Tag: SARS-CoV-2

COVID-19 exposes deep-rooted structural inequities affecting vaccine uptake among ACB groups

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In a recent review published in Vaccines, researchers explored the influence of poor vaccination uptake among African, Caribbean, and Black (ACB) communities on public health in high-income nations.

Study: Understanding Low Vaccine Uptake in the Context of Public Health in High-Income Countries: A Scoping Review. Image Credit: SeventyFour/Shutterstock.com

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a massive vaccination drive; however, ACB communities have experienced significant adverse consequences and are unwilling to get the vaccine.

These communities are at risk due to health disparities, such as the greater prevalence of SARS-CoV-2 infections and hospitalizations. These imbalances significantly impact the social determinants of health (SDOH), and vaccine hesitancy can lead to delayed or uncertain immunization.

Global vaccination uptake has fallen; therefore, public health initiatives must adapt to present conditions and plan for future epidemics.

About the review

In the present review, researchers explored the variables contributing to poor vaccination uptake by ACB individuals, emphasizing healthcare in developed nations.

They sought to find current data sources, map the evidence, identify research gaps, and identify existing treatments for increasing vaccination uptake in the study population.

The team searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, APA PsycInfo, CINAHL, Web of Science, Open Science Framework, and the Allied and Complimentary Medicine databases.

They followed the Joanna Briggs Institute (JBI) model, supplemented by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping literature reviews (PRISMA-ScR). They included articles published in English or French between 2020 and July 19, 2022.

The researchers performed the data search using the population, concept, and context (PCC) model to identify records discussing vaccine uptake among ACB residents of high-income nations, as defined by the World Bank.

Evidence sources included primary studies, secondary research, abstracts, posters, conference proceedings, reports, and commentaries.

Two researchers screened the data independently, and a third researcher resolved disagreements. The team used the social determinants of health (SDOH) method, the socioeconomic model (SEM), and thematic mapping (TM) to analyze and interpret the data.

TM phases included individual-level, intra- and inter-group analyses to generate descriptive, analytical, and primary themes.

Results

Initially, the team identified 9,378 records, from which they removed 4246 duplicates. After title and abstract screening, they excluded 2,746 records.

Of the remaining 2,386 records undergoing full-text screening, 60 eligible records were analyzed, including 24 quantitative, ten qualitative, 19 commentary records, and seven mixed-method records. Most records were from the United Kingdom, Canada, and the United States.

Analysis performed via thematic mapping highlighted four primary themes: (i) inequities and racism, (ii) behaviors and sentiments, (iii) communication and knowledge, and (iv) influence and engagement.

Inequities and racism in the healthcare system originate from mistrust, racial burden, and institutional impediments to access. Vaccine hesitancy (VH) is associated with increased rates of unwillingness to receive vaccinations, thereby perpetuating health inequities in black communities.

The demographics of individuals exhibiting vaccine hesitancy reflect societal determinants of health, such as age, housing instability, poor income, and low education.

Black vaccination starting in the United States is lower among immigrants from other countries, with the Americas and Caribbean Islands having a lower incidence than Africa.

Factors like willingness, vaccination views, life events, and vaccine confidence determine vaccine uptake. Key causes include a lack of vaccination requirements, religious and political opinions, abuse, mortality exposure, and prior diseases.

Mistreatment, exposure to mortality, and past diseases exemplify lived experiences. Vaccine confidence encompasses skepticism, timeliness, novelty, side effects, effectiveness, and safety.

Black individuals are more likely to be vaccinated because of their existing health or their view that immunizations are the incorrect strategy.

Vaccine hesitation might be due to a desire to protect oneself, a need for school or a job, or a desire to avoid infection. To lower vaccination uptake and COVID-19 infections, the government and healthcare institutions must address these variables.

The lack of knowledge, disinformation, and misunderstandings in black communities all contribute to vaccination hesitation. Black parents are actively looking for information about kid vaccines, but the highest barrier is a lack of research on the short- and long-term impacts.

Education, confidence in vaccine information, and open communication are critical for increasing immunization. Addressing distrust can boost vaccine confidence and intentions, while customizing messages to target populations can encourage immunization. Racism and prejudice, which serve as structural impediments to fair health care, must be addressed through culturally responsive techniques.

Conclusion

The review findings showed that ACB populations had lower vaccination uptake than high-income nations. Complacency, discomfort, and a lack of confidence are factors that contribute to vaccination reluctance, which past and contemporary racism and prejudice cannot entirely explain.

The issue is complicated, encompassing knowledge and psychological, economic, and organizational constraints contributing to structural injustices. High-income nations should collect race-specific data for targeted treatments and increase the number of ACB participants in vaccine studies to boost vaccination trust.

