Hantavirus disease and the need for pathogenesis-guided therapy

The 2026 cluster of severe hantavirus disease among passengers from the MV Hondius was numerically small but conceptually large. By early May, international authorities had reported a multicountry event caused by Andes hantavirus, with confirmed cases and deaths among people linked to a cruise ship that had departed Ushuaia, Argentina (Velavan and Schmidt-Chanasit, 2026; WHO, 2026). For all of us the episode should be a reminder that viruses remain imminent threats even when they are familiar, geographically constrained, or inefficiently transmitted. A pathogen does not need pandemic transmissibility to expose gaps in diagnosis, preparedness, and treatment. Therefore, this episode should also be read as a reminder that we lack specific treatments for most viruses and have an incomplete understanding of the pathogenesis of many viral diseases—altogether hindering administration of treatments when outbreaks hit.

Hantaviruses are not new. They are segmented negative-sense RNA viruses maintained in chronically infected small mammals, classically rodents. Humans are accidental hosts, usually infected by inhalation of aerosolized excreta. Most hantaviruses are not transmitted efficiently between people, but Andes hantavirus is the important exception: person-to-person transmission has been documented, typically after close or prolonged contact with symptomatic individuals (Alonso et al., 2020; Vial et al., 2023). Furthermore, the onset of disease is slow and poorly understood. With severe disease only arising in a subset of individuals weeks after initial infection. This unusual virological and epidemiological profile makes hantavirus disease a useful lens through which to examine a broader problem in infectious disease medicine: we often know how infection begins but too often know too little about how they progress and cause disease.

The central argument of this viewpoint is simple: the next generation of medicine against virus-induced diseases must be guided by in-depth knowledge of both the virus and disease pathogenesis. Direct-acting antivirals are an important component of our fight against viruses. However, they are typically most effective at early time points after infection. For diseases where symptoms arise later in the course of infection, some direct-acting antivirals show little efficacy. For hantaviruses, unfortunately, we have no approved targeted therapeutics. Furthermore, given that symptoms arise late in the infection course, it is unclear if direct-acting antivirals would be sufficient to mitigate disease outcomes. Additional strategies are needed for complex diseases such as those caused by hantaviruses.

For some acute viral infections, the clinical trajectory is determined by viral load; however, for some infections, outcomes are not determined solely by the amount of virus present at the time of hospital presentation. Tissue injury can continue after peak replication, and the immune response that initially protects the host can become a driver of vascular leakage, organ failure, coagulopathy, or neurological damage. Hantavirus disease illustrates this problem with clarity. Therefore, treatment with direct-acting antivirals at the time of hospitalization may not be sufficient to alter the trajectory of the disease. If a patient presents during the early phase of infection where viral replication is high, direct-acting drugs will be decisive, and we desperately need such therapeutics. If the patient presents after endothelial activation, capillary leakage, thrombocytopenia, pulmonary edema, or renal injury are established, viral inhibition alone may be insufficient. At that stage, effective therapy may require targeting of secondary pathogenic mechanisms—often a specific immune effector function. The conceptual challenge is to know when the disease is virus-driven and when it has become more host-response-driven and, in this case, which processes to target therapeutically. This problem extends beyond hantaviruses. These issues are at play during severe influenza, severe COVID-19, viral hemorrhagic fevers, and viral encephalitis (Paludan and Mogensen, 2022; Tyler, 2018).

A striking feature of hantavirus biology is the contrast between reservoir hosts and humans. In adult rodent reservoirs, infection is typically persistent and asymptomatic; in humans, spillover can cause severe disease. Old World hantaviruses, including Hantaan and Puumala viruses, are associated mainly with hemorrhagic fever with renal syndrome (HFRS) and its milder form, nephropathia epidemica. New World hantaviruses, including Sin Nombre virus and Andes virus, are associated mainly with hantavirus pulmonary syndrome or hantavirus cardiopulmonary syndrome (HPS/HCPS) (Avšič-Županc et al., 2019; Vial et al., 2023).

The early clinical picture is often nonspecific, resembling what is seen in many viral infections: fever, myalgia, headache, gastrointestinal symptoms, and malaise. This indistinct prodrome is a diagnostic problem because the transition to severe disease can be abrupt. And we do not know the triggers or in which patients this may occur. In HFRS, thrombocytopenia, hypotension, vascular leakage, and acute kidney injury dominate. In HPS/HCPS, the major clinical threat is rapidly progressive pulmonary edema, respiratory failure, and shock. Mortality differs substantially between hantaviruses, with the Andes hantavirus being one of the most pathogenic, but severe HPS generally has a high case fatality rate, often estimated in the range of 30–40% (Avšič-Županc et al., 2019; Vial et al., 2023). Despite clinical differences, the kidney-predominant and lung-predominant diseases have shared underlying mechanisms; both syndromes are vascular diseases. Both involve thrombocytopenia and increased permeability. This raises the question: why does infection of cells that are often not overtly destroyed produce life-threatening leakage across specialized vascular beds?

Hantavirus tissue tropism is central to pathogenesis. Pathogenic hantaviruses infect endothelial cells, and viral antigens can be detected in microvascular beds of affected organs. Yet infected endothelial cells are not usually killed by infection, and in vitro infection of endothelial cells does not by itself reproduce the dramatic permeability seen in patients (Terajima and Ennis, 2011). This observation has shaped the field (Vaheri et al., 2013). Severe disease likely reflects an interplay between the infected endothelium, platelets, complement, innate cytokines, lymphocytes, and the local tissue context rather than a simple virus-induced cytopathic process. Yet, we have incomplete understanding of these pathogenic processes, thus preventing effective treatment of patients with severe disease, e.g., HPS/HCPS.

