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Polyamine depletion inhibits norovirus infection by blocking virus-induced apoptosis

Maryna Chaika, Heike Laschin, Marina Pekelis, Carmen Mirabelli, Sandra Niendorf, Christiane E. Wobus, Stefan Taube

Posted on: 2 October 2025 , updated on: 6 October 2025

Preprint posted on 14 September 2025

Stopping norovirus at the gate: Polyamines as a possible new lead for therapeutics against norovirus

Selected by Leonie Brüne

Categories: immunology, microbiology, molecular biology

Background

Acute Gastroenteritis (AGE) is a disease caused primarily by Human norovirus (HNoV), an icosahedral positive sense-single-stranded RNA virus [1]. Virus infection affects approximately 685 million people worldwide annually, particularly severe in elderly people, children, and immunocompromised individuals [2]. The virus is transmitted from person to person, whereby healthcare facilities, schools, as well as cruise ships demonstrate common hotspots for outbreaks [3]. Despite considerable scientific interest in a vaccine or pre- and post-infection treatment, the development of suitable drugs remains unsuccessful due to the wide genetic range of the virus [4].

Due to poor system models, therapeutic strategies for norovirus infections remain limited. One of the most promising models for studying the virus is the murine norovirus (MNV), which is the only norovirus species that can be cultivated. During early infection by MNV, the intrinsic apoptosis pathway of host cells is modulated by activation of the Pi3K/Akt signalling pathway, resulting in prolonged cell survival and therefore enhanced virus replication [5].

To ensure a rapid infection cycle in the host cell, viruses rely on cofactors, including polyamines (PAs). Representatives of PAs include putrescine, spermidine, or spermine, which are small, polycationic metabolites derived from amino acid metabolism. Reduction of intracellular PA levels decreases the activation of the apoptotic machinery, as shown by reduced expression of caspase and proapoptotic regulators Bax/Bad, thereby promoting resistance against intrinsic apoptotic stimuli. Since studies performed on other viruses have already demonstrated that the availability of PAs has a demonstrable influence on the replication cycle of the virus, the question remains whether norovirus also falls into this category, potentially uncovering a new target for therapeutic agents.

The paper highlighted here shows that norovirus is also one of the viruses that are PA-dependent, demonstrating that depletion of PAs prevents virus induced cell apoptosis.

Key Findings

Experiments were conducted in immune and epithelial cell types.

PA depletion facilitates reduced infection rate with MNV-1 in various cell lines reversibly: The infection potential of MNV-1 was reduced by increased degradation of PAs spermidine and spermine, triggered by the addition of N¹,N¹¹-diethylnorspermine, an activator of spermine/spermidine N¹-acetyltransferase 1 (SAT1). By adding the inhibitor difluoromethylornithine (DFMO), the synthesis of PAs is slowed down, resulting in reduced levels. This demonstrated a significant inhibition of MNV infection. Addition of spermine or spermidine could restore the infection potential.

Reduced PA levels decrease MNV-1 virion release: Cells were treated with DFMO four days prior to the actual infection in order to draw conclusions about a possible release phenotype. It was shown that PAs are relevant in the early stages of infection and that depletion of PAs results in reduced virion release.

PA depletion demonstrates positive effect on cell apoptosis of infected cell lines: MNV-1 infection led to a loss of uncleaved PARP, a marker for cell apoptosis. In PA depleted cell lines, no virus-induced loss of PARP occurred 24 hpi, suggesting apoptosis inhibition. Thereby, induced cell death is mediated via the PI3K/Akt signalling pathway, as LY294002, an inhibitor of PI3K, restores apoptosis in PA-depleted cells.

Why I highlight this work

Noroviruses are not among the viruses commonly discussed in the media because they have to compete with epidemiologically much stronger pathogens such as SARS-Cov2, Ebola, and measles, especially in America, which does not detract them from their clinical relevance.

Nevertheless, research into noroviruses is important, as shown by the increasing incidence of cases in the US [6], in order to generate reliable active substances for both treatment and prevention of infection. The paper highlighted in this post paves the way for possible therapeutic approaches by analysing the role of PAs in the context of a norovirus infection. I find the use of the inhibitor DFMO particularly promising, which is currently already in clinical trials for the treatment of trypanosomosis, so why not also for norovirus? As the paper has shown, the use of the inhibitor and the associated depletion of PAs leads to reduced virion release and reduced cell apoptosis, interesting and promising especially for patients with chronic norovirus infection or for prevention in hotspot regions. It will be interesting to see whether PAs can play a key role in the discovery of new drugs for the treatment of noroviruses.

I am certainly no expert in the field of virology, but I would also recommend this article to people who have found their profession in other areas. Thanks to its rigorous guidance through the experimental setups, observations, and analyses, the article is easy to read and follow, even for someone who is not a luminary on norovirus but certainly wants to broaden one’s horizon.

Future Direction

Even though this paper demonstrates the positive effect of PA depletion on viral infection, the mechanistic mode of action of PAs and the mechanistic utilization of PAs by the virus remain unknown. Further analyses could therefore focus in particular on PA in the context of viral protein translation and virus assembly. Furthermore, it is essential to investigate the effect of PAs in in vivo studies, especially if the focus of the work is to be on a therapeutic approach.

