Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection, 2026, Verma et al.

[SNT Gatchaman]

Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection

Spoiler: Authors

Verma, Abhishek Kumar; Tan, Lu; Schuster, Noah; Moye, Skyler L; Lin, Li-Chun; Lowery, Shea; Duraisami, Eazhisaivallabi; Lloréns, Juan E Abrahante; Qiu, Qiang; Hefti, Marco; Meyerholz, David K; Coleman, Mitchell C; Yu, C Ron; Albers, Mark W; Perlman, Stanley

Post-acute sequelae of COVID-19 (PASC) encompasses persistent neurological disease, including olfactory and cognitive dysfunction. The basis for this dysfunction is poorly understood.

Here, we report neurological dysfunction for at least 120 d postinfection in mice infected with a virulent nonneurotropic mouse-adapted SARS-CoV-2. Long after recovery from nasal infection, we observed diminished tyrosine hydroxylase expression in olfactory bulb glomeruli and in substantia nigra.

Similar changes were observed in brains of COVID-19 deceased patients. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased proinflammatory cytokines, and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, similar to human neurodegenerative diseases.

Treatment with antivirals (nirmatrelvir and molnupiravir) at the time of infection minimally prevented neurological abnormalities, consistent with patient data. In contrast, antivirals plus corticosteroids resulted in nearly complete recovery of neurological function. Remarkably, initiation of combined therapy even three days after infection improved outcomes.

Together these results demonstrate that neurological dysfunction in SARS-CoV-2 infected mice resembles human neurodegenerative disease and indicate that minimizing inflammation early after SARS-CoV-2 infection may be critical for decreasing neurological PASC. The requirement for decreasing inflammation soon after infection may also explain why antiviral therapy has had inconsistent effects in patients.

SIGNIFICANCE
Persistent neurological disease after COVID-19 is a major problem, yet the underlying mechanism is unclear. Using mouse-adapted SARS-CoV-2, we show that infection confined to the respiratory tract triggers long-lasting loss of dopaminergic neurons in the olfactory bulb and substantia nigra, mirroring pathology in COVID-19 decedents. These deficits arise without viral persistence but with sustained microglial activation and inflammatory gene expression resembling human neurodegenerative disease. Behavioral analyses reveal corresponding neurobehavioral impairments. Antiviral therapy alone fails to prevent most of these effects, whereas combining antivirals with corticosteroids, even when initiated three days after infection, restores behavioral function. These findings identify inflammation as the major driver of post-COVID neurological sequelae and suggest early immunomodulation as an effective intervention.


Web | DOI | PDF | Proceedings of the National Academy of Sciences | Paywall

 

[SNT Gatchaman]

Here, we show that many of the features of neurological PASC are also present in mice infected with sublethal amounts of mouseadapted SARS-CoV-2. We show that biochemical and behavioral changes persist in the mouse brain for several months after infection in the absence of infectious virus or viral RNA or protein.

We found vulnerability of dopaminergic cells in the OB [Olfactory Bulb] and SN [Substantia Nigra], two areas in the brain that are prominently affected in human neurodegenerative disease.

Most importantly, we showed that ameliorating the inflammatory response with corticosteroids in conjunction with antiviral therapy soon after infection, is effective in diminishing neurological PASC in mice, while neither modality by itself is as effective. Thus, an effective therapeutic strategy to decrease PASC development may involve dampening the immune response very soon after the infection is initiated.

Infectious virus and viral RNA and protein cannot be detected in the murine olfactory mucosa at later times after infection but IFN-I and ISGs are upregulated, consistent with studies of late-stage human COVID-19.

Collectively, these results indicate that, whether or not neurological disease is triggered by sustentacular cell infection, continued infection of the OE [Olfactory Epithelium] is not required for persisting dysfunction.

We show that microglial activation, a known marker of neuroinflammation, was observed in the OB and elsewhere in the SARS-CoV-2-infected brain, in agreement with previous results. […] While the basis of microglia activation is not known with certainty, systemic inflammation is known to activate microglia in the CNS, leading to their transition to a proinflammatory state and if persistent, could contribute to the progression of CNS disorders and neurodegenerative diseases.

There is precedent for respiratory virus infection contributing to neurological disease. In specific, the 1918 influenza pandemic led to a significant increase in neurological disease, including an increase in numbers of cases of PD.

 

[Utsikt]

Is that another blow to the viral persistence hypothesis because it isn’t necessary to get continued ill health?