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March 6, 2024
CUNY and Pfizer launch new project to track acute respiratory infections across the United States

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The City University of New York (CUNY) Institute for Implementation Science in Population Health (ISPH) and the CUNY Graduate School of Public Health and Health Policy (CUNY SPH), in collaboration with Pfizer, are initiating a critical two-year prospective epidemiologic study in the spring of 2024 to track acute respiratory infections across the United States.

Project PROTECTS (Prospective Respiratory Outcomes from Tracking and Evaluating Community-based TeSting) builds on the pivotal CHASING COVID Cohort Study, which has monitored SARS-CoV-2 infection rates and associated risk factors through questionnaires and at-home serological testing since March 2020. The cohort’s participants have shown remarkable commitment, with the study recently concluding its 22nd questionnaire and fourth round of serological testing. “The sustained engagement of CHASING COVID Cohort Study participants has made the cohort one of the most enduring and thorough community-based studies of the SARS-CoV-2 pandemic, and represents an invaluable resource for ongoing scientific inquiry,” says CUNY SPH Distinguished Professor of Epidemiology Denis Nash, who is also the principal investigator of the study.

This new project will harness both at-home rapid and PCR tests to investigate the incidence and symptom severity of several major respiratory viruses (SARS-CoV-2, RSV, influenza A, and influenza B), and characterize the performance of a new at-home multi-pathogen rapid test. “The study will address significant gaps in our understanding of the prolonged effects of these viruses on daily life, in the context of existing vaccines, background immunity, and treatments,” says Nash. The study will use a single rapid test for four different viruses that is currently in the research pipeline and not yet available to providers or patients.

To achieve study aims, Project PROTECTS aims to enroll up to 6,000 participants, starting with individuals who were engaged in the CHASING COVID cohort. Participants will complete quarterly questionnaires on existing symptoms, health status, quality of life, occupational activities, vaccination history, past respiratory illnesses, and healthcare utilization using a study-specific web platform and mobile app.

When participants exhibit symptoms of an acute respiratory infection, they will self-administer the multi-pathogen rapid test designed to test for all four respiratory viruses. It is administered in the same way as at-home SARS-CoV-2 tests. However, it simultaneously tests for SARS-CoV-2, RSV, influenza A, and influenza B, and can also detect co-infections. Those who test positive for one or more pathogens will complete questionnaires over the ensuing six months, with additional measures detailing symptoms, healthcare engagements and treatments, and new clinical diagnoses.

The findings are expected to be pivotal in shaping future public health strategies and interventions to mitigate the impact of severe respiratory viruses on population health outcomes.”

Denis Nash, CUNY SPH Distinguished Professor of Epidemiology

Source:

CUNY Graduate School of Public Health and Health Policy

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March 5, 2024
COVID-19 linked to long-lasting cognitive deficits, study finds
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In a recent study published in the New England Journal of Medicine, researchers assessed cognitive functioning among adults with varying levels of persistence of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in England.

Their results suggest that COVID-19 is associated with measurable cognitive deficits, which may persist in the long term.

Study: Cognition and Memory after Covid-19 in a Large Community Sample. Image Credit: Berit Kessler / Shutterstock

Background

The first documented cases of ‘brain fog,’ with symptoms such as poor memory, impaired concentration, and difficulty thinking, emerged as early as 2020, indicating that COVID-19 could have long-term cognitive impacts.

Though the phenomenon is well-known, what is lacking is information on how it may persist and which aspects of cognitive functioning are most affected.

About the study

In this study, researchers hypothesized that cognitive deficits after the onset of COVID-19 should be quantifiable and associated with covariates related to illness severity and duration.

Their second hypothesis was that individuals with prolonged COVID-19 symptoms should show more observable memory and executive function impairment, including brain fog and poor memory.

They conducted a cohort-based study tracking the prevalence of SARS-CoV-2 infection among 3,099,386 individuals aged over 18 years. Of these, 800,000 people were invited to complete a cognitive assessment and follow-up survey.

To be included, they should have received a positive result on a SARS-CoV-2 diagnostic test or suspected that they had COVID-19 and experienced symptoms for 12 weeks or more. Additionally, unvaccinated people with SARS-CoV-2 immunoglobulin-G antibodies and other randomly selected people from the full sample were included.

The cognitive assessment tested immediate and spatial working memory, verbal analogical reasoning, two-dimensional mental manipulation, spatial planning, word definitions, delayed memory, and information sampling. For each domain, participants were scored on accuracy; secondary information was collected on types of errors and response times.

Individuals were categorized into six groups based on SARS-CoV-2 duration. The first category included those who had never experienced an infection or had an unconfirmed one; all other categories required a positive test result.

