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Tag: SARS

  • Corticosteroids may restore sense of smell in COVID-19 patients

    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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  • Unlocking coronavirus structure through M protein research

    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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  • Scientists uncover a new doorway for SARS-CoV-2 into human cells

    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 / ShutterstockStudy: 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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  • Vaping increases susceptibility to COVID-19 infection, study finds

    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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  • Study reveals early death predictors in COVID-19 patients with cardiac injury

    Study reveals early death predictors in COVID-19 patients with cardiac injury

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    Announcing a new article publication for Cardiovascular Innovations and Applications journal. The activation of immune and thrombotic biomarkers at admission, and their ability to predict cardiac injury and mortality patterns in COVID-19, remains unclear.

    This retrospective cohort study included 170 patients with COVID-19 with cardiac injury at the time of admission to Tongji Hospital in Wuhan between January 29, 2020, and March 8, 2020. The temporal evolution of inflammatory cytokines, coagulation markers, clinical treatment, and mortality were analyzed. Continuous variables are expressed as median (interquartile range). The Mann-Whitney test was used for two-group comparisons, whereas the Kruskal-Wallis test was used for comparisons among three groups. Categorical variables are expressed as proportions and percentages, and Fisher’s exact test was used to compare differences. A multivariate regression model was used to predict in-hospital death. A simple linear regression analysis was applied to examine the correlation between baseline biomarkers and peak cTnI levels.

    Of the 170 patients, 60 (35.3%) died early (<21 d), and 61 (35.9%) died after a prolonged stay. The admission laboratory findings correlating with early death were elevated interleukin 6 (IL-6) (P < 0.0001), tumor necrosis factor-α (P = 0.0025), and C-reactive protein (P < 0.0001). We observed the trajectory of biomarker changes in patients after admission hospitalization, and determined that early mortality was associated with a rapidly increasing D-dimer level, and gradually decreasing platelet and lymphocyte counts. Multivariate and simple linear regression models indicated that the risk of death was associated with immune and thrombotic pathway activation. Elevated admission cTnI levels were associated with elevated IL-6 (P = 0.03) and D-dimer (P = 0.0021) levels.

    In patients with COVID-19 with cardiac injury, IL-6 and D-dimer levels at admission predicted subsequently elevated cTnI levels and early death, thus highlighting the need for early inflammatory cytokine-based risk stratification in patients with cardiac injury.

     

    Source:

    Journal reference:

    Peng, K., et al. (2024). IL-6 and D-dimer Levels at Admission Predict Cardiac Injury and Early Mortality during SARS-CoV-2 Infection. Cardiovascular Innovations and Applications. doi.org/10.15212/cvia.2024.0009.

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  • Study reveals how long COVID can affect brain function through vascular disruption

    Study reveals how long COVID can affect brain function through vascular disruption

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    In a recent study published in Nature Neuroscience, researchers investigated whether the neurological response to coronavirus disease 2019 (COVID-19) may be due to brain-brain barrier (BBB) disruption and subsequent extravasation of serum components.

    Study: Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Image Credit: fran_kie/Shutterstock.comStudy: Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Image Credit: fran_kie/Shutterstock.com

    Background

    COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a respiratory viral infection resulting in severe acute respiratory distress syndrome (ARDS) and long-term neurological consequences such as headache, lethargy, malaise, and altered consciousness.

    BBB breakdown allows serum components and cytokines to penetrate the brain. The cerebrovascular pathophysiology and processes remain unknown, warranting further research.

    About the study

    The present study determined the association between COVID-19-related cognitive impairment and BBB breakdown in COVID-19 patients.

    The researchers collected blood and plasma samples from 76 acute COVID-19 patients, evaluated them for inflammatory, coagulation, and BBB dysfunction indicators, and rated their severity using World Health Organization (WHO) severity guidelines.