Several mechanisms by which infection leads to leakage are plausible and not mutually exclusive. First, infection may prime endothelial cells to respond abnormally to permeability factors such as Vascular Endothelial Growth Factor (VEGF), bradykinin, or inflammatory cytokines. Second, platelet–endothelial interactions may contribute to thrombocytopenia and barrier dysfunction. Third, complement activation by infection may amplify vascular injury, particularly in HFRS. Fourth, robust T cell responses may be double-edged: necessary for viral clearance, but capable of increasing permeability through cytokines, cytotoxic mediators, or endothelial activation. Human studies have associated activated T cells, natural killer (NK) cells, cytokines, and HLA alleles with disease severity, supporting an immunopathogenic component (Ma et al., 2013; Raftery et al., 2014; Rasmuson et al., 2016), but detailed cellular and molecular mechanisms are lacking.

Therefore, we suggest a sequential progression of disease (Fig. 1). Transmission leads to early replication in a mucosal or local tissue context. Dissemination allows infection of endothelium and perhaps mononuclear phagocytes. The host response determines whether infection resolves, remains clinically mild, or crosses a threshold into systemic vascular dysfunction. In this model, viral load matters, but so does timing, endothelial state, tissue-specific vascular programs, preexisting immunity, genetic background, and, not least, the quality of the inflammatory response. This framework also explains why hantavirus disease is difficult to treat empirically. A drug that reduces replication may be most effective before the vascular phase. A cytokine inhibitor may be harmful if given before sufficient immune control, but beneficial if given during destructive amplification.

The field of hantavirus disease pathogenesis is therefore facing a series of key unresolved questions, answers to which will enhance the prospect of better treatments. For instance, what determines the transition from infection to vascular leakage? The field needs high-resolution, longitudinal studies that connect viral load, endothelial activation, platelets, complement, cytokines, lymphocyte phenotypes, and clinical physiology. This should be linked to perturbation experiments demonstrating mechanistic causality. The decisive events may occur before hospitalization, during the short interval when a nonspecific febrile illness becomes vascular collapse. Second, which immune pathways are protective, pathogenic, or both? It is not enough to label hantavirus disease as immunopathology, detailed cellular and molecular mechanisms are needed. CD8 T cells, NK cells, interferons, inflammatory monocytes, complement, and cytokines may each have phase-specific roles. The goal should be to define causal circuits and therapeutic windows. This will require animal models that reproduce human vascular disease, human organotypic endothelial systems, and clinical sampling aligned to disease stage rather than calendar time alone.

Third, why is Andes hantavirus transmissible between people when most hantaviruses are not? Epidemiological and genomic analyses have established person-to-person spread in Andes virus outbreaks, including superspreading-like events (Alonso et al., 2020; Martinez et al., 2020). The mechanistic basis remains inadequately understood. Does Andes hantavirus achieve higher replication in respiratory or salivary compartments? Does it differ in stability, receptor use, tissue tropism, immune evasion, or shedding kinetics? Answering these questions has implications beyond hantavirus, because it addresses how a primarily zoonotic virus acquires limited human transmission without becoming efficiently pandemic. In fact, all of the above questions are not specific to hantaviruses. They address a recurring theme in viral hemorrhagic fevers: many severe viral diseases are vascular and immunological syndromes superimposed on infection. Ebola, dengue, Crimean-Congo hemorrhagic fever, and severe arenavirus infections differ profoundly virologically, but they converge on endothelial dysfunction, inflammation, coagulopathy, and organ-specific injury. Hantavirus research can therefore contribute to a general framework for understanding how antiviral defense becomes vascular disease.

The MV Hondius outbreak will likely remain a limited event, not a global crisis. That is precisely why it is scientifically useful. It allows us to ask, outside the distortions of a pandemic, what kind of knowledge is needed to improve treatment of viral infections. Hantaviruses remind us that pathogenesis is not an academic afterthought to virology. It is the route to rational treatment. The future of infectious disease medicine should combine rapid pathogen identification and antiviral development with mechanistic maps of tissue injury, immune amplification, and tissue failure. This outbreak is of course only one of many to likely emerge. Therefore, we need to be prepared; we need direct-acting antivirals and host-directed immunomodulators. Lastly, we need vaccines for use in endemic regions to reduce spillover and in outbreak settings to mitigate spread. Only then will we be able to move from watching an outbreak unfold to treating infection and the disease that infection causes.

The work in the Paludan laboratory is supported by grants from the Lundbeck Foundation (R359-2020-2287), the Novo Nordisk Foundation (NNF23OC0084931), the Danish National Research Foundation (Center for Immunology of Viral infections, DNRF164), and the Swedish Research Council (2024-02549). The work in the Cherry laboratory is supported by grants from the National Institutes of Health (75N93021C00015, R21AI183111, 1U19AI181960, R01AI152362, 1R01AI150246, RO1AI140539), the Gates Foundation (INV-094995), the Colton Center, the Burroughs Welcome Fund, the Dean's Innovation Fund, and PolyBi.

Author contributions: Søren R. Paludan: conceptualization and writing—original draft, review, and editing. Sara Cherry: funding acquisition and writing—review and editing.