People in the second category had asymptomatic infections, those in the third had short COVID-19 that resolved in four weeks or less, and those in the fourth had symptoms that resolved in less than 12 weeks. To be in the fifth category, individuals had symptoms that persisted for more than 12 weeks; those in the sixth had persistent symptoms continuing until the cognitive assessments.

Researchers assessed nonresponse bias to examine which factors were associated with accessing and completing the cognitive assessment. Linear regressions, factor analysis, and propensity-score matching (PSM) were used to analyze the data. Sensitivity analyses were also conducted to test the validity and robustness of the results.

Findings

Of the 800,000 people invited to participate, 34.6% completed the questionnaire, with 141,583 completing at least one cognitive testing task and 112,964 completing all eight.

Among individuals infected with SARS-CoV-2 once, being infected earlier during the pandemic was associated with greater decreases in the overall cognitive score compared to those infected later. However, the gap narrowed after adjusting for the severity of the illness.

On average, people who were ill for longer, were hospitalized, or were infected early on in the pandemic had lower overall cognitive scores than those who had never had COVID-19.

Multivariate regression results indicated that people infected during the initial stages (when the original virus or alpha variant dominated) showed higher cognitive functioning decreases than those infected with the alpha or omicron variants.

Similarly, greater decreases were seen in people with persistent and unresolved symptoms compared to those who never had COVID-19 and among people who were hospitalized compared to those who were not.

The PSM analysis showed similar trends; cognitive advantages were observed based on vaccination status, with people who received two or more doses performing best. There was, however, no significant difference based on which vaccine was taken.

Conclusions

This large-sample community-based study suggests that COVID-19 may be associated with long-term and quantifiable cognitive deficits. However, people infected with more recent variants may experience more negligible effects on cognitive functioning.

This could be because earlier strains of SARS-CoV-2 were dominant at a time when effective treatments were not available, and the health system faced heavy burdens. Repeated infections do not appear to have any effect, but vaccination (particularly two or more doses) may provide small cognitive advantages.

Limitations of this study include the possibility of participant self-selection bias and reliance on self-reported data. Certain groups were overrepresented in the sample, including White persons and women; younger people and certain underprivileged groups were underrepresented.

Further studies are required to provide information on the longer-term implications of these findings.
Journal reference:

Cognition and memory after Covid-19 in a large community sample. Hampshire, A., Azor, A., Atchison, C., Trender, W., Hellyer, P.J., Giunchiglia, V., Husain, M., Cooke, G.S., Cooper, E., Lound, A., Donnelly, C.A., Chadeau-Hyam, M., Ward, H., Elliott, P. New England Journal of Medicine (2024). DOI: 10.1056/NEJMoa2311330, https://www.nejm.org/doi/10.1056/NEJMoa2311330
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March 5, 2024
How long do cognitive and memory dysfunctions persist after SARS-CoV-2 infection?
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A recent New England Journal of Medicine study assessed whether cognitive deficits can be measured after severe acute respiratory syndrome (SARS-CoV-2) infection, the causal agent of the coronavirus disease 2019 (COVID-19) pandemic.

This study further explored the period for which these symptoms persist.

Study: Cognition and Memory after Covid-19 in a Large Community Sample. Image Credit: Orawan Pattarawimonchai/Shutterstock.com

Background

Brain fog is the common name for problems associated with thinking, concentrating, or memory. It has been observed frequently in patients recovered from COVID-19, but there is a dearth of objective data on cognitive performance.

Furthermore, it is not clear which cognitive functions are most vulnerable and how long such deficits persist.

About the study

The primary hypothesis in this observational study was that cognitive deficits after COVID-19 were measurable and scalable regarding illness severity and duration.

The secondary hypothesis was that objective impairments in memory and executive functions would be noted in patients showing prolonged symptoms.

These hypotheses were tested using data from the Real-Time Assessment of Community Transmission (REACT) cohort in England.

Eight hundred thousand adults were invited to complete an online assessment of cognitive function.

Across eight tasks, a global cognitive score was estimated. These tasks helped test immediate memory, verbal analogical reasoning, two-dimensional mental manipulation, verbal analogical reasoning, spatial working memory, word definitions, delayed memory, spatial planning, and information sampling.

Individuals who were invited to participate in this study were SARS-CoV-2 test positive or with persistent COVID-19 symptoms for at least 12 weeks.

The eligible participants were categorized into six groups based on the duration of SARS-CoV-2 infection.