    They next examined brain fog status to identify changes in patients’ inflammatory profiles. During the first round of COVID-19 in March and April 2020, they recruited participants from St. James’ Hospital at Trinity College in Dublin.
    To investigate BBB function, the researchers selected ten recovered individuals, 11 suffering from long COVID or post-acute COVID-19 (PASC) and 11 with PASC-related brain fog, diagnosed with SARS-CoV-2 infection during the disease’s April 2020 outbreak in Ireland.

    All patients had polymerase chain reaction (PCR)-verified moderate-intensity COVID-19, requiring no antiviral therapy or hospitalization.

    The researchers used the quick smell identification test (Q-SIT) to evaluate anosmia status, grouping them based on self-reported cognition difficulties known as brain fog.

    They classified subjects as recovered in the case of no symptom recurrence after recovering from acute COVID-19. They used the Montreal Cognitive Assessment (MOCA) to measure cognitive impairment.

    The researchers used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) volume and thickness measurements on recovered individuals with PASC and 60 age-matched healthy controls from the IXI dataset to investigate structural brain alterations associated with increased BBB permeability.

    They used multiplexed assays to assess 50 BBB integrity and inflammation markers and correlation analysis adjusting for age and sex to identify associations between neuroinflammatory and BBB dysfunction markers in the recovered and PASC cohort.

    RNA-seq was also used to evaluate gene expression alterations in peripheral blood mononuclear cells (PBMCs) and the human brain endothelial cell line hCMEC/d3 isolated from unaffected, recovered, and patients with protracted COVID in the absence or presence of brain fog.

    They used gene ontology (GO) to examine the transcriptome profiles of those with and without brain fog in the group with extended COVID.

    The study included COVID-19 convalescents aged ≥18 years without neurological symptoms and individuals suffering from long-term COVID with symptoms lasting over 12 weeks after infection.

    Results

    COVID-19-induced brain fog was associated with BBB impairment. This disturbance is visible during acute COVID-19 and in individuals with long-term COVID-related cognitive impairment, popularly termed brain fog.

    In addition, the team found that PBMCs showed coagulation system instability and a suppressed adaptive immunological response in those with brain fogging.

    In vitro, PBMCs showed enhanced adherence to cells of the human brain endothelium, whereas the endothelial cells were exposed to sera from individuals with prolonged COVID-19-induced inflammation.

    The findings indicated that assessing BBB integrity might be a clinically helpful indicator of neurological sequelae linked with COVID-19 in a few individuals. Furthermore, targeted control of BBB integrity may provide a novel strategy for therapeutically treating patients with chronic COVID.

    Common symptoms of brain fog include dyspnea, loss of smell and taste, coughing, weariness, and fever. Patients with brain fogging had a higher average age, were more likely to be hospitalized, and needed oxygen treatment.

    There was a strong association between COVID-19 severity and age, hospitalization length, and comorbidities.

    BBB failure was linked to long-term COVID-induced cognitive impairment, indicating that both active and acute SARS-CoV-2 infections may cause BBB dysfunction in individuals with neurological disabilities.

    MRI imaging indicated significantly higher brain leakage in individuals with PASC and brain fog, with volumetric deficits mostly in the frontal and temporal lobes and increases in the occipital lobes and lateral ventricles.

    White blood cells from COVID-19 patients stimulated brain endothelial cells. Compared to unaffected individuals, there were 950 differentially expressed genes (DEGs) in recovered individuals, 481 in individuals with protracted COVID, and 126 in those with brain fogging.

    Upregulated genes were associated with T cell development and activation pathways, immune response negative control, and gene expression circadian regulation.

    Conclusion

    Overall, the study findings showed that PASC-related brain fog is associated with systemic inflammation and persistent localized BBB malfunction, with disruption apparent up to a year after infection.

    Dysregulation of the coagulation system is a primary cause of prolonged COVID-19. BBB disruption is associated with neurological impairment during acute COVID-19, and high serum levels in neurological diseases such as epilepsy, traumatic brain injury, and schizophrenia.

    Understanding the long-term effects of COVID-19 is critical to developing new treatments.

