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Brain injury markers associated with dysregulated immunological responses in COVID-19

Jacob Scott

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The coronavirus disease 2019 (COVID-10) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to over 265 million documented COVID-19 cases and over 5.26 million deaths so far. In many cases, it has been found to be associated with neurological complications including stroke, delirium, Guillain-Barre syndrome, and autoimmune encephalitis. A new preprint describes the presence of inflammatory markers and autoantibodies in COVID-19 patients, and their correlation with brain injury.Study: Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity. Image Credit: Dusan Petkovic/Shutterstock


Background


Many patients with COVID-19 have neurological presentations, while a prolonged neuropsychiatric post-viral syndrome is also known to occur in up to a third of cases, even without very severe disease. While the actual incidence remains unknown, dysregulated inflammation appears to be a key aspect of severe COVID-19, and could be related to the neurological damage in this condition.


The current study, which appears on the medRxiv* preprint server, explores the changing status of serum markers of neurological damage and abnormal autoinflammatory/autoimmune responses in patients with COVID-19 The former includes neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau. In the second category are proinflammatory cytokines and autoimmune antibodies.


What did the study show?


We have demonstrated that markers of brain injury are associated with dysregulated immunological responses in COVID-19, and that there may be a separate late process irrespective of initial disease severity which is characterised by elevated serum total Tau concentrations and the presence of IgM autoantibodies.”


The researchers found that in patients hospitalized with COVID-19, both Nfl and GFAP were raised in proportion to the severity of illness. Even when examined four months later, patients continued to show evidence of continuing dysregulated immune responses, with Nfl levels still higher than normal, though reduced in magnitude compared to the acute stage of illness.


High levels of these markers were linked to higher pro-inflammatory cytokine measurements, as well as the presence of autoantibodies.


Besides this, another process of brain injury seems to have been set in motion, with total Tau protein levels being raised even in patients without initially severe COVID-19 or high levels of pro-inflammatory cytokines. Autoantibodies, mainly immunoglobulin M (IgM) to a number of targets were also observed, including the lung surfactant protein A1 and myelin-associated glycoprotein.


The latter was directed chiefly against lung surfactant and certain brain proteins like myelin-associated glycoprotein, but autoantibodies were also detected against a number of other antigens. Moreover, serum total Tau was found to be elevated in patients at follow-up, perhaps reflecting an ongoing neurological process. This did not correlate with disease severity in the initial COVID-19 episode, nor to the levels of GFAP or Nfl.


What are the implications?


The study observed a link between brain injury biomarkers and dysregulated innate and immune responses. When coupled with the fact that the most effective treatments for COVID-19 are those that target the inflammatory or immune response, the findings seem to be indicative of an underlying inflammatory-immune mechanism for neurologic damage, rather than direct brain invasion by the virus.


In fact, there is little experimental proof of such neuroinvasion. In contrast, the inflammatory damage hypothesis would be in agreement with the postulate that severe COVID-19 is due to uncontrolled inflammation and the resulting multi-system injury, rather than direct viral damage. The inflammation could be directed against the neurons themselves or against the cerebrovascular bed, the latter being associated with microvascular ischemic brain injury.


It seems that as the number of autoantibodies rises, it indicates a more general type of underlying immune activation. Furthermore, brain injury is related in the degree to the extent of immune activation rather than to the presence of specific brain tissue targets.


Of the various autoantibodies found in this condition, both polyreactive and specific antibodies have been identified, including those often associated with rheumatological disorders and the much more recently identified anti-interferon antibodies. The researchers suggest that in many cases they may be the result of tissue damage and may be involved in debris clearance. However, anti-interferon antibodies may also drive severe disease, while the formation of immune complexes could trigger a cascade of secondary cellular immune responses in COVID-19.


Conclusions


Blood Nfl levels were found to be correlated with the severity of acute COVID-19, and therefore predict a poorer outcome. An earlier study involving some of the same researchers showed that the Nfl and GFAP levels return to normal by six months, which may indicate that the raised levels of Nfl observed at four months in the current study were captured at the fag-end of this period of active brain injury.


The study observed, for the first time, an elevation in Tau protein level during the follow-up period. This protein is found to be raised in Alzheimer’s disease and frontotemporal dementia, and the degree of rise correlates with cognitive impairment in such patients. This finding needs to be confirmed by larger studies.


The most interesting part of this observation is its occurrence irrespective of the initial severity of the disease, which may indicate its potential as an easily measured biomarker of risk for the long-term neuropsychiatric syndromes of long COVID-19.


The late Tau protein elevation and the presence of IgM autoantibodies could mark a persistent abnormality of the immune response that is responsible for brain injury, especially directed against the neuronal dendrites and axons – since Tau is a protein found in these processes.


Finally, it is possible that the neurologic injury and immune-inflammatory markers observed here are not specific to COVID-19, but occur in all severe illnesses.


