Virus World

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 is 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 the dorsal medulla and in the substantia nigra of five 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 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.

Published (Feb. 13, 2023) in npj Parkinson's Disease:

https://doi.org/10.1038/s41531-023-00467-3 

Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, the Omicron BA.1 variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5 has now started to dominate globally, with the potential to supplant BA.2. To address the relative threat of BA.5, we determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a well characterised, genetically engineered ACE2/TMPRSS2 cell line.

We then assessed the impact of BA.5 infection on humoral neutralisation in vitro, in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. The infectivity of virus in primary swabs and expanded isolates revealed whilst BA.1 and BA.2 are attenuated through ACE2/TMPRSS2, BA.5 infectivity is equivalent to that of an early 2020 circulating clade and has greater sensitivity to the TMPRSS2 inhibitor Nafamostat. As with BA.1, we observed BA.5 to significantly reduce neutralisation titres across all donors. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 7-fold with BA.5. Of all therapeutic antibodies tested, we observed a 14.3-fold reduction using Evusheld and 16.8 reduction using Sotrovimab when neutralising a Clade A versus BA.5 isolate. These results have implications for ongoing tracking and management of Omicron waves globally.

Preprint available in medRxiv (JUly 10, 2022):

https://doi.org/10.1101/2022.07.07.22277128 

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures. 

Published in Nature Comm. (Dec. 12, 2022):

https://doi.org/10.1038/s41467-022-35225-1 

New research helps explain why long COVID can occur in people who had mild or asymptomatic COVID-19 cases.  The coronavirus that causes COVID-19, SARS-CoV-2, can spread within days from the airways to the heart, brain and almost every organ system in the body, where it may persist for months, a study found. In what they describe as the most comprehensive analysis to date of the virus’s distribution and persistence in the body and brain, scientists at the U.S. National Institutes of Health said they found the pathogen is capable of replicating in human cells well beyond the respiratory tract. The results, released online Saturday in a manuscript under review for publication in the journal Nature, point to delayed viral clearance as a potential contributor to the persistent symptoms wracking so-called long COVID sufferers. Understanding the mechanisms by which the virus persists, along with the body’s response to any viral reservoir, promises to help improve care for those afflicted, the authors said. “This is remarkably important work,” said Ziyad Al-Aly, director of the clinical epidemiology center at the Veterans Affairs St. Louis Health Care System in Missouri, who has led separate studies into the long-term effects of COVID-19. “For a long time now, we have been scratching our heads and asking why long COVID seems to affect so many organ systems. This paper sheds some light, and may help explain why long COVID can occur even in people who had mild or asymptomatic acute disease.” The findings haven’t yet been reviewed by independent scientists, and are mostly based on data gathered from fatal COVID cases, not patients with long COVID or “post-acute sequelae of SARS-CoV-2,” as it’s also called.

Contentious Findings

The coronavirus’s propensity to infect cells outside the airways and lungs is contested, with numerous studies providing evidence for and against the possibility.  The research undertaken at the NIH in Bethesda, Maryland, is based on extensive sampling and analysis of tissues taken during autopsies on 44 patients who died after contracting the coronavirus during the first year of the pandemic in the U.S.  The burden of infection outside the respiratory tract and time to viral clearance isn’t well characterized, particularly in the brain, wrote Daniel Chertow, who runs the NIH’s emerging pathogens section, and his colleagues. The group detected persistent SARS-CoV-2 RNA in multiple parts of the body, including regions throughout the brain, for as long as 230 days following symptom onset. This may represent infection with defective virus, which has been described in persistent infection with the measles virus, they said.  In contrast to other COVID autopsy research, the NIH team’s post-mortem tissue collection was more comprehensive and typically occurred within about a day of the patient’s death. 

Culturing Coronavirus

The NIH researchers also used a variety of tissue preservation techniques to detect and quantify viral levels, as well as grow the virus collected from multiple tissues, including lung, heart, small intestine and adrenal gland from deceased COVID patients during their first week of illness. “Our results collectively show that while the highest burden of SARS-CoV-2 is in the airways and lung, the virus can disseminate early during infection and infect cells throughout the entire body, including widely throughout the brain,” the authors said. The researchers posit that infection of the pulmonary system may result in an early “viremic” phase, in which the virus is present in the bloodstream and is seeded throughout the body, including across the blood-brain barrier, even in patients experiencing mild or no symptoms. One patient in the autopsy study was a juvenile who likely died from unrelated seizure complications, suggesting infected children without severe COVID-19 can also experience systemic infection, they said.

Immune Response

The less-efficient viral clearance in tissues outside the pulmonary system may be related to a weak immune response outside the respiratory tract, the authors said.  SARS-CoV-2 RNA was detected in the brains of all six autopsy patients who died more than a month after developing symptoms, and across most locations evaluated in the brain in five, including one patient who died 230 days after symptom onset. The focus on multiple brain areas is especially helpful, said Al-Aly at the Veterans Affairs St. Louis Health Care System.  “It can help us understand the neurocognitive decline or ‘brain fog’ and other neuropsychiatric manifestations of long COVID,” he said. “We need to start thinking of SARS-CoV-2 as a systemic virus that may clear in some people, but in others may persist for weeks or months and produce long COVID -- a multifaceted systemic disorder.”

Preprint (Dec. 20, 2021) of the research cited available at:

https://assets.researchsquare.com/files/rs-1139035/v1_covered.pdf?c=1640020576