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  • SARS-CoV-2-infection and vaccine-induced antibodies wane initially but stabilize for lasting protection

    SARS-CoV-2-infection and vaccine-induced antibodies wane initially but stabilize for lasting protection

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    In a recent observational study published in the journal Immunity, researchers from the United States of America investigated the longevity of antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. They found that the humoral responses to SARS-CoV-2 infection and vaccination were long-lasting and biphasic, with an initial decline followed by stabilization after seven to nine months.

    Study: SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Kateryna Kon / ShutterstockStudy: SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Kateryna Kon / Shutterstock

    Background

    The COVID-19 pandemic, which began four years ago, prompted the rapid development of messenger RNA (mRNA) vaccines, including the BNT162b2 and mRNA-1273, helping save millions of lives. However, emerging variants of SARS-CoV-2 and the waning immunity against them pose challenges. Although mRNA-based vaccine-induced immunity is perceived to decline rapidly, this perception is based on limited data, primarily from short-term studies.

    Amidst the exponential rise of SARS-CoV-2 cases in March 2020, the New York metropolitan area faced a crisis, with essential healthcare workers at a high infection risk. In response, a specific and sensitive SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) was developed, and the Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study was launched. This initiative tracked antibody responses, reinfection rates, and immunity factors in healthcare workers, offering vital insights into pandemic dynamics. Researchers in the present study utilized data from the PARIS study, one of the most comprehensive investigations on SARS-CoV-2 immunity longevity, and analyzed the humoral responses to SARS-CoV-2 infection and vaccination.

    About the study

    The PARIS study was an observational, longitudinal study conducted from April 2020 to March 2023 and enrolled 501 healthcare workers. Their mean age was 41 years, and 67% of them were female. Weekly saliva samples and bi-weekly blood samples were collected for the first two months. Nasopharyngeal/ante-near swabs were taken for respiratory symptoms or after vaccination. About 38% of participants showed baseline SARS-CoV-2-spike-binding immunoglobulin G (IgG) antibodies. A total of 93% of participants were vaccinated– 0.2% received four mRNA boosters, 2.6% had three boosters, 16.6% had two boosters, and 53.7% had one booster. Approximately 21.3% of the participants chose not to receive boosters.

    The study utilized REDCap for monthly surveys on general health and SARS-CoV-2 risk, focusing on side effects after mRNA vaccinations and booster doses. Data from 228 participants were analyzed, and severity scoring was conducted, revealing reported incidence and severity trends across doses and subgroups.

    Antibody titers in serum were assessed using enzyme-linked immunosorbent assay (ELISA) and optical density at 490 nm (OD490). Statistical and quantitative analysis involved the use of the Wilcoxon test, Mann-Whitney U test, log-rank test, unweighted pair group method with arithmetic mean (UPGMA) clustering, antibody kinetic modeling including nonlinear mixed-effects (NLME) models, and demographic factor assessment in post-vaccine and post-boost models.

    Results and discussion

    While 38% of the participants had detectable spike-binding IgG antibodies at baseline, 62% were seronegative at the first visit. Vaccination-naïve individuals exhibited low antibody titers after the first mRNA vaccine dose, with a substantial increase after the second dose. However, individuals with pre-existing immunity reached higher and faster peak titers, maintaining over threefold higher responses after primary immunization.

    Seven to nine months post-primary vaccination, antibody titers were found to achieve a steady state. Individuals with hybrid immunity maintained higher and more stable titers compared to naïve recipients, indicating the induction of long-lasting serum antibodies. Furthermore, vaccine type and age were found to affect the antibody titers in participants without hybrid immunity modestly. As per the study, the administration of booster doses elevated the threshold at which long-term serum antibody responses reached a stable state.

    A total of 225 SARS-CoV-2 infections were observed in the study period, predominantly occurring after immunization, with breakthrough infections more prevalent during the Omicron wave. In individuals with vaccine-only immunity, breakthrough infections acted as equivalent boosts to antibody responses, while in those with hybrid immunity, vaccination had a more robust boosting effect compared to a second infection.

