Immune Escape by Monkeypox Virus

Human monkeypox (MPX) is a zoonotic disease caused by the monkeypox virus (MPXV) affecting rodents and primates mostly in western and central Africa that incidentally causes disease in humans similar to smallpox, although with notably lower mortality. The current outbreak of the disease in various parts of the world is considered an epidemic and a new global threat. MPXV, a double-stranded DNA virus, belongs to the Orthopoxvirus genus of the Poxviridae family. Monkeypox virus is considered less pathogenic than vaccinia but more pathogenic than variola (Ref.1).

 

In response to the monkeypox infection, the human immune system becomes activated which leads to the cell antiviral signaling and inflammatory responses. Pro-inflammatory cytokines, Interferons, and nuclear factor kappa B (NF-kappaB) are important in cellular mechanisms like cell proliferation, apoptosis, inflammation, and immune responses. Inhibition of these antiviral proteins is crucial for the immune escape mechanisms adopted by the virus to cause the disease. Like other poxviruses, the monkeypox virus also uses multiple mechanisms to escape the immune recognition and response by the host immune system. Infection of monkeypox virus inhibits the interferon-stimulated gene (ISG) expression, the major antiviral gene in human innate immunity. MPXV proteins also suppress TNF-alpha, Interleukin 1 alpha and beta, IL-18 as well as C-C Chemokines. Multiple proteins encoded by MPXV are responsible for the immune evasion mechanism. B16R and B9R are responsible for inhibiting type I interferon-induced signaling. B16R is an interferon-alpha/beta binding protein whereas B9R is an interferon-gamma binding protein. Similarly, D7L and D6L are secreted IL-18-binding proteins that inactivate the pro-inflammatory cytokine IL-18 to inhibit anti-viral and inflammatory responses. Tumor necrosis factor binding proteins J2L and K1R inhibit TNF-alpha. Another protein B14R is an Interleukin-1beta-binding protein that inhibits Il-1 signaling. B14R along with B12R MPXV proteins are also Serine protease SPI-2 inhibitor homologs that inhibit apoptosis. F3L is an interferon resistance factor that binds the dsRNA inhibiting the anti-viral response and thus escaping the immune system. MPXV B13R protein interacts with IKK to inhibit the activation of NF-kappaB. J1R and J3R are secreted CC-chemokine binding proteins that play important role in inhibiting anti viral response (Ref.2 and 3).

 

MPXV complement control proteins can prevent the complement pathways and interfere with the innate immune system. Some MPXV proteins can also inhibit the CD4+ and CD8+ T cell response thus affecting the adaptive immune responses. Inhibiting the MPXV proteins that are responsible for the immune escape mechanisms can be the answer to monkeypox disease. MPXV A29L, M1R, and B6R antigens can be used as MPXV vaccine candidates that can elicit an immune response against the monkeypox virus (Ref.3 and 4). 

 

References

 

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Emerg Microbes Infect. 2022 Dec;11(1):1768-1777. doi: 10.1080/22221751.2022.2095309.

 

2. Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus.

Arndt WD, Cotsmire S, Trainor K, Harrington H, Hauns K, Kibler KV, Huynh TP, Jacobs BL.

J Virol. 2015 Oct;89(20):10489-99. doi: 10.1128/JVI.00304-15. Epub 2015 Aug 5.

 

3. Analysis of the monkeypox virus genome. Virology.

Shchelkunov SN, Totmenin AV, Safronov PF, Mikheev MV, Gutorov VV, Ryazankina OI, Petrov NA, Babkin IV, Uvarova EA, Sandakhchiev LS, Sisler JR, Esposito JJ, Damon IK, Jahrling PB, Moss B.

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4. Monkeypox virus: a re-emergent threat to humans.

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Virol Sin. 2022 Aug;37(4):477-482. doi: 10.1016/j.virs.2022.07.006. Epub 2022 Jul 9.