Nexus of Pathophysiology and Therapeutics (NPT)
This is the official journal for mechanistic pathophysiology and translational therapeutic research, and a leading journal advancing the mechanistic understanding of disease and translating molecular and cellular insights into therapeutic innovation and precision medicine.

Pro-inflammatory Cytokine Storm in Puumala Virus Infection: Immunopathogenesis and Therapeutic Implications

Document Type : Systematic Review

Authors

Atefe Yaghoubi 1
Elham Soleimani 2
Shima Davoudi 3

1 Department of Anatomy, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.

2 Department of Neuroscience, School of Advanced Technologies in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.

3 Neurophysiology Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

https://doi.org/10.22034/npt.2026.1.010
Abstract
Puumala orthohantavirus (PUUV) is the principal cause of hemorrhagic fever with renal syndrome in Europe, where it manifests as nephropathia epidemica. Although clinical features of PUUV infection are well described, disease severity is increasingly recognized to result from dysregulated host immune responses rather than direct viral cytopathicity. This review synthesizes current evidence on the immunopathogenic roles of interleukins in PUUV infection, with a particular focus on cytokine-mediated endothelial dysfunction and its translational implications. Acute PUUV infection is characterized by a pronounced systemic inflammatory response, often described as a cytokine storm, involving elevated levels of both pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, IL-2, IL-8) and regulatory mediators (IL-10, TGF-β1). Among these, IL-6 and TNF-α are consistently associated with disease severity, renal impairment, and thrombocytopenia, and contribute to endothelial activation and increased vascular permeability. IL-6 trans-signaling has emerged as a key mechanism in endothelial barrier disruption, while TNF-α promotes vascular leakage and immune cell recruitment. In contrast, IL-10 and TGF-β1 appear to function as compensatory anti-inflammatory mediators whose delayed or insufficient responses may contribute to uncontrolled inflammation and tissue injury. Additional interleukins, including IL-2, IL-8, and IL-18, further contribute to T-cell activation, neutrophil recruitment, and inflammasome-associated inflammation, highlighting the complexity of cytokine networks in PUUV pathogenesis. Collectively, these pathways converge on endothelial dysfunction, which represents the central event driving vascular leakage and organ damage. Understanding interleukin dynamics in PUUV infection provides important mechanistic insight and identifies potential biomarkers for disease severity. Moreover, selective targeting of cytokine pathways, particularly IL-6 trans-signaling and TNF-α activity, offers promising therapeutic opportunities. However, given the dual protective and pathogenic roles of cytokines, precise immunomodulation rather than broad suppression is required. Overall, PUUV infection serves as a model of immune-mediated vascular disease, where cytokine-driven endothelial dysfunction determines clinical outcome and therapeutic strategies.

Graphical Abstract

Pro-inflammatory Cytokine Storm in Puumala Virus Infection: Immunopathogenesis and Therapeutic Implications