    Participants with pre-existing immunity experienced more side effects after the first vaccine dose, with overall reactogenicity decreasing after subsequent doses. Booster doses induced fewer systemic side effects than the second dose in naïve participants, while those with hybrid immunity had a different pattern, showing slightly increased side effects with booster doses.

    However, the study is limited by the inability to analyze mucosal immune responses, the lack of measuring neutralizing antibodies or antibodies to specific epitopes, and the lack of assessment of later variant spikes or nucleoprotein.

    Conclusion

    In conclusion, the present study provides evidence that antibody responses to SARS-CoV-2 mRNA vaccination exhibit a classical biphasic decay, transitioning from rapid waning to stabilization. The findings emphasize the prolonged protection provided by hybrid immunity against several variants and the potential booster-like effect of breakthrough infections in enhancing immunity.

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  • Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID

    Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID

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    SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle ache and depression. New research shows that in Long COVID patients, IFN-y production persists until symptoms improve, highlighting a potential biomarker and a target for therapies.

    Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID
    Woman sitting on sofa in the dark, placing a hand to her forehead. Image Credit: Annie Spratt via Unsplash

     A University of Cambridge-led study identifies the protein interferon gamma (IFN-γ) as a potential biomarker for Long COVID fatigue and highlights an immunological mechanism underlying the disease, which could pave the way for the development of much needed therapies, and provide a head start in the event of a future coronavirus pandemic.

     The study, published today in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.

    Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still waiting for an effective treatment.

    The study shows that initial infection with SARS-CoV-2 triggers production of the antiviral protein IFN-γ, which is a normal reaction from the immune system. For most people, when their infection clears, COVID-19 symptoms cease and production of this protein stops, but the researchers found that high levels of IFN-γ persisted in some Long COVID patients for up to 31 months.

    We have found a potential mechanism underlying Long COVID which could represent a biomarker – that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis.”

    Dr Benjamin Krishna, Co-author, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).

    The research began in 2020 when Dr Nyarie Sithole set up a Long COVID clinic in Cambridge’s Addenbrooke’s Hospital, where he started collecting blood samples from patients and set about studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the University of Cambridge’s Dept. of Medicine.

    “When the clinic started, a lot of people didn’t even believe Long COVID was real,” Dr Sithole said. “We are indebted to all the patients who volunteered for this study, without whose support and participation we would obviously not have accomplished this study.”

    The team studied 111 COVID-confirmed patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days following symptom onset. Between August 2020 and July 2021, they recruited 55 Long COVID patients – all experiencing severe symptoms at least 5 months after acute COVID-19 – attending the Long COVID clinic at Addenbrooke’s.

    The researchers analysed blood samples for signs of cytokines, small proteins crucial to the functioning of immune system cells and blood cells. They found that the white blood cells of individuals infected with SARS-CoV-2 produced IFN-γ, a pro inflammatory molecule, and that this persisted in Long COVID patients.

    Dr Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C but it causes symptoms including fatigue, fever, headache, aching muscles and depression. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.”

    By conducting ‘cell depletion assays’, the team managed to identify the precise cell types responsible for producing IFN-γ. They pinpointed immune cells known as CD8+ T cells but found that they required contact with another immune cell type: CD14+ monocytes.

    Previous studies have identified IFN-γ signatures using different approaches and cohorts, but this study’s focus on fatigue revealed a much stronger influence. Also, while previous studies have noticed IFN-y levels rising, they have not followed patients long enough to observe when they might drop back down.

    The Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN- γ.

    Vaccination helping Long COVID patients

    The team measured IFN-γ release in Long COVID patients before and after vaccination and found a significant decrease in IFN-γ post vaccination in patients whose symptoms resolved.

    “If SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-γ response, then vaccination may be helping to clear this. But we still need to find effective therapies,” Dr Krishna said.

