specific molecular mechanisms through which Mpox proteins interfere with NF-κB signaling and other antiviral pathways, and how do these mechanisms contribute to the virus’s ability to evade the innate immune system?

Heydarifard The innate immune system serves as the first line of defense against mpox infection. Several innate immune pathways work to combat npox, but the virus has evolved defenses to block these pathways.

Cytosolic DNA sensors (CDSs), including Toll-like receptors (TLRs), detect viral double-stranded DNA (dsDNA) in the cytoplasm and activate NF-κB and IRF3/IRF7 signaling pathways. This leads to the production of pro-inflammatory cytokines, type I interferons (IFN-I), and type III interferons (IFN-III), which help fight viral infections. However, mpox encodes proteins, such as A47R, OPG176, D11L, and OPG029, that interfere with these pathways by inhibiting NF-κB, IRF3, and IRF7 activation.

Mpox also secretes viral TNF receptor (TNFR) orthologs that compete with cellular TNFRs for binding to TNF, thereby blocking its inflammatory and apoptotic effects. Additionally, mpox can modulate inflammasome signaling, a pathway that activates inflammatory responses, and encode cytokine-binding proteins (vIL-1βBPs, vIL-18BPs) to help modulate the host’s innate immune defenses, viral replication, and productive infection.

Another pathway in which mpox interferes with the innate immune system is through the complement system, a crucial component of the innate immune response that consists of proteins working together to recognize and eliminate pathogens. The Central African mpox strain, but not the West African strain, encodes the monkeypox inhibitor of the complement enzyme (MOPICE). This protein binds to C3 and C5 convertases, key enzymes involved in the complement cascade.

An interesting counteraction between mpox and the innate immune system lies in the inhibition of natural killer (NK) cell activation, the primary arm of the innate immune system. NK cells play a vital role in innate immunity, and mpox encodes a secreted MHC class I-like protein (OMCP) that competes with NKG2DL for binding to NKG2D, ultimately inhibiting NK cell-mediated killing.

Contagion: How do the findings on mpox’s impact on cytokine production and immune cell recruitment inform the development of targeted antiviral treatments or vaccines?

Heydarifard The molecular mechanism of innate immune responses during mpox infection, as well as how virus evade or manipulate these pathways, provide important insight into viral pathogenesis. This understanding can aid in the development of novel antiviral drugs and vaccines through several approaches:

1. Targeting immune evasion viral proteins: Researchers can develop therapies that specifically target the proteins encoded by the virus to evade or inhibit innate immune pathways. For example, designing peptides or small molecules that effectively target SPI-2, MOPICE, OMCP, and BCL-2-like proteins can help restore the host’s immune defenses against mpox.

2. Boosting innate immunity: Enhancing the innate immune response, particularly in immunocompromised individuals, has the potential to improve therapeutic outcomes. Specifically, activating NK cells, which play a significant role in viral elimination, can be a promising strategy. mpox infection also leads to the downregulation of pro-inflammatory cytokines and chemokines. Administration of recombinant cytokines or agonists of pattern recognition receptors like TLR3, TLR7, or TLR9 can stimulate the host’s innate immune response, promoting the clearance of mpox. Designing effective vaccine: 3. Developing mpox vaccines that elicit robust and protective immune responses, especially those that activate innate immunity, can help prevent infections or reduce disease severity. These vaccines can be used in clinical settings for individuals at high risk of mpox exposure or during outbreak scenarios. Adjuvants have become integral components of many vaccines, maximizing protection by extending and intensifying immune responses. Recent research has focused on a new class of adjuvants targeting pattern recognition receptors (PRRs) on innate immune cells. Examples of approved vaccine adjuvants include inorganic aluminium salts (alum), oil-in-water emulsion MF59, monophosphoryl lipid A (MPL) absorbed on aluminium salts (AS04), and toll-like receptor 9 (TLR9) agonist CpG. TLR agonists and cytosolic pattern recognition receptor activators, such as stimulators of interferon genes (STING) agonists, have also been studied as vaccine adjuvants. According to a notion, vaccine adjuvants that mimic natural infections, like live attenuated vaccines, may activate innate immune-sensing pathways, generating potent and long-lasting immune responses. Subunit vaccines containing membrane proteins A33, B5, L1, A27, and alum CpG were tested on primates for smallpox etiology, followed by a lethal dose of mpox administered intravenously. While adjuvanted alum vaccines showed only limited protection, those with the addition of adjuvant CpG offered complete protection and a more uniform antibody response, along with more substantial IgG1 responses. These findings provide encouraging evidence for the development of a highly effective subunit vaccine against orthopoxvirus (OPXV) infections, serving as a safer alternative to live vaccinia virus (VACV) immunization.

Contagion: Given the study’s insights into how mpox interferes with innate immune responses, what specific antiviral strategies or therapeutic approaches are being explored to counteract these immune evasion mechanisms? How might these approaches be adapted or prioritized in response to the current global mpox outbreak?

Zandi The study’s findings on mpox’s ability to disrupt innate immune responses, particularly through interference with NF-κB signaling and interferon pathways, have led to the exploration of several antiviral strategies aimed at counteracting these immune evasion mechanisms. One key approach involves the development of antiviral drugs that can either enhance the host’s innate immune response or directly inhibit the viral proteins responsible for immune suppression. For instance, small-molecule inhibitors that target viral proteins involved in blocking NF-κB activation or interferon signaling, such as those that mimic or boost the action of interferons, are being considered. Additionally, there is interest in developing therapeutic agents that can modulate Toll-like receptors (TLRs) or NOD-like receptors (NLRs) to enhance the recognition and response to mpox infection, thereby restoring the immune system’s ability to fight the virus effectively. Given the current global mpox outbreak, these strategies are being prioritized for rapid development and deployment, particularly in regions with limited access to vaccines. The adaptation of these approaches to the global context involves scaling up production, ensuring equitable distribution, and integrating these therapies with existing public health measures to control the spread of the virus while mitigating severe disease outcomes.¹

Overall, addressing mpox’s immune evasion requires a multi-faceted approach, including improved therapeutic strategies and vaccine development. Ongoing research will be crucial in managing and mitigating the impacts of mpox.

References

1. Parnian R, Heydarifard F, Mousavi FS, Heydarifard Z, Zandi M. Innate Immune Response to MPOX Infection: Mechanisms and Immune Escape. Journal of Innate Immunity. 2024:1-.

2. Zandi M, Shafaati M, Hosseini F. Mechanisms of immune evasion of monkeypox virus. Frontiers in microbiology. 2023 Feb 1;14:1106247.

3. Shafaati M, Zandi M. Human monkeypox (hMPXV) re‐emergence: host immunity status and current vaccines landscape. Journal of medical virology. 2023 Jan;95(1):e28251.