The categories were defined as follows:
- Category 1: No infection with SARS-CoV-2 detected.
- Category 2: Infected with SARS-CoV-2, but no symptoms developed (asymptomatic infection).
- Category 3: Experienced a brief infection period, with symptoms lasting less than four weeks.
- Category 4: The period of infection lasted between 4 and 12 weeks.
- Category 5: Symptoms were resolved at least 12 weeks after the onset of the infection.
- Category 6: Symptoms persisted for more than 12 weeks after the infection began and were present during the cognitive assessment.
Study findings

This community-based study noted that COVID-19 and long-term objectively measurable cognitive deficits were associated with each other.

The difference in the cognitive score between the no-COVID group and the group of participants whose symptoms had resolved was small. The difference was, however, large for participants who experienced unresolved symptoms.

The probability of task performance was below the cut-off point in the case of moderate impairment.

Relative to the no-COVID group, larger cognitive differences were noted in the group where ICU admission was needed. This finding is consistent with the ones documented in previous studies where medium-to-large-scale cognitive deficits were observed in patients who were hospitalized in a critical care unit.

It was noted that with the progression of the pandemic, the association between cognitive deficits and COVID-19 attenuated.

Smaller cognitive declines were noted among those infected with newer variants, compared to the original strain or the Alpha strain. Individuals who had received two or more vaccine doses were seen to have a small cognitive advantage.

A progressive decline in cognitive deficits was observed among those infected during the pandemic’s first wave.

The observation that patients whose persistent symptoms had resolved had experienced global cognitive deficits similar in nature to patients with shorter-duration symptoms is indicative of the fact that individuals with persistent symptoms could experience some degree of cognitive improvement once symptoms resolve.

The executive, memory, and reasoning tasks were the most sensitive to COVID-19. The performance was dependent on hospitalization and illness duration.

The scores were also weakly correlated with recent brain fog or poor memory. The results documented here validated the associations between mood swings, fatigue, and cognitive deficits, besides a variety of other symptoms.

Limitations of the study

A key limitation centers around subjective reporting to identify patients with persistent symptoms.

Linking these results to the literature is difficult owing to the lack of definitive criteria for post–COVID-19 syndromes. Furthermore, causality could not be inferred owing to the observational nature of the data.

The global cognitive score calculation adjusted for demographic characteristics and pre-existing health conditions. However, some residual confounding could have remained due to the observational nature of the data.

To mitigate this bias, the propensity score matching method was used to show a highly consistent pattern of results.

As with any study requiring active participant engagement, self-selection bias could not be ruled out.

Patients with the most severe cognitive impairment may not have been willing or able to take a cognitive assessment.

Additionally, some groups were less representative compared to the base population. Individuals from deprived backgrounds and younger persons were underrepresented.
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March 4, 2024
Broad-spectrum neutralizing antibody mAb-39 targets conserved S2 epitope in SARS-CoV-2

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The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. The most emergency-use authorized (EUA) therapeutic monoclonal antibodies, are more likely to lose their neutralizing activities as the viral epitopes (e.g. the receptor-binding domain, RBD) within spike protein of SARS-CoV-2 they target are more prone to mutate. By contrast, the S2 subunit of spike protein, has a much lower frequency of mutation than the RBD and exhibits a high degree of homology among human SARS-like CoVs. As such, developing antibodies targeting the more conserved S2 epitopes are able to exert an incredibly broad neutralization spectrum against SARS-like CoV viruses.

This study is led by Dr. Suping Zhang (Shenzhen University), Dr. Zhenhong Lin (Chongqing University), and Dr Lanfeng Wang (Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences). They isolated one neutralizing mAb, called mAb-39, against SARS-CoV-2 and its variants from convalescent adult. This mAb exhibited good potency in neutralization SARS-CoV2 original strain, previous and current circulating Omicron variants (e.g. Omicron BA.1, BA.2.86, BA.4, BA.5, EG.5.1) in a cell-based assay.

This antibody binds to a highly conserved new epitope on the glycoprotein from SARS-CoV2.

This is very exciting! The good activity and highly conserved epitope of this antibody suggested its potential for clinical translation”.

Dr. Hang Su, Shenzhen University

The team found the mAb-39 greatly improved the neutralizing activity of anti-RBD antibody, the same type of EUA therapeutic monoclonal antibodies, against the highly neutralization-resistant Omicron variants. The study also extended the knowledge to the neutralizing and protective epitopes of SARS-CoV-2.

Source:

Tsinghua University Press

Journal reference:

Su, H., et al. (2024). A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants by targeting the upstream region of spike protein HR2 motif. hLife. doi.org/10.1016/j.hlife.2024.02.001.