    “The number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that. But new cases are still cropping up, and then there is the big question of what happens when the next coronavirus pandemic comes along. We could face another wave of Long COVID. Understanding what causes Long COVID now could give us a crucial head start.”

    Microclotting

    Some well-publicised previous studies have proposed microclotting as a principle cause of Long COVID.

    While not ruling out a role of some kind, these new findings suggest that microclotting cannot be the only or the most significant cause.

    Classifying long COVID

    This study argues that the presence of IFN-γ could be used to classify Long COVID into subtypes which could be used to personalise treatment.

    “It’s unlikely that all the different Long COVID symptoms are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to know why,” Dr Krishna said.

    Source:

    Journal reference:

    Krishna, B. A., et al. (2024) Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid. Science Advances. doi.org/10.1126/sciadv.adi9379.

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  • Major discovery improves the understanding of brain fog associated with Long COVID

    Major discovery improves the understanding of brain fog associated with Long COVID

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    Today, a team of scientists from Trinity College Dublin and investigators from FutureNeuro announced a major discovery that has profound importance for our understanding of brain fog and cognitive decline seen in some patients with Long COVID.

    In the months after the emergence of the novel coronavirus SARS-CoV2 in late 2019 a patient-reported syndrome termed Long-COVID began to come to the fore as an enduring manifestation of acute infection.

    Long COVID has up to 200 reported symptoms to date, but in general patients report lingering symptoms such as fatigue, shortness of breath, problems with memory and thinking and joint/muscle pain. While the vast majority of people suffering from COVID-19 make a full recovery, any of these symptoms that linger for more than 12 weeks post infection can be considered Long COVID. 

    Long COVID has now become a major public health issue since the outbreak of the pandemic in 2020. While international incidence rates vary, it is estimated to affect up to 10% of patients infected with the SARS-CoV2 virus. Of these patients suffering from Long-COVID, just under 50% of them report some form of lingering neurological effect such as cognitive decline, fatigue and brain fog. 

    Now, the findings reported by the Trinity team in the top international journal Nature Neuroscience showed that there was disruption to the integrity of the blood vessels in the brains of patients suffering from Long COVID and brain fog. This blood vessel “leakiness” was able to objectively distinguish those patients with brain fog and cognitive decline compared to patients suffering from Long-COVID but not with brain fog. 

    The team led by scientists at the Smurfit Institute of Genetics in Trinity’s School of Genetics and Microbiology and neurologists in the School of Medicine have also uncovered a novel form of MRI scan that shows how Long-COVID can affect the human brain’s delicate network of blood vessels. 

    For the first time, we have been able to show that leaky blood vessels in the human brain, in tandem with a hyperactive immune system may be the key drivers of brain fog associated with Long COVID. This is critically important, as understanding the underlying cause of these conditions will allow us to develop targeted therapies for patients in the future,”


     Prof. Matthew Campbell, Professor in Genetics and Head of Genetics at Trinity, and Principal Investigator at FutureNeuro

    This project was initiated by a rapid response grant funded by Science Foundation Ireland (SFI) at the height of the pandemic in 2020 and involved recruiting patients suffering from the effects of Long-COVID as well as patients who were hospitalised in St James’ Hospital. 

    “Undertaking this complicated clinical research study at a time of national crisis and when our hospital system was under severe pressure is a testament to the skill and resource of our medical trainees and staff. The findings will now likely change the landscape of how we understand and treat post-viral neurological conditions. It also confirms that the neurological symptoms of Long Covid are measurable with real and demonstrable metabolic and vascular changes in the brain,” said Prof. Colin Doherty, Professor of Neurology and Head of the School of Medicine at Trinity, and Principal Investigator at FutureNeuro. 

    Moving beyond COVID-19 

    In recent years, it has become apparent that many neurological conditions such as Multiple sclerosis (MS) likely have a viral infection as the initiating event that triggers the pathology. However, proving that direct link has always been challenging.

