The resurgence of a neglected orthopoxvirus: Immunologic and clinical aspects of monkeypox virus infections over the past six decades

Abstract

Monkeypox is a zoonotic Orthopoxvirus which has predominantly affected humans living in western and central Africa since the 1970s. Type I and II interferon signaling, NK cell function, and serologic immunity are critical for host immunity against monkeypox. Monkeypox can evade host viral recognition and block interferon signaling, leading to overall case fatality rates of up to 11%. The incidence of monkeypox has increased since cessation of smallpox vaccination. In 2022, a global outbreak emerged, predominantly affecting males, with exclusive human-to-human transmission and more phenotypic variability than earlier outbreaks. Available vaccines are safe and effective tools for prevention of severe disease, but supply is limited. Now considered a public health emergency, more studies are needed to better characterize at-risk populations and to develop new anti-viral therapies.

Keywords: Immune evasion; Monkeypox virus; Public health; Vaccination.

Fig. 1

Mechanisms utilized by MPXV to evade host immunity. A) Following viral entry into monocytes and production of viral dsRNA intermediates, the F3 protein binds these intermediates and sequesters them away from PKR, preventing downstream antiviral mechanisms, while the TLR3 response to these intermediates is also reduced. IFNα/βBP prevents binding of type I IFN on the cell surface. B) NK cells demonstrate decreased chemotaxis, IFNγ and TNFα secretion, and cytotoxicity during MPXV infection.

Fig. 2

Progression of clinical symptoms after MPXV infection. The classic presentation of an infection with monkeypox virus starts with an incubation period of about 7–17 days, followed by a prodromal period of 1–4 days, characterized by fever, myalgias, and fatigue. The fever resolves as the characteristic rash presents, typically around 12 days after exposure. The rash evolves for the duration of the illness, usually resolving by 28 days after exposure. The arrows represent the spectrum of phenotypes that have been described, with more variability and shorter incubation periods in the 2022 outbreak.