bioRxivNeurosciencePreprint
Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes
Madeline G. AndrewsiD, Tanzila MukhtariD, Ugomma C. EzeiD, Camille R. SimoneauiD, Yonatan PereziD, Mohammed A. Mostajo-RadjiiD, Shaohui WangiD, Dmitry VelmesheviD, Jahan Salma, G. Renuka KumariD, Alex A. PolleniD, Elizabeth Erin CrouchiD, Mélanie OttiD, Arnold R. KriegsteiniD
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.
Abstract summary
Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-NC-ND 4.0
In primary human cortical tissue and stem cell-derived organoids, SARS-CoV-2 infects astrocytes almost exclusively, apparently through DPP4 rather than ACE2, leaving them reactive and stressed.
A sizeable fraction of COVID-19 cases come with neurological symptoms, yet it was unclear whether cortical cells are infected directly, particularly as they carry little ACE2. This work points to astrocytes as the susceptible cortical population and to DPP4 as an alternative entry route, offering a candidate cellular mechanism for the injury.
Key results
SuggestedAcross both model systems, infection concentrated in cortical astrocytes while other cortical cell types were largely spared.
Reported as significant, predominant astrocyte infection in primary human cortical tissue and in cortical organoids, with minimal infection elsewhere; no infection rates or statistics are given in the abstract. · Abstract
SuggestedAstrocytes carry candidate entry receptors other than ACE2, and blocking one of them cut infection.
Cortical cells including astrocytes show minimal ACE2, while infected astrocytes carry DPP4 and CD147 (described as alternative coronavirus receptors) at high levels; DPP4 inhibition lowered infection and reduced the stress marker ARCN1. No effect sizes are reported. · Abstract
SuggestedInfection pushed astrocytes towards a reactive, stressed phenotype.
Infected astrocytes showed raised reactivity characteristics, growth factor signaling and cellular stress, summarised by the authors as reactive gliosis-type injury; no quantification appears in the abstract. · Abstract
Methods, data and reproducibility
Primary human cortical tissue and stem cell-derived cortical organoids were exposed to SARS-CoV-2 and scored for which cell populations became infected. Receptor levels (ACE2, DPP4, CD147) and reactivity and stress markers were assessed in infected astrocytes, and DPP4 was inhibited to test whether it mediates entry.
- Primary human cortical tissue used for infection experiments · human
- Stem cell-derived cortical organoids used for infection experiments · human
- Methods & tools
- SARS-CoV-2, stem cell-derived cortical organoids
Limitations (2)
- No infection rates, cell counts or statistics appear in the abstract, so the size of the astrocyte preference and of the DPP4-inhibition effect cannot be judged. · noted in this summary
- The case for DPP4 as the entry route rests on receptor levels plus one pharmacological inhibition; no genetic knockout, and no parallel test of CD147, is reported here. · noted in this summary
Read this if you work on SARS-CoV-2 neurotropism, human cortical organoid models or astrocyte reactivity, and want a candidate ACE2-independent entry route to follow up.
- Citations
- 49
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