*Important notice


medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Needham, E. J. et al. (2021). Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity. medRxiv. doi: https://doi.org/10.1101/2021.12.03.21266112. https://www.medrxiv.org/content/10.1101/2021.12.03.21266112v1.

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Unraveling How Strigoractone Hormone Regulates Massive Gene Networks Controlling Plant Growth

Jacob Scott

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As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.

New research from Nitzan Shabek’s laboratory at the UC Davis College of Biological Sciences, published in Nature Plants, unravels the underlying mechanism of protein targeting and destruction in a specific plant hormone signaling pathway.

Our lab aims at deciphering sensing mechanisms in plants and understanding how specific enzymes function can be regulated at the molecular levels. We have been studying a new plant hormone signal, strigolactone, that governs numerous processes of growth and development including branching and root architecture.”

Nitzan Shabek, assistant professor of biochemistry and structural biology, Department of Plant Biology

The work stems from a study by Shabek, published in Nature in 2018, unravelling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that “tag” other proteins for destruction within a cell.

To find the key to unlock MAX2 and to better understand its molecular dynamics in plants, postdoctoral fellows Lior Tal and Malathy Palayam, with junior specialist Aleczander Young, used an approach that integrated advanced structural biology, biochemistry, and plant genetics.

“We leveraged structure-guided approaches to systemically mutate MAX2 enzyme in Arabidopsis and created a MAX2 stuck in an unlocked form”, said Shabek, “some of these mutations were made by guiding CRISPR/Cas9 genome editing thus providing us a discovery platform to study and analyze the different signaling outputs and illuminate the role of MAX2 dynamics.”


They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed – activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.

Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only target the repressors proteins, but once it is locked the strigolactone sensor itself gets destroyed, returning the system to its original state.

Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch.

“Beyond the implication in plants signaling, this is the first work that placed a primary metabolite as a direct new regulator of this type of ubiquitin ligase enzymes and will open new avenues of study in this direction,” Shabek said.

Additional coauthors on the paper are specialist Mily Ron and Professor Anne Britt, Department of Plant Biology. The study was supported by NSF CAREER and EAGER grants to Shabek. X-ray crystallography data was obtained at the Advanced Light Source, Lawrence Berkeley National Laboratory, a U.S. Department of Energy user facility.

Source:
Journal reference:

Tal, L., et al. (2022) A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature Plants. doi.org/10.1038/s41477-022-01145-7.

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UrFU Sociologists Identify Digital Fears Among Young People

Jacob Scott

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Sociologists at the Ural Federal University (UrFU) have identified digital fears among young people. According to experts, these are additional fears that do not replace, but complement and reinforce traditional ones. They emerged against the background of uncertainty, the growth of forces beyond human control. Developed emotional intelligence, creativity, and the ability to collaborate help to overcome them.

In the study, sociologists interviewed 1,050 people aged 18-30. Respondents were asked to assess which digital risks concern them most. The study was launched in 2020 and the results were published in April 2022 in the Changing Societies & Personalities journal.

The first group of fears is influence and control. It touches on the problem of interference with privacy by technical means. This category is the most significant for young people: 55.8% are afraid of total control by means of video-surveillance and monitoring software on their mobile devices. 48.5% of respondents believe they are at risk of wiretapping, tracking content in social networks, and inability to keep correspondence secret.”

Natalia Antonova, Professor, Department of Applied Sociology, UrFU

45.8% of young people fear the manipulative influence of the media and an increase in fake news. At the same time, only 27.8% and 18.1% of respondents are concerned about microchipping and genetic manipulation, respectively. It is likely that these threats seem more controllable, both from the individual (through control of food choices, medical procedures, etc.) and from government programs, the researchers believe.

The second group of concerns is crime and security. Here young people are wary of illegal actions using digital technology.

“One of the main fears of 56% of young people is the security of personal data. This is related both to the growth of personal information in social networks and messengers, and to the growth of hacker attacks and viruses. 42.9% of young citizens are afraid of Internet fraudsters, and 25.8% are afraid of losing important information, including smashing their phones, not saving data, forgetting their passwords, or being without an Internet connection,” explains Sofia Abramova, Associate Professor at the Department of Applied Sociology at UrFU.

The third group of fears is based on changes in the way and pace of life, ways of interaction. Thus, 28.4% of respondents indicate a constant lack of time, the acceleration of communications, and worries about not being able to complete all tasks in time. Respondents are also concerned about the growth of online communications and communications with electronic systems (bots, autoresponders, product systems, etc.).

“As a result, 15.3% of young people raise problems related to increasing social distrust against the background of increasing dependence of human life and health on other people and electronic systems: in public transport, planes, elevators, medical intervention,” explains Sofia Abramova.

Respondents also fear the negative consequences of technological development. For example, 22.2% of young citizens fear the robotization of labor processes and the displacement of humans by robots. 14.6% speak directly about negative emotions in relation to the expansion of artificial intelligence.