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March 1, 2024
Long-term smell and taste loss
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A recent study published in Life investigates the mechanisms responsible for severe olfactory dysfunction (OD) and gustatory dysfunction (GD) following recovery from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: Persistent Olfactory and Taste Dysfunction after COVID-19. Image Credit: DimaBerlin / Shutterstock.com

Background

SARS-CoV-2 is the causal agent of the coronavirus disease 2019 (COVID-19). A sudden loss of smell or taste is one of the most common symptoms of SARS-CoV-2 infection.

Typically, OD and GD occur in the early phase of the infection, which has led these symptoms to be used as a screening tool for COVID-19. Both OD and GD occur primarily among young patients and are independent of gender.

COVID-19 patients with OD often experience a spontaneous return of their sense of smell to pre-symptomatic levels within one month of infection. However, between 7-20% of COVID-19 patients report prolonged OD, even after other symptoms have resolved.

Mechanistically, patients with severe nasal and sinus symptoms undergo swelling of the mucous membranes of the olfactory cleft, which increases mucus secretion. This increase in mucus causes a mechanical blockage to odor molecules, manifesting as conductive OD. Infiltration of viral particles into the non-neural cells of the olfactory epithelium also induces significant immune responses.

In the context of immune responses to viral infiltration into olfactory epithelium, pro-inflammatory cytokines such as interleukin 1 β (IL-1β) and tumor necrosis factor α (TNF- α) are released. The impaired non-neural cells subsequently disrupt the connection between nerve cells and sensory OD, which inhibits the transfer of olfactory stimuli to the brain.

Importantly, the precise mechanism of action on the penetration of SARS-CoV-2 into the central nervous system remains unclear. One possible mechanism could be the direct penetration of SARS-CoV-2 into the cerebrospinal fluid from non-neural cells of the olfactory epithelium.

The penetration of SARS-CoV-2 into the olfactory neuroepithelium causing sensorineural OD has been well documented. In this context, the spike (S) protein of SARS-CoV-2 binds to the angiotensin-converting-enzyme-2 (ACE2) receptor, which triggers the synthesis of the transmembrane serine protease 2 (TMPRSS2), thereby causing membrane fusion.

To date, few studies have elucidated the mechanism that underlies the manifestation of GD due to COVID-19.

About the study

The current prospective and single-center study involved a subjective and physical examination of patients. Study participants also underwent multiple olfactory and gustatory tests, such as the Sniffin’ Sticks Test (SST) and Taste Strips Test (TS).

A total of 81 participants were recruited, including 16 men and 65 women between 12 and 73 years of age. All participants experienced OD due to COVID-19, which persisted for at least one month after the resolution of other acute symptoms.

Study findings

The study participants experienced persistent OD or GD (OGD) with durations ranging between one and 25 months.

Few clinical facilities offer help to patients with persistent OGD following recovery from COVID-19. This could be because clinicians are still developing their knowledge regarding long-term COVID and formulating strategies to combat the condition. Additionally, patients often seek treatment for OD only after resolving more serious symptoms.

The degree of damage in the olfactory cells by SARS-CoV-2 penetration dictates the duration of OD. For conductive disorders that occur in most infected individuals, the sense of smell improves after a reduction in acute inflammation of the nasal mucosa. Patients with damaged olfactory cells exhibit persistent OD, as neurons take longer to recover and re-establish adequate intercellular connections.

About 64% of the study participants had hyposmia, and 22% had functional anosmia. SST scores revealed that the participants scored lowest on the threshold part of the test. The SST score of other parts concerning discrimination and identification of odor revealed that patients could sense intense smell correctly.

SST scores significantly depend on the function of the olfactory epithelium, which suggests that post-COVID-19 OD is predominantly associated with damage in peripheral olfactory due to acute immune responses. More specifically, the cytokine storm leads to leukocytic infiltration and disrupts olfactory epithelial cells, including stem cells.

There was no difference in recognizing odorants that stimulate only the olfactory nerve and those that trigger the trigeminal nerve, such as mint and lemon. Interestingly, some participants with subjective ODs scored within a normal range on the SST test.

Around 17% of participants reported abnormal taste. The best-recognized taste was sweet, followed by salty. Only bitter taste was marginally correlated with TTS and TS scores.

Conclusions

The findings provide important insights into the relationship between OD and SARS-CoV-2 infection. It is possible that the relationship between OD and COVID-19 is more peripheral than central; therefore, clinicians must pay close attention to the condition of the nasal mucosa and provide better information to patients about good nasal hygiene that can help alleviate the condition.
Journal reference:

Buksinska, M., Skarzynski, P. H., Raj-Koziak, D., et al. (2024) Persistent Olfactory and Taste Dysfunction after COVID-19. Life 14(3); 317. doi:10.3390/life14030317.
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March 1, 2024
Corticosteroids may restore sense of smell in COVID-19 patients

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COVID-19 is known to cause loss of smell in certain patients. While this symptom is generally temporary, approximately 10% of patients may suffer from it for 6 months or more.

