Mpox: disease manifestations and therapeutic development

Abstract

Mpox, caused by monkeypox virus (MPXV) infection, has emerged as a significant global health threat. The World Health Organization (WHO) has twice declared a Public Health Emergency of International Concern for mpox: first for the 2022-2023 global outbreak and subsequently for concurrent outbreaks in Africa. Beyond MPXV, other members of the Orthopoxvirus genus also pose growing risks of zoonotic spillover, with the potential to jump from animal reservoirs to humans. Clinically, mpox is distinguished from other Orthopoxvirus infections by its propensity to cause severe systemic manifestations alongside localized skin lesions, disproportionately affecting vulnerable groups such as children, pregnant women, and immunocompromised individuals. Although vaccines are available, effective therapeutics are equally essential in combating the mpox crisis. Current antiviral agents, including tecovirimat and brincidofovir, have demonstrated uncertain or disappointing efficacy in preclinical and clinical studies, underscoring the urgent need for further therapeutic development. This review provides a concise synthesis of recent advances in understanding mpox epidemiology and clinical features and offers an in-depth discussion of the current status and future directions in therapeutic development. We highlight the importance of innovative experimental models that can authentically replicate mpox disease manifestations and serve as robust platforms for therapeutic testing. Advancing these research efforts is critical for responding to the ongoing mpox emergency and for sustaining preparedness against future poxvirus epidemics.

Keywords: clinical feature; experimental model; monkeypox virus; therapeutic development.

Fig 1

Clinical features, disease manifestations, and experimental models of mpox. (A) Skin and systemic manifestations of mpox. In addition to skin lesions, monkeypox virus (MPXV) infection can cause systemic symptoms and manifestations. Mpox-associated systemic manifestations include cardiovascular complications, neurological complications, kidney injury, proctitis (inflammation of the rectum), respiratory symptoms, digestive complications, circulatory manifestations, and pregnancy-related manifestations. MPXV transmission occurs mainly through respiratory and cutaneous routes. In the respiratory tract, the virus infects not only airway epithelial cells but also immune cells such as dendritic cells and macrophages. In the skin, MPXV infects keratinocytes and fibroblasts and may also infect skin-resident immune cells such as dendritic cells, macrophages, and Langerhans cells. A key feature of mpox is swelling of lymph nodes (lymphadenopathy), reflecting systemic inflammatory response, which may be caused by abnormal proliferation and retention of natural killer (NK) cells, and infected macrophages and dendritic cells. Following its spread through lymphoid tissue, MPXV may target other organs such as the liver. MPXV has been shown to infect hepatocytes and Kupffer cells in the liver. (B) Experimental models for MPXV infection. Immortalized cell lines originating from monkey and human sources have been widely used for MPVX infection studies in vitro. A number of animal models have been established to support MPXV infection and can be used for testing antiviral treatments. Among these models, monkeys, rabbits, and dogs can develop skin lesions upon MPXV infection. To study neurological complications, human-induced pluripotent stem cells (hiPSC)-derived neural progenitor cells have been used to model MPXV infection. To study the broad-spectrum tissue tropism and disease manifestations, a variety of organoids—including human skin, kidney, brain, intestine, and liver organoids generated from hiPSC or primary tissues—have been employed to model MPXV infection. A recent study has demonstrated the proof of concept of simultaneously modeling MPXV infection and the resultant inflammatory response by integrating macrophages into organoids to establish macrophage-augmented organoids (MaugOs). Furthermore, reconstructed human skin (RHS) models developed by integrating primary human keratinocytes and stromal cells can be explored for studying MPXV infection and testing therapeutics in future research. The pattern was created using BioGDP.com (18)

Fig 2

Therapeutic development for treating mpox. (A) Antiviral drugs prescribed for compassionate use in mpox. Tecovirimat, brincidofovir, and cidofovir are currently prescribed as compassionate use in treating mpox. However, results from two recent randomized, placebo-controlled trials showed that tecovirimat failed to benefit both clade I and clade II monkeypox virus (MPXV) infected patients. A randomized, double-blind, placebo-controlled trial is currently underway to evaluate the efficacy of brincidofovir in treating mpox. (B) Drug repurposing, discovery, and development for mpox therapeutics. MPXV encodes a large number of viral proteins and enzymes necessary for its life cycle, which serve as promising targets for therapeutic development. For example, in addition to viral DNA polymerase and F13 protein, viral thymidine kinase and methyltransferase VP39 can be explored for developing direct-acting antivirals. MPXV actively interacts with human host factors to drive infection and disease manifestations, making these host pathways important targets for developing host-directed therapies. Drug (virtual) screening, bioinformatics, and AI-driven techniques can be used to repurpose, discover, and develop new therapeutics. (C) Potential drug combination approaches for mpox treatment. Combinational antiviral therapies often can exhibit synergism and prevent the development of drug resistance. This highlights the potential of combining antiviral agents to achieve synergistic anti-MPXV activity and to prevent drug resistance. Severe mpox is often accompanied by pathological inflammation driven by immune cells, which exacerbates disease severity. Current antiviral therapies target the pathogen but do not address hyperinflammation. Therefore, combining antivirals with anti-inflammatory drugs should be investigated to simultaneously inhibit infection and control hyperinflammation. (D) Broad-spectrum anti-poxvirus drugs. In addition to MPXV, the Orthopoxvirus genus includes several other members, such as variola virus (which causes smallpox), vaccinia virus (used in the smallpox vaccine), as well as cowpox, rabbitpox, and camelpox viruses, which can cause spillover infections from animals to humans. Orthopoxviruses continue to pose an emerging threat to public health. Therefore, it is important to identify drug candidates with broad-spectrum antiviral activity to prepare for future poxvirus epidemics. The pattern was created using BioGDP.com (18).