Monkeypox: disease epidemiology, host immunity and clinical interventions

Abstract

Monkeypox virus (MPXV), which causes disease in humans, has for many years been restricted to the African continent, with only a handful of sporadic cases in other parts of the world. However, unprecedented outbreaks of monkeypox in non-endemic regions have recently taken the world by surprise. In less than 4 months, the number of detected MPXV infections has soared to more than 48,000 cases, recording a total of 13 deaths. In this Review, we discuss the clinical, epidemiological and immunological features of MPXV infections. We also highlight important research questions and new opportunities to tackle the ongoing monkeypox outbreak.

Fig. 1. Geographical distribution of confirmed and suspected monkeypox cases during the outbreak between May and August 2022.

Data presented as of 5 August 2022 were obtained from Global.health. Diagram generated with Datawrapper.

Fig. 2. Immunopathogenesis of human monkeypox.

a–h | Monkeypox virus (MPXV) might enter the body via the respiratory (panel a) or skin (panel b) route. In the respiratory tract, the virus can infect airway epithelial cells such as ciliated cells. Antigen-presenting cells such as dendritic cells and macrophages (MΦ) are also susceptible to MPXV infection. Upon inoculation in the skin, the virus infects keratinocytes and fibroblasts. Skin-resident immune cells such as Langerhans cells, dendritic cells and macrophages are also targeted. In both scenarios (panels a and b), it is hypothesized that infected antigen-presenting cells travel to nearby draining lymph nodes and facilitate its spread through the lymphatic system (panel c). Direct viral access to the lymphatics has been also speculated. A common feature of human monkeypox is swelling of lymph nodes (lymphadenopathy). The abnormal proliferation and retention of natural killer cells might be one of the causes. Following its spread through lymphoid tissue, MPXV may target other large organs such as the spleen and liver (panel d). Of note, MPXV antigens have been previously been detected in both hepatocytes and Kupffer cells in non-human primate (NHP) models. The viraemia wave could then allow the virus to further spread to distant organs such as the skin and gonads. Recently, MPXV was isolated from semen of infected individuals, highlighting the possibility of sexual transmission (panel e). The infection of skin and mucosae leads to the appearance of infective pustules (panel f) and ulcers (panel g). The latter release high quantities of virus into the saliva, which potentially leads to aerosolized transmission of MPXV (panel h).

Fig. 3. Immune evasion by MPXV.

Monkeypox virus (MPXV) is known to encode numerous viral proteins that are involved in evading the host immunity. These can be involved in interfering with the signalling cascade of pathogen recognition receptors, disrupting key transcription factors for the expression of inflammatory genes, such as interferon regulatory factor 3 (IRF3) and NF-κB. MPXV can also interfere with interferon signalling by blocking IFNα/β binding or suppressing IFNα/β production and by blocking protein kinase R (PKR)-mediated pathways. In addition, MPXV secretes proteins that can target key inflammatory molecules such as TNF, IFNγ, IL-1β, IL-18 and IL-6. Moreover, MPXV can prevent apoptosis in infected cells by expressing numerous viral proteins that target the apoptotic pathways. The Central African MPXV Zaire strain also expresses D14 which blocks the activation of the complement cascade. However, this viral protein is not expressed in the West African MPXV strain. Lastly, MPXV can also downregulate the activities of natural killer cells and T cells by interfering with their activation processes (see also Table 1). PRR, pattern recognition receptor.