The Pathogenesis of Atypical Clinical Presentations of Monkeypox Virus Infections

Monkeypox virus (MPXV) is an ongoing global public health concern. Historically associated with zoonotic infection, in 2022, a major epidemiological shift occurred when sustained transmission was identified across multiple countries that previously had not had endemic circulation of the virus. While mpox typically presents with characteristic clinical features, infection can also lead to a spectrum of less common manifestations involving multiple organ systems. The extent of viral dissemination and disease severity appear to be modulated by host factors such as immune status, vaccination history, co-infections, and potentially the viral clade. Although complications associated with mpox are infrequent, they can lead to significant morbidity and mortality. Moreover, the underlying pathogenesis and to what extent the viral clade may be playing a role remain incompletely understood. This review summarizes the less common clinical complications of mpox, explores the underlying mechanisms of viral pathogenesis, and discusses what insights can be gained from cell culture and animal models. Additionally, we highlight knowledge gaps that can guide future research priorities.