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Friday, July 17, 2020

Elevated glucose levels favor SARS-CoV-2 infection and monocyte response via HIF-1α/glycolysis dependent axis


Author Footnotes
16 These authors contributed equally to this work.
Ana Campos Codo
Footnotes
16 These authors contributed equally to this work.
Affiliations
Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Author Footnotes
    16 These authors contributed equally to this work.
    Gustavo Gastão Davanzo
    Footnotes
    16 These authors contributed equally to this work.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Author Footnotes
    16 These authors contributed equally to this work.
    Lauar de Brito Monteiro
    Footnotes
    16 These authors contributed equally to this work.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Gabriela Fabiano de Souza
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Stéfanie Primon Muraro
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • João Victor Virgilio-da-Silva
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Juliana Silveira Prodonoff
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Victor Corasolla Carregari
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Carlos Alberto Oliveira de Biagi Junior
    Affiliations
    Department of Genetics at Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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  • Fernanda Crunfli
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Jeffersson Leandro Jimenez Restrepo
    Affiliations
    Department of Clinical and Toxicological analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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  • Pedro Henrique Vendramini
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Guilherme Reis-de-Oliveira
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Karina Bispo dos Santos
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Daniel Augusto de Toledo Teixeira
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Pierina Lorencini Parise
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    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Matheus Cavalheiro Martini
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    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Rafael Elias Marques
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    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Helison R. Carmo
    Affiliations
    Department of Clinical Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Alexandre Borin
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    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Laís Durço Coimbra
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    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Vinícius O. Boldrini
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Natalia S. Brunetti
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Andre S. Vieira
    Affiliations
    Department of Animal Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Eli Mansour
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    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Raisa G. Ulaf
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    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Ana F. Bernardes
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    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Thyago A. Nunes
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    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Luciