Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Hilligan, Kerry L.; Namasivayam, Sivaranjani; Clancy, Chad S.; O’Mard, Danielle; Oland, Sandra D.; Robertson, Shelly J.; Baker, Paul J.; Castro, Ehydel; Garza, Nicole L.; Lafont, Bernard A. P.; Johnson, Reed F.; Ronchese, Franca; Mayer‐Barber, Katrin D.; Best, Sonja M.; Sher, Alan

doi:10.1084/jem.20211862

Cited by 80 publications

(96 citation statements)

References 47 publications

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“…Such non-specific protection by BCG against non-mycobacterial infections and perhaps other non-infectious disorders include induction of: (i) a heterologous TH1, TH17, and CD8+ lymphocytic response and (ii) a non-specific memory in innate immune cells (natural killer cells, monocytes, and macrophages) through epigenetic effects and metabolic rewiring in a paradigm known as "trained immunity" [33]. Of contemporary note is the investigation of BCG in the COVID-19 pandemic; BCG benefit has been shown in both animal COVID-19 studies and humans where BCG demonstrated a "synergy" with COVID-19 vaccination [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

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Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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“…Plates were stained with crystal violet after 96 h to assess CPE. Viral titers were determined using the Reed-Muench method (54).…”

Section: Mitochondrial Superoxide Assaymentioning

confidence: 99%

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

et al. 2022

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The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16− monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.

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“…The type of vaccines available includes the following: (1) inactive or live attenuated whole virus vaccine (US20060039926 13 and CoronaVac [Sinovac Biotech in China]); (2) nucleic acid vaccines, including DNA and mRNA vaccines, such as ino-4800 and mRNA-1273; 14 (3) recombinant protein vaccines, including recombinant S protein vaccines, recombinant S protein subunit vaccines, 15 and virus-like particle vaccines; (4) viral vector vaccines, including replication-incompetent vector vaccines, replication-competent vector vaccines, and inactivated virus vectors such as adenoviral vector vaccine; 16 and (5) other types of vaccines, such as Bacille Calmette-Guerin (BCG) Vaccines. 17 Moreover, various potential drugs have been proposed for the treatment of COVID-19. These can be divided into the following groups: (1) chemical medicines, such as nucleoside analogs (chloroquine, hydroxychloroquine, remdesivir, tenofovir, and sofosbuvir); 18 , 19 (2) Traditional Chinese medicines, such as Lianhua Qingwen; 20 and (3) biological agents, including antibodies, vaccines, peptides, oligonucleotides (aptamer, antisense oligonucleotides, small interfering RNAs [siRNAs], RNA interference [RNAi]), interferons, 21 corticosteroids, 22 plasma, 23 and mesenchymal stem cells.…”

Section: Introductionmentioning

confidence: 99%

Structural biology of SARS-CoV-2: open the door for novel therapies

Zheng

Zeng

et al. 2022

Sig Transduct Target Ther

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of the pandemic disease COVID-19, which is so far without efficacious treatment. The discovery of therapy reagents for treating COVID-19 are urgently needed, and the structures of the potential drug-target proteins in the viral life cycle are particularly important. SARS-CoV-2, a member of the Orthocoronavirinae subfamily containing the largest RNA genome, encodes 29 proteins including nonstructural, structural and accessory proteins which are involved in viral adsorption, entry and uncoating, nucleic acid replication and transcription, assembly and release, etc. These proteins individually act as a partner of the replication machinery or involved in forming the complexes with host cellular factors to participate in the essential physiological activities. This review summarizes the representative structures and typically potential therapy agents that target SARS-CoV-2 or some critical proteins for viral pathogenesis, providing insights into the mechanisms underlying viral infection, prevention of infection, and treatment. Indeed, these studies open the door for COVID therapies, leading to ways to prevent and treat COVID-19, especially, treatment of the disease caused by the viral variants are imperative.

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Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Cited by 80 publications

References 47 publications

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

Structural biology of SARS-CoV-2: open the door for novel therapies

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