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Usutu-Infected Blackbird Brains Showed Strong Activation of Programmed Cell Death

Adult male Eurasian blackbird perched on a wooden post
Research · Disease, parasites & microbiology

Brains from naturally infected Eurasian blackbirds (Turdus merula) showed strong activation of programmed cell death during Usutu virus infection. A study published in the Journal of NeuroVirology on 2 March 2026 found evidence for both major apoptosis pathways, with the extrinsic pathway showing the stronger response.

Usutu virus is a mosquito-borne flavivirus that circulates mainly between birds and mosquitoes. Eurasian blackbirds are particularly susceptible to severe disease, including inflammation and damage in the central nervous system. The study examined molecular processes involved in that brain damage in naturally infected birds.

Apoptosis is a controlled form of programmed cell death. Its intrinsic pathway begins with damaging signals inside the cell, including mitochondrial damage, and activates caspase 9. The extrinsic pathway begins with external death signals acting through receptors on the cell surface and activates caspase 8. Both routes can then activate caspase 3, one of the enzymes that carries out the final dismantling of the cell.

Infected and Uninfected Blackbird Brains Were Compared

The researchers compared brain tissue from 26 blackbirds infected with Usutu virus and 16 uninfected birds submitted to the Dutch Wildlife Health Centre. Both the Africa 3 and Europe 3 virus lineages were represented among the infected birds. In brain tissue they looked for cleaved caspase-3, which shows that caspase 3 has been activated, and used a TUNEL assay to detect the fragmented DNA characteristic of apoptosis. They also measured expression of caspase 8 and caspase 9 to compare activation of the extrinsic and intrinsic pathways.

Infected Birds Showed Much More Apoptosis

Usutu-infected blackbirds had many more cleaved-caspase-3-positive cells than uninfected birds. A TUNEL assay of a smaller subset showed the same pattern for DNA fragmentation. Virus antigen and cleaved caspase-3 partly overlapped in the tissue, and areas with more virus-positive cells also tended to contain more cleaved-caspase-3-positive cells.

The affected cells had morphology consistent with neurons, glial cells and endothelial cells. Cleaved-caspase-3-positive cells were also found beyond areas where virus antigen was detected, which the authors say suggests that both direct infection and indirect processes may contribute to cell death.

Microscopic brain sections and graphs comparing apoptosis markers in Usutu-infected and uninfected blackbirds
TUNEL and cleaved-caspase-3 staining and cell counts in Usutu-virus-infected and uninfected blackbirds. Figure 1 from Giglia et al. (2026), Journal of NeuroVirology, CC BY 4.0.

The Extrinsic Pathway Showed the Stronger Response

Both caspase 8 and caspase 9 were upregulated in infected blackbirds. Caspase 8 expression was about 4.4 times higher than in uninfected birds, while caspase 9 expression was about 1.8 times higher. The stronger increase in caspase 8 supports a particularly important role for the extrinsic apoptosis pathway in Usutu-associated encephalitis.

The study detected no clear differences in the measured apoptosis responses between birds infected with the Africa 3 and Europe 3 virus lineages. The authors conclude that caspase-dependent apoptosis is involved in Usutu-associated encephalitis in naturally infected blackbirds. They note that the identities of affected cell types were inferred from morphology because suitable blackbird-specific cellular markers were unavailable, and direct co-localisation of virus antigen and cleaved caspase-3 within the same cells could not be tested with the antibodies used.

Sources and image credit

  1. Giglia, G., Agliani, G., Oude Munnink, B. B., Sikkema, R. S., Mandara, M. T., Fast, C., Gosens, M., Schrauwen, E. J. A., de Bruin, E., Gröne, A., & van den Brand, J. M. A. (2026). Neuropathogenesis of Usutu virus-associated disease in Eurasian blackbirds (Turdus merula) involves apoptosis through the extrinsic pathway. Journal of NeuroVirology, 32(2), 9. https://doi.org/10.1007/s13365-025-01302-6Primary peer-reviewed open-access study published and version of record dated 2 March 2026 under CC BY 4.0. The study compared brains from 26 Usutu-virus-infected and 16 uninfected Eurasian blackbirds and found significantly increased apoptosis markers, with stronger upregulation of caspase 8 than caspase 9.

Image: Stuutje1979 — adult male Eurasian blackbird; Wikimedia Commons; representative species image, not one of the study birds · CC BY-SA 3.0 · Source

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