References

[1] Burke, R. M. & Hall, A. J. in Norovirus Vol. 1 (ed Melhem, N. M.) Ch. 1–29 (Springer Nature Switzerland AG, 2021)
[2] Atmar RL. Noroviruses: state of the art. Food Environ. Virol. 2010;2:117–126. doi: 10.1007/s12560-010-9038-1.
[3] Carlson, K. B., Dilley, A., O’Grady, T., Johnson, J. A., Lopman, B., & Viscidi, E. (2024). A narrative review of norovirus epidemiology, biology, and challenges to vaccine development. NPJ vaccines, 9(1), 94. https://doi.org/10.1038/s41541-024-00884-2
[4] Tan M. (2021). Norovirus Vaccines: Current Clinical Development and Challenges. Pathogens (Basel, Switzerland), 10(12), 1641. https://doi.org/10.3390/pathogens10121641
[5] Owusu IA, Passalacqua KD, Mirabelli C, Lu J, Young VL, Hosmillo M, Quaye O, Goodfellow I, Ward VK, Wobus CE. 2022. Akt Plays Differential Roles during the Life Cycles of Acute and Persistent Murine Norovirus Strains in Macrophages. J Virol 96:e0192321.
[6] https://www.cdc.gov/norovirus/php/reporting/norostat-data.html ata | Norovirus | CDC (Last visited: 24.09.2025)

Tags: infection, virology

doi: https://doi.org/10.1242/prelights.41519

Read preprint (1 votes)

Author's response

Maryna Chaika and Stefan Taube shared

How can you rule out that the observed inhibition is not due to nonspecific cellular stress response?

DFMO and DENSpm are generally considered safe and well-tolerated compounds. Both compounds have been tested in multiple clinical trials, with minimal safety concerns reported by participants (Meyskens et al. 1994, J Natl Cancer Inst; Horn et al. 1987, Eur J Cancer Clin Oncol). In academic research, these drugs are also well characterized in terms of their cytotoxic profiles and effective concentrations.

To investigate the effects of DFMO and DENSpm against murine norovirus, we first performed dose titrations to determine effective concentrations for subsequent experiments. As expected, the concentrations we identified were consistent with those reported in previous studies on the antiviral activity of polyamine-depleting drugs (Mounce et al. 2017, Microbiol Mol Biol Rev).

To assess potential adverse effects, we evaluated metabolic activity and membrane integrity in both immortalized cells and 3D human intestinal enteroids treated with DFMO or DENSpm, or subjected to polyamine depletion. We observed no significant cytotoxicity following treatment. Apart from published data, our additional experiments showed that DFMO-treated cells remained capable of exogenous proteins synthesis, confirming that DFMO does not induce substantial cellular stress or impair overall cell health.

Do you see polyamide depletion as a realistic therapeutic strategy or rather as a tool to identify new antiviral targets?

Norovirus disease is an acute, self-limiting illness. While the symptoms can be quite severe and unpleasant, the disease usually resolves within 2–3 days in healthy individuals. This leaves only a narrow window for pharmacological intervention. However, in immunocompromised patients, norovirus can lead to chronic infection, with symptoms persisting for months. For these individuals, therapeutic options are limited. Traditional treatments such as nitazoxanide, ribavirin, and immunoglobulins, have shown inconsistent efficacy. Especially, with the effectiveness of nitazoxanide and ribavirin being questioned in the research community (Lewis et al. 2023, Antimicrob. Agents Chemother; González‑Morcillo et al. 2022, Clin Res Hepatol Gastroenterol).

Although polyamine depletion requires a relatively long timeframe (3–4 days) to take effect, we believe it may be a viable therapeutic strategy for chronically infected patients. Such individuals could undergo treatment for sufficient time for DFMO to exert its antiviral effects and, if needed, they could even receive long-term therapy, as DFMO has been reported to be safe and well tolerated for periods of up to three months (Meyskens et al. 1994, J Natl Cancer Inst). Importantly, DFMO is already approved for clinical use in both USA and Europe for the treatment of trypanosomiasis, which opens a possibility of its off-label use.

All above-mentioned facts and confirmed effectiveness of DFMO in reduction of polyamine levels in gastrointestinal mucosa (Meyskens et al. 1998, J Natl Cancer Inst), supporting polyamine depletion as a realistic therapeutically strategy for chronic norovirus infections.

Do you think polyamide depletion could be combined with already established antiviral agents to observe possible additive effects?

Among the currently available antiviral options for chronic norovirus infection, such as immunoglobulins, nitazoxanide and ribavirin, only immunoglobulins have support in the literature as an effective treatment (van Kampen et al. 2022, J Infect Dis; Chung et al. 2024, Am J Gastroenterol; Buskandar et al. 2025, Am J Transplant). Combining immunoglobulins with polyamine depletion therapy may represent a promising strategy to quicken symptom resolution in patients. However, the potential additive effect of such a combination would need to be confirmed through controlled studies.

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