    Prof. Campbell added: “Here, the team at Trinity was able to prove that every patient that developed Long-COVID had been diagnosed with SARS-CoV2 infection, because Ireland required every documented case to be diagnosed using the more accurate PCR-based methods. The concept that many other viral infections that lead to post-viral syndromes might drive blood vessel leakage in the brain is potentially game-changing and is under active investigation by the team.” 

    Dr Chris Greene, Postdoctoral research fellow and first author of the study, added: “Our findings have now set the stage for further studies examining the molecular events that lead to post-viral fatigue and brain fog. Without doubt, similar mechanisms are at play across many disparate types of viral infection and we are now tantalizingly close to understanding how and why they cause neurological dysfunction in patients.”  

    The research was supported by Science Foundation Ireland, the European Research Council and FutureNeuro, the SFI Centre for rare and chronic neurological, neurodevelopmental and neuropsychiatric conditions.

    Source:

    Journal reference:

    Greene, C., et al. (2024). Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. doi.org/10.1038/s41593-024-01576-9.

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  • Study reveals high prevalence of persistent COVID-19 infections in general population

    Study reveals high prevalence of persistent COVID-19 infections in general population

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    A new study led by the University of Oxford has found that a high proportion of SARS-CoV-2 infections in the general population lead to persistent infections lasting a month or more. The findings have been published today in the journal Nature.

    It has long been thought that prolonged COVID-19 infections in immunocompromised individuals may have been the source of the multiple new variants that arose during the coronavirus pandemic and seeded successive waves of infection, including the Alpha and Omicron variants. But until now, the prevalence of persistent COVID-19 infections in the general population and how the virus evolves in these situations remained unknown.

    To investigate this, the researchers used data from the Office for National Statistics Covid Infection Survey (ONS-CIS), which tested participants approximately monthly. Of the 90,000+ participants, 3,603 provided two or more positive samples between November 2020 to August 2022 where the virus was sequenced. Of these, 381 individuals tested positive with the same viral infection over a period of a month or longer. Within this group, 54 individuals had a persistent infection which lasted at least two months. The researchers estimate that between one in a thousand to one in 200 (0.1-0.5%) of all infections may become persistent, and last for at least 60 days.

    In some cases, individuals remained infected with viral variants that had gone extinct in the general population. In contrast, the researchers found that reinfection with the same variant was very rare, likely due to the host developing immunity to that variant and the variant reducing in frequency to very low levels after a few months.

    Of the 381 persistent infections, 65 had three or more PCR tests taken over the course of their infection. Most (82%) of these individuals demonstrated rebounding viral dynamics, experiencing high, then low, then high viral load dynamics. According to the researchers, this demonstrates that the virus can maintain the ability to actively replicate during prolonged infections.

    In the study, people with persistent infections were 55% more likely to report having Long-COVID symptoms more than 12 weeks since the start of the infection than people with more typical infections.

    Certain individuals showed an extremely high number of mutations, including mutations that define new coronavirus variants, alter target sites for monoclonal antibodies, and introduce changes to the coronavirus spike protein. However, most individuals did not harbour a large number of mutations, suggesting that not every persistent infection will be a potential source for new concerning variants.

    Our observations highlight the continuing importance of community based genomic surveillance both to monitor the emergence and spread of new variants, but also to gain a fundamental understanding of the natural history and evolution of novel pathogens and their clinical implications for patients.”


    Dr Mahan Ghafari, Co-lead author of the study, Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford

    Co-lead author Dr Katrina Lythgoe (Department of Biology and Pandemic Sciences Institute, University of Oxford) said: ‘Although the link between viral persistence and Long Covid may not be causal, these results suggest persistent infections could be contributing to the pathophysiology of Long Covid. Indeed, many other possible mechanisms have been suggested to contribute to Long Covid including inflammation, organ damage, and microthrombosis.’

    Source:

    Journal reference:

    Ghafari, M., et al. (2024). Prevalence of persistent SARS-CoV-2 in a large community surveillance study. Nature. doi.org/10.1038/s41586-024-07029-4.

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