Earlier research carried out by a team of researchers from INRAE and ENVA observed that the SARS-CoV-2 infected olfactory mucosa is invaded by immune cells leading to its destruction and prolonged inflammation. Based on these observations, the same team decided to assess the effectiveness of corticosteroids–known for their anti-inflammatory properties-;in restoring the sense of smell.

Their results support the existence of a direct link between the loss of smell caused by the virus and a decrease in the olfactory neuron population in the nasal mucosa. In addition, they show that early treatment with dexamethasone, a commonly used corticosteroid, improves the recovery of olfactory abilities in animals.

The improvement of the olfactory capacities is associated with a reduction of the immunity cells in the mucosa, and an increased level of regeneration of the olfactory neuron population. These results suggest that the corticosteroid treatments currently used-;which have not been very successful in the treatment of prolonged anosmia-;could be more effective if prescribed early, at the onset of symptoms of loss of smell.

Source:

INRAE – National Research Institute for Agriculture, Food and Environment

Journal reference:

Merle-Nguyen, L., et al. (2024). Early corticosteroid treatment enhances recovery from SARS-CoV-2 induced loss of smell in hamster. Brain, Behavior, and Immunity. doi.org/10.1016/j.bbi.2024.02.020.

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February 29, 2024
Unlocking coronavirus structure through M protein research

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For centuries, coronaviruses have triggered health crises and economic challenges, with SARS-CoV-2, the coronavirus that spreads COVID-19, being a recent example. One small protein in SARS-CoV-2, the Membrane protein, or M protein, is the most abundant and plays a crucial role in how the virus acquires its spherical structure. Nonetheless, this protein’s properties are not well understood.

A research team led by a physicist at the University of California, Riverside, has devised a new method to make large quantities of M protein, and has characterized the protein’s physical interactions with the membrane -; the envelope, or “skin,” -; of the virus. The team’s theoretical modeling and simulations show how these interactions are likely contributing to the virus assembling itself.

The researchers report in their paper published today in Science Advances that when the M protein, which is adjacent to the spike protein on SARS-CoV-2, gets lodged in the membrane, it coaxes the membrane to curve by locally reducing the membrane thickness. This induction of curvature leads to SARS-CoV-2’s spherical shape.

“If we can better understand how the virus assembles itself, then, in principle, we can come up with ways to stop that process and control the virus’ spread,” said Thomas E. Kuhlman, an assistant professor of physics and astronomy, who led the research project. “M protein has previously resisted any kind of characterization because it is so hard to make.”

Kuhlman and his colleagues overcame this difficulty by using Escherichia coli bacteria as a “factory” to make the M protein in large numbers. Kuhlman explained that although E. coli can make copious amounts of M proteins, the proteins tend to clump together in the E. coli cells, eventually killing them. To circumvent this challenge, the researchers induced the E. coli cells to produce the protein Small Ubiquitin-related Modifier, or SUMO, along with the M protein.

In our experiments, when E. coli makes M protein, it makes SUMO at the same time. The M protein fuses with the SUMO protein, which prevents the M proteins from sticking to one another. The SUMO protein is relatively easy to remove via another protein that simply cuts it off. The M protein is thus purified and separated from SUMO.”

Thomas E. Kuhlman, assistant professor of physics and astronomy, UCR

The work provides fundamental insights into the mechanisms driving SARS-CoV-2 viral assembly.

“As M proteins are an integral component of other coronaviruses as well, our findings provide useful insights that can enhance our understanding and potentially enable interventions in viral formation not only in SARS-CoV-2 but also in other pathogenic coronaviruses,” Kuhlman said.

Next, the researchers plan to study the interactions of the M protein with other SARS-CoV-2 proteins to potentially disrupt these interactions with drugs.

Kuhlman was joined in the research by fellow-UCR physicists Roya Zandi and Umar Mohideen. Kuhlman was charged with making the M proteins. Mohideen, a distinguished professor of physics and astronomy, used atomic force microscopy and cryogenic electron microscopy to measure how the M protein interacts with the membrane. Zandi, an expert on virus assembly and a professor of physics and astronomy, developed simulations of how the M proteins interact with each other and with the membrane.

Other coauthors on the paper are Yuanzhong Zhang, Siyu Li, Michael Worcester, Sara Anbir, Joseph McTiernan, Pratyasha Mishra, and Ajay Gopinathan of UCR; and Michael E. Colvin of UC Merced. Co-first authors Zhang and Anbir contributed equally to the work.

