[Preprint] COVID-19 Neuropathology: evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei, 2022, Emmi et al

[SNT Gatchaman]

COVID-19 Neuropathology: evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei
Aron Emmi, Stefania Rizzo, Luisa Barzon, Michele Sandre, Elisa Carturan, Alessandro Sinigaglia, Silvia Riccetti, Mila della Barbera, Rafael Boscolo-Berto, Patrizia Cocco, Veronica Macchi, Angelo Antonini, Monica De Gaspari, Cristina Basso, Raffaele De Caro, Andrea Porzionato

Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it’s still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms.

Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia / respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in specific brainstem nuclei of 5 COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2, the role of SARS-CoV-2 neurotropism in COVID-19 and its long-term sequelae require further investigation.

BioRxiv | PDF (preprint)

 

[SNT Gatchaman]

Postmortem study during the Italian first wave. Matched controls (mostly pre-pandemic, and/or deemed Covid-19 neg). Cases and controls died of pneumonia / respiratory failure.

The main cause of death in COVID-19 subjects was diffuse alveolar damage. Twenty-four COVID-19 patients were included in our study. [...] Eleven were females, while 13 were males. The mean age of the included subjects was 73±13.7 years. Most included subjects were affected by preexisting chronic medical conditions. Eleven patients (7 female, 4 male) were affected by neurological or neurodegenerative disease prior to SARS-CoV-2 infection.

The main cause of death of the control cohort was respiratory failure and pneumonia, aside from other relevant comorbidities. Eighteen age- and sex-matched subjects with comparable ante-mortem medical conditions were included as controls. All patients were negative for SARS-CoV-2 infection or died prior to the COVID-19 pandemic in Italy. Eight were female, while 10 were male. The mean age of included controls was 72±12 years. The mean hospitalization time was 20±15.6 days. Thirteen patients died due to pneumonia, while the remaining subjects died due to respiratory insufficiency, multiorgan failure or ischaemic heart disease. One patient died due to septic shock. Five patients had a clinical diagnosis of cognitive decline.

Highlighted limitation (presume they mean pre-hospitalisation neurological status):

However, as most subjects died during the sanitary emergency of the first wave of the COVID-19 pandemic in Italy, ante-mortem clinical data were at times limited, especially when concerning post-hospitalization neurological status. This represents one of the main limitations of our study, determining significant constrains to the association between antemortem neurological findings and encountered neuropathological alterations, which is often not unequivocal.

 

[SNT Gatchaman]

Some quotes that stood out to me —

SARS-CoV-2 Viral proteins were detected in neurons of the medulla and midbrain in a subset of COVID-19 subjects, but not in controls.

immunoreactive neurons within the anatomically defined boundaries of the solitary tract nucleus, dorsal motor nucleus of the vagus, nucleus ambiguus and substantia nigra

Viral antigens are associated to higher microglial densities within affected anatomical loci, but no differences are found in overall microgliosis, suggesting a specific topographical response.

Indeed, subjects with detectable viral genomic sequences and antigens (RT-PCR+/IHC+) were characterized by higher microglial densities in the medullary (p=0.017) and midbrain tegmentum (p=0.0074) when compared to negative (RT-PCR-/IHC-) COVID-19 subjects

this finding suggests a peculiar microglial response towards anatomical loci of the brainstem in which SARS-CoV-2 antigens were detected

SARS-CoV-2 viral antigens, on the other hand, were confined to specific loci of the CNS [...] appears to be localized preferentially within neurons of the vagal nuclei of the medulla and the substantia nigra

ACE2 Receptor and TMPRSS-2 protein immunohistochemistry support this topographical localization, with neurons within the dorsal motor nucleus of the vagus, solitary tract nucleus, nucleus Ambiguus and Substantia Nigra being moderately immunoreactive

SARS-CoV and MERS-CoV, which are known to be able to infect the brainstem, and particularly the dorsal motor nucleus of the vagus, solitary tract nucleus and nucleus ambiguus.

Additionally —

CNS platelet-enriched microthrombi in small parenchymal vessels were detected in COVID-19 subjects, but not in controls. Small vessel thromboses were detected in 9 COVID-19 patients at the level of the pons, deep cerebellar nuclei and cerebral cortex, with one patient presenting small vessel thromboses in multiple sites. No CNS or systemic thromboses were detected in controls. In all COVID-19 cases, CD61 immunoperoxidase staining revealed platelet-rich microthrombi

In 3 out of 9 cases, microthromboses were identified only within the CNS, while in the remaining 6 subjects, pulmonary thromboses were also detected. Interestingly, 3 out of 9 subjects with CNS microthrombi were on antithrombotic medication.

CNS microthromboses appear to be peculiar to the COVID-19 cohort, with no control subject presenting either fibrin- or platelet-enriched microthrombi in the CNS or other organs regardless of the cause of death.

Platelet and fibrin microthrombi, in particular, were characteristic findings of the COVID-19 cohort, and often affected multiple organs, such as the lungs, liver, intestine, hypopharynx and even the carotid body

 

[SNT Gatchaman]

And, of course, this paragraph represents "a bit of a worry" for the long, long tail of long Covid (cf post-polio syndrome) —

SARS-CoV-2 may gain access to other districts of the CNS either through a yet-unknown neuronal route or, as suggested by our findings in the midbrain and as seen in Schwabeland et al.’s study, by crossing the blood-brain-barrier and infecting structures of the peri- and juxtavascular compartment. We believe these findings encourage further research on the possibility that these events may be the trigger of a neurodegenerative process such as Parkinson disease in susceptible individuals. Future studies on COVID-19 survivors and Long COVID patients are therefore warranted.

 

[alex3619]

I have long wondered if ME could be triggered not so much by certain pathogens but by pathogens getting into critical areas, one of which is the brain. It could be strongly symptomatic (encephalitis, meningitis etc.) or largely asymptomatic, but the immune system might enact emergency measures it does not normally do. The latest hypothesis that fits this, still unproven, is the Itaconate shunt hypothesis.

So a virus in heart, brain or eyes, the latter two being immune privileged areas, could trigger a deep antipathogen response.

I also like that the Itaconate shunt is looking at innate immunity, not acquired immunity. We do not look at that nearly enough in my opinion. I have long wondered what innate immune responses occur to the higher quantities of lipopolysaccharides sometimes found in ME patient blood.

Viral presence in the brain would be exactly this kind of thing. Not nearly enough for proof of course, but a start.

 

[SNT Gatchaman]

Interestingly, although immunosuppression is required for cardiac transplants, heart valves are immune privileged, although that doesn't prevent rheumatic heart disease of course.