The fifth type of fear is social inequality. Young people negatively assess the growth of inequality in access to information resources and technology, the exclusion of citizens from the economy depending on the level of digital competence and education, and age. As a result, they fear that benefits will be distributed more and more unequally, both among the inhabitants of the country and between countries.

“It is noteworthy that young people are simultaneously afraid of total surveillance via phone and afraid of being left without mobile devices. Fears shape the irrational behavior of the digital generation, entailing serious transformations in everyday life,” says Natalia Antonova.

Source:
Journal reference:

Abramova, S.B., et al. (2022) Digital Fears Experienced by Young People in the Age of Technoscience. Changing Societies & Personalities. doi.org/10.15826/csp.2022.6.1.163.

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Study demonstrates increased incidence of SARS-CoV-2 Omicron breakthrough infection in cancer patients

Jacob Scott

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In a recently published article in the journal Cancer Cell, scientists have demonstrated the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients residing in Austria and Italy. The study reveals an induction in Omicron breakthrough infections in patients with hematologic and solid cancers.

Study: Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron. Image Credit: Lightspring/Shutterstock

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has been found to cause severe infections in immunocompromised patients, including cancer patients. Moreover, a relatively lower level of neutralizing antibodies in response to COVID-19 vaccines has also been observed in cancer patients, especially those receiving B cell-targeting therapies.

The emergence of SARS-CoV-2 variants with improved immune fitness, such as delta and Omicron variants, has caused a sharp increase in breakthrough infections even in fully vaccinated individuals. However, the vaccines still show high protective efficacy against severe and fatal infections. COVID-19 vaccines have shown acceptable efficacy against severe disease, even in Omicron-infected cancer patients. However, the isolation and quarantine measures associated with SARS-CoV-2 infection may impair the routine administration of anticancer therapy, which can reduce the survival prognosis in cancer patients.

In the current study, the scientists have assessed the incidence of SARS-CoV-2 infection in cancer patients throughout the pandemic.

Study design

The study included 3,959 cancer patients, of whom 77% had solid cancer, and 23% had hematologic cancer. About 69% of the patients did not receive any anticancer treatment at the time of COVID-19 vaccination. Regarding vaccine coverage, about 85% of the patients had received at least one vaccine dose, and 15% remained unvaccinated. The incidence of SARS-CoV-2 infection in these patients was assessed between February 2020 and 2022.

Important observations

SARS-CoV-2 infection was detected in about 24% of the patients during the study period. During the delta-dominated wave, vaccine breakthrough infection was observed in 43% of the patients. In contrast, a significantly higher percentage of breakthrough infection (70%) was observed among the patients during the Omicron-dominated wave. During both delta and Omicron waves, cancer patients receiving systemic anticancer treatment showed a significantly higher percentage of breakthrough infection than those not receiving treatment (83% vs. 56%).

Regarding disease severity irrespective of vaccination status, a higher frequency of COVID-19-related hospitalization was observed during the delta wave compared to that during the Omicron wave. However, a relatively shorter duration of hospital stay was observed in vaccinated patients compared to that in unvaccinated patients. In addition, only 9% of patients with breakthrough infections were admitted to the intensive care unit (ICU). This highlights the protective efficacy of COVID-19 vaccines against severe disease.

Humoral immune response to vaccination

To determine vaccine-induced antibody response against delta and Omicron variants, the scientists measured blood levels of anti-delta and anti-Omicron spike receptor-binding domain (RBD) antibodies in a total of 78 cancer patients. In the analysis, they also included 25 healthcare workers as controls.

In response to vaccination, healthcare workers showed higher levels of total anti-spike antibodies compared to cancer patients. The lowest level of wildtype RBD-specific antibodies was observed in hematologic cancer patients receiving B cell-targeted treatment, followed by hematologic cancer patients not receiving B cell-targeted treatment and patients with solid tumors. A similar trend was observed for delta- and Omicron-specific spike RBD antibodies.

The serum samples collected from hematologic cancer patients without B cell-targeted treatment and solid tumor patients significantly inhibited the interaction between wildtype/delta RBD and angiotensin-converting enzyme 2 (ACE2; host cell receptor for viral entry). However, a significantly lower level of inhibition was observed for patients receiving B cell-targeted treatment. Importantly, a marked reduction in inhibition of Omicron RBD – ACE2 interaction was observed for all patients with solid tumors and hematologic cancer.

Study significance

The study demonstrates an increased incidence of vaccine breakthrough infections but a reduced disease severity among patients with solid tumors and hematologic cancer during the Omicron wave compared to the delta wave.

The study also highlights that COVID-19 vaccine-induced antibody response is lower in cancer patients than in healthy individuals. The reduction in antibody response is highest among hematologic patients receiving B cell-targeted treatment. Overall, a significant impairment in vaccine-induced Omicron neutralization has been observed in cancer patients.

Journal reference:
Mair, M. et al. (2022) “Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron”, Cancer Cell. doi: 10.1016/j.ccell.2022.04.003. https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00165-9

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