The research was supported by a grant from the University of California Office of the President to investigate how the COVID-19 virus assembles itself.

Source:

University of California – Riverside

Journal reference:

Zhang, Y., et al. (2024) Synthesis, insertion, and characterization of SARS-CoV-2 membrane protein within lipid bilayers. Science Advances. doi.org/10.1126/sciadv.adm7030.

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February 28, 2024
Scientists uncover a new doorway for SARS-CoV-2 into human cells

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In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers demonstrated that human transferrin receptor (TfR) mediates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, presents influenza-like manifestations, including mild-to-severe pneumonia, acute respiratory distress syndrome, multiorgan failure, and fatal lung injury. Further, the etiology and pathogenesis of COVID-19 are not entirely understood and targeted therapies remain inadequate.

The viral spike protein binds to the host receptor, angiotensin-converting enzyme 2 (ACE2), for cellular entry. Although SARS-CoV-2 preferentially infects cells in the respiratory tract, the virus has been detected in virtually all organs. Studies have revealed the presence of SARS-CoV-2 RNA in diverse cells lacking ACE2, suggesting that other receptors or co-receptors may mediate viral entry.

Study: Human transferrin receptor can mediate SARS-CoV-2 infection. Image Credit: Kateryna Kon / Shutterstock

The study and findings

In the present study, researchers identified TfR as an alternative receptor mediating the cellular entry of SARS-CoV-2. First, they used co-immunoprecipitation (Co-IP) to identify host proteins interacting with the viral spike in Calu-3 cells. This revealed 293 proteins, including 42 transmembrane proteins; two proteins were associated with entry (ACE2 and TfR). Next, the team evaluated TfR expression in the respiratory tract and liver in mice.

TfR expression, both transcript and protein levels, was substantially higher in the lungs and trachea than in other tissues. Using immunohistochemical analysis, the researchers investigated the effects of SARS-CoV-2 on TfR expression in the lungs of humanized ACE2 (hACE2) mice and monkeys. This revealed a 1.5- and 1.8-fold increase in TfR expression in mice and monkeys, respectively.

In addition, surface plasmon resonance revealed direct interactions between the viral spike and human TfR. Notably, the spike protein lacked interactions with Syrian hamster or mouse TfR. Docking analysis predicted two peptide sequences (QK8: QDSNWASK and SL8 SKVEKLTL) in TfR to be involved at the interface of TfR-spike interactions.

Mutagenesis and Co-IP revealed that the A529 residue in TfR was essential for interactions with the spike. Further analysis indicated that physiological interactions between spike and TfR occurred at the cellular surface and during endocytosis. This was confirmed by electron microscopy using SARS-CoV-2 pseudoviral spike and HEK293/hACE2 and BHK-21/TfR cells.

Next, the team evaluated the effects of soluble TfR, anti-TfR antibody, and SL8 and QK8 peptides on SARS-CoV-2 infection using reverse-transcription polymerase chain reaction (RT-PCR) and plaque assays. Results showed their inhibitory effects on SARS-CoV-2 in Vero E6 and Calu-3 cells. Cytotoxicity was not observed even at 1,000 nM.

Confocal microscopy revealed that TfR was widespread on the surface of Calu-3 and Vero E6 cells, with the colocalization of TfR and SARS-CoV-2 at the surface and during endocytosis. Notably, treatment with the anti-TfR antibody inhibited the colocalization. Further, electron microscopy showed that viral particles were present in the cytosol and clathrin-coated pits in Vero E6 cells; likewise, treatment with anti-TfR antibody inhibited viral internalization.

Next, ACE2 was knocked out (KO) from Calu-3 and Vero E6 cells and the cells were infected with SARS-CoV-2. This inhibited infection by 40% to 50%, suggesting that ACE2 might not be the only receptor mediating infection. In addition, TfR knockdown (KD) inhibited infection by 30%, whereas its overexpression (OE) promoted infection. TfR KO was not performed as it is lethal. TfR OE or KD did not impact ACE2 expression.

Further, the team transfected C57 mice with adenovirus vector (Ad5) expressing hACE2 or humanized TfR (hTfR) and infected them with SARS-CoV-2. Viral load in the lungs in Ad5-hTfR and Ad5-hACE2 mice was significantly higher than in Ad5-empty mice. Finally, the researchers evaluated the effects of the anti-TfR antibody on infection in rhesus macaques. Anti-TfR antibody inhibited viral replication and reduced pneumonia.

Viral load in the respiratory epithelium was also significantly lower between 3- and 7 days post-infection (dpi) compared to controls. Radiographs taken at 0 and 5 dpi revealed significantly less severe pulmonary infiltration in antibody-treated macaques relative to controls. Antibody-treated animals had no significant pulmonary lesions, while controls showed lung lesions of varying degrees.