Keywords

Puumala Orthohantavirus
Cytokine Storm and Interleukins
Endothelial Dysfunction
Hemorrhagic Fever with Renal Syndrome
Immunopathogenesis
1. Tscherne A, Guardado-Calvo P, Clark JJ, Krause R, Krammer F. Puumala orthohantavirus: prevalence, biology, disease, animal models and recent advances in therapeutics development and structural biology. Frontiers in immunology. 2025;16:1575112. https://doi.org/10.3389/fimmu.2025.1575112.
2. Outinen TK, Mäkelä S, Pörsti I, Vaheri A, Mustonen J. Severity Biomarkers in Puumala Hantavirus Infection. Viruses. 2021;14(1). https://doi.org/10.3390/v14010045.
3. Terajima M, Vapalahti O, Van Epps HL, Vaheri A, Ennis FA. Immune responses to Puumala virus infection and the pathogenesis of nephropathia epidemica. Microbes and infection. 2004;6(2):238-45. https://doi.org/10.1016/j.micinf.2003.10.017.
4. Vaheri A, Smura T, Vauhkonen H, Hepojoki J, Sironen T, Strandin T, et al. Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome. Viruses. 2023;15(3). https://doi.org/10.3390/v15030805.
5. García M, Carrasco García A, Weigel W, Christ W, Lira-Junior R, Wirth L, et al. Innate lymphoid cells are activated in HFRS, and their function can be modulated by hantavirus-induced type I interferons. PLoS pathogens. 2024;20(7):e1012390. https://doi.org/10.1371/journal.ppat.1012390.
6. Sadeghi M, Eckerle I, Daniel V, Burkhardt U, Opelz G, Schnitzler P. Cytokine expression during early and late phase of acute Puumala hantavirus infection. BMC immunology. 2011;12(1):65. https://doi.org/10.1186/1471-2172-12-65.
7. Khaiboullina SF, Levis S, Morzunov SP, Martynova EV, Anokhin VA, Gusev OA, et al. Serum Cytokine Profiles Differentiating Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome. Frontiers in immunology. 2017;8:567. https://doi.org/10.3389/fimmu.2017.00567.
8. Baigildina AA, Khaiboullina SF, Martynova EV, Anokhin VA, Lombardi VC, Rizvanov AA. Inflammatory cytokines kinetics define the severity and phase of nephropathia epidemica. Biomarkers in medicine. 2015;9(2):99-107. https://doi.org/10.2217/bmm.14.88.
9. Maleki KT, Niemetz L, Christ W, Wigren Byström J, Thunberg T, Ahlm C, et al. IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS. PLoS pathogens. 2025;21(4):e1013042. https://doi.org/10.1371/journal.ppat.1013042.
10. Davoudi S, Yaghoubi A. Hantavirus Pathophysiology: Insights from Tissue and Cellular Perspectives. Nexus of Pathophysiology and Therapeutics (NPT). 2026;1(1): 004. https://doi.org/10.22034/npt.2026.1.004.
11. Sadeghi M, Lahdou I, Ettinger J, Navid MH, Daniel V, Zeier M, et al. Association of low serum TGF-β level in hantavirus infected patients with severe disease. BMC immunology. 2015;16:19. https://doi.org/10.1186/s12865-015-0085-0.
12. Azadi A. Endothelial Dysfunction and Immune Dysregulation in Hantavirus Infection: Mechanisms of Vascular Leakage and Disease Severity. Nexus of Pathophysiology and Therapeutics (NPT). 2026;1(1): 2026;1(1): 002. https://doi.org/10.22034/npt.2026.1.002.
13. Mäkelä S, Hurme M, Ala-Houhala I, Mustonen J, Koivisto AM, Partanen J, et al. Polymorphism of the cytokine genes in hospitalized patients with Puumala hantavirus infection. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2001;16(7):1368-73. https://doi.org/10.1093/ndt/16.7.1368.
14. Outinen TK, Mäkelä SM, Ala-Houhala IO, Huhtala HS, Hurme M, Paakkala AS, et al. The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC infectious diseases. 2010;10:132. https://doi.org/10.1186/1471-2334-10-132.
15. Charbonnel N, Pagès M, Sironen T, Henttonen H, Vapalahti O, Mustonen J, et al. Immunogenetic factors affecting susceptibility of humans and rodents to hantaviruses and the clinical course of hantaviral disease in humans. Viruses. 2014;6(5):2214-41. https://doi.org/10.3390/v6052214.
16. Libraty DH, Mäkelä S, Vlk J, Hurme M, Vaheri A, Ennis FA, et al. The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica. PloS one. 2012;7(4):e35402. https://doi.org/10.1371/journal.pone.0035402.
17. Mäkelä S, Mustonen J, Ala-Houhala I, Hurme M, Koivisto AM, Vaheri A, et al. Urinary excretion of interleukin-6 correlates with proteinuria in acute Puumala hantavirus-induced nephritis. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2004;43(5):809-16. https://doi.org/10.1053/j.ajkd.2003.12.044.  
18. Saksida A, Wraber B, Avšič-Županc T. Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome. BMC infectious diseases. 2011;11:142. https://doi.org/10.1186/1471-2334-11-142. 
19. Klingström J, Plyusnin A, Vaheri A, Lundkvist A. Wild-type Puumala hantavirus infection induces cytokines, C-reactive protein, creatinine, and nitric oxide in cynomolgus macaques. Journal of virology. 2002;76(1):444-9. https://doi.org/10.1128/jvi.76.1.444-449.2002.
20. Klingström J, Falk KI, Lundkvist A. Delayed viremia and antibody responses in Puumala hantavirus challenged passively immunized cynomolgus macaques. Archives of virology. 2005;150(1):79-92. https://doi.org/10.1007/s00705-004-0389-5. 
21. Lee GY, Kim WK, No JS, Yi Y, Park HC, Jung J, et al. Clinical and Immunological Predictors of Hemorrhagic Fever with Renal Syndrome Outcome during the Early Phase. Viruses. 2022;14(3). https://doi.org/10.3390/v14030595.
22. Strandin T, Mäkelä S, Mustonen J, Vaheri A. Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells. Frontiers in immunology. 2018;9:2098. https://doi.org/10.3389/fimmu.2018.02098.
23. Noack D, Travar M, Mrdjen V, Voermans JJC, van de Vijver D, Molenkamp R, et al. Serum Markers Associated with Disease Severity in a Bosnian Hemorrhagic Fever with Renal Syndrome Cohort. Viruses. 2022;14(7). https://doi.org/10.3390/v14071377.
24. Tuuminen T, Kekäläinen E, Mäkelä S, Ala-Houhala I, Ennis FA, Hedman K, et al. Human CD8+ T cell memory generation in Puumala hantavirus infection occurs after the acute phase and is associated with boosting of EBV-specific CD8+ memory T cells. Journal of immunology (Baltimore, Md : 1950). 2007;179(3):1988-95. https://doi.org/10.4049/jimmunol.179.3.1988.
25. Van Epps HL, Terajima M, Mustonen J, Arstila TP, Corey EA, Vaheri A, et al. Long-lived memory T lymphocyte responses after hantavirus infection. The Journal of experimental medicine. 2002;196(5):579-88. https://doi.org/10.1084/jem.20011255.
26. Borges AA, Campos GM, Moreli ML, Moro Souza RL, Saggioro FP, Figueiredo GG, et al. Role of mixed Th1 and Th2 serum cytokines on pathogenesis and prognosis of hantavirus pulmonary syndrome. Microbes and infection. 2008;10(10-11):1150-7. https://doi.org/10.1016/j.micinf.2008.06.006.
27. Khaiboullina SF, Martynova EV, Khamidullina ZL, Lapteva EV, Nikolaeva IV, Anokhin VV, et al. Upregulation of IFN-γ and IL-12 is associated with a milder form of hantavirus hemorrhagic fever with renal syndrome. European Journal of Clinical Microbiology & Infectious Diseases. 2014;33:2149 - 56. https://doi.org/10.1007/s10096-014-2176-x. 
Nexus of Pathophysiology and Therapeutics (NPT)
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