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Review
. 2024;16(1):413-424.
doi: 10.1159/000540815. Epub 2024 Aug 13.

Innate Immune Response to Monkeypox Virus Infection: Mechanisms and Immune Escape

Reza Parnian  1 , Fatemeh Heydarifard  2 , Fatemeh Sadat Mousavi  3 , Zahra Heydarifard  1 , Milad Zandi  4
Affiliations
Review

Innate Immune Response to Monkeypox Virus Infection: Mechanisms and Immune Escape

Reza Parnian et al. J Innate Immun. 2024.

Abstract

Background: The reemergence of monkeypox virus (Mpox, formerly monkeypox) in 2022 in non-endemic countries has raised significant concerns for global health due to its high transmissibility and mortality rate. A major challenge in combating Mpox is its ability to evade the host's innate immune system, the first line of defense against viral infections.

Summary: Mpox encodes various proteins that interfere with key antiviral pathways and mechanisms, such as the nuclear factor kappa B signaling, cytokine production, complement and inflammasome activation, and chemokine binding. These proteins modulate the expression and function of innate immune mediators, such as interferons, interleukins, and Toll-like receptors, and impair the recruitment and activation of innate immune cells, such as natural killer cells. By suppressing or altering these innate immune responses, Mpox enhances its replication and infection in the host tissues and organs, leading to systemic inflammation, tissue damage, and organ failure.

Key messages: This study reveals new insights into the molecular and cellular interactions between Mpox and the host's innate immune system. It identifies potential targets and strategies for antiviral interventions, highlighting the importance of understanding these interactions to develop effective treatments and improve global health responses to Mpox outbreaks.

Keywords: Immune response; Immunity; Innate; Mpox; Reemerging viral.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Activation and inhibition of cytosolic DNA sensors by Mpox infection. Cytosolic DNA sensors (CDSs) detect double-stranded DNA (dsDNA) in the cytoplasm and trigger NF-κB and IRF3/IRF7 signaling pathways, leading to the production of pro-inflammatory cytokines, type I interferons (IFN I) and type III interferons (IFN III) to combat viral infection. Mpox encodes proteins that interfere with these pathways, such as A47R and OPG176, which inhibit NF-κB activation, and D11L and OPG029, which inhibit 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. The various Mpox inhibitors are shown in red boxes. IRF1/3/7, interferon regulatory factor 1/3/7; IκB, inhibitor κBα; MAVS, mitochondrial antiviral-signaling protein; STING, stimulator of interferon genes; NF-κB, nuclear factor kappa B; RIG-I, retinoic acid-inducible gene I; TBK1, TRAF family member-associated NF-κB activator (TANK)-binding kinase 1; TNF, tumor necrosis factor-alpha; TRADD, tumor necrosis factor receptor type 1-associated DEATH domain protein; TRAF, tumor necrosis factor receptor-associated factor.
Fig. 2.
Fig. 2.
Modulation of inflammasome signaling by Mpox infection. Inflammasomes are multiprotein complexes that sense cytosolic dsDNA and activate caspase-1, leading to the production of inflammatory cytokines such as IL-1β and IL-18 and the induction of pyroptosis, a form of programmed cell death. The various Mpox inhibitors are shown in red boxes. For more details and the underlying molecular mechanisms, see the main text. AIM2, absent in melanoma 2; IL-1b, interleukin-1 beta; IL-18, interleukin-18; ALR, absent in melanoma-like receptors 2; ASC, apoptosis-associated speck-like protein containing a CARD; ROS, reactive oxygen species; SPI-2, serine proteinase inhibitor 2; TLRs, Toll-like receptors; TRAF6, tumor necrosis factor receptor-associated factor 6; PYD, pyrin domain; HIN-200, hematopoietic IFN-inducible nuclear proteins with a 200 amino acid repeat; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activating and recruiting domains.
Fig. 3.
Fig. 3.
Modulation of NK cell activation by Mpox infection. NK cells recognize virus-infected cells through the NKG2D receptor, which binds to NKG2D ligands (NKG2DL) that are upregulated by cellular stress and viral infection. NKG2D activation also depends on the downregulation of MHC class I expression on infected cells, which reduces the inhibitory signals from MHC class I receptors. Mpox encodes a secreted MHC class I-like protein (OMCP) that competes with NKG2DL for binding to NKG2D and inhibits NK cell killing.
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Grants and funding

This study was not supported by any sponsor or funder.