Conclusions

Taken together, the study described the human TfR as a receptor for SARS-CoV-2. TfR can directly bind to the viral spike at an affinity comparable to that of ACE2. Notably, mouse TfR and the viral spike lacked interactions. Soluble TfR, SL8, and QK8 peptides and anti-TfR antibodies can inhibit infection. The team also illustrated the antiviral effects of the anti-TfR antibody in rhesus macaques. Overall, TfR could serve as an alternative infection pathway, facilitating viral entry through endocytosis.

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February 28, 2024
Vaping increases susceptibility to COVID-19 infection, study finds

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Vapers are susceptible to infection by SARS-CoV-2, the virus that spreads COVID-19 and continues to infect people around the world, a University of California, Riverside, study has found.

The liquid used in electronic cigarettes, called e-liquid, typically contains nicotine, propylene glycol, vegetable glycerin, and flavor chemicals. The researchers found propylene glycol/vegetable glycerin alone or along with nicotine enhanced COVID-19 infection through different mechanisms.

Study results appear in the American Journal of Physiology.

The researchers also found that the addition of benzoic acid to e-liquids prevents the infection caused by propylene glycol, vegetable glycerin, and nicotine.

Users who vape aerosols produced from propylene glycol/vegetable glycerin alone or e-liquids with a neutral to basic pH are more likely to be infected by the virus, while users who vape aerosols made from e-liquids with benzoic acid -; an acidic pH -; will have the same viral susceptibility as individuals who do not vape.”

Rattapol Phandthong, postdoctoral researcher, Department of Molecular, Cell and Systems Biology and research paper’s first author

The researchers obtained airway stem cells from human donors to produce a 3D tissue model of human bronchial epithelium. They then exposed the tissues to JUUL and BLU electronic cigarette aerosols to study the effect on SARS-CoV-2 infection. They found all tissues showed an increase in the amount of ACE2, a host cell receptor for the SARS-CoV-2 virus. Further, TMPRSS2, an enzyme essential for the virus to infect cells, was found to show increased activity in tissues exposed to aerosols with nicotine.

Prue Talbot, a professor of the graduate division and Phandthong’s advisor, said e-cigarette users should be cautious about vaping as some products will increase their susceptibility to SARs-CoV-2 infection.

“It would probably be best for vapers to quit vaping for the protection of their health and to stop nicotine dependency,” she said. “If they cannot stop vaping, it is better to vape aerosols produced from an e-liquid with acidic pH or with benzoic acid to prevent the enhanced SARS-CoV-2 infection caused by nicotine, propylene glycol, and vegetable glycerin. However, inhalation of benzoic acid has its own risk, and data is still limited on this topic.”

The researchers acknowledge that the relationship between e-cigarettes and SARS-CoV-2 susceptibility is complex.

“The complexity is attributed to a wide range of available e-liquids, the chemical composition of each e-liquid, and different models of e-cigarettes,” Phandthong said. “Our study only used Classic Tobacco Flavor JUUL e-cigarette and BLU Classic Tobacco e-cigarette. Even with just these two e-cigarettes, we found the aerosols and individual ingredients produced different effects on SARS-CoV-2 infection.”

Phandthong and Talbot hope the Food and Drug Administration will use their findings to implement regulatory laws on e-cigarette products.

“Our findings could also help improve the design of clinical trials involving the use of tobacco products and SARS-CoV-2 infection,” Phandthong said. “In the meantime, it is worth bearing in mind that the scientific literature has shown that a vaper who contracted SARS-CoV-2 has more complications during the recovery period and is more likely to develop long COVID-19, which can be serious and last many months post-infection. We hope our findings encourage vapers to stop vaping and discourage non-users from starting to vape.”

Phandthong acknowledged the team only investigated the initial stage of SARS-CoV-2 infection.

“There are many later stages involved in infection, such as viral replication,” he said. “It is likely that these additional stages can also be affected by inhalation of e-cigarette aerosols.”

Phandthong and Talbot were joined in the study by Man Wong, Ann Song, and Teresa Martinez.

The research was funded by grants from the Tobacco-Related Disease Research Program, National Institute of Environmental Health Sciences, Center for Tobacco Products of the Food and Drug Administration, and California Institute of Regenerative Medicine.

Source:

University of California – Riverside

Journal reference:

Phandthong, R., et al. (2023). Does Vaping Increase the Likelihood of SARS-CoV-2 Infection? Paradoxically Yes and No. American Journal of Physiology-Lung Cellular and Molecular Physiology. doi.org/10.1152/ajplung.00300.2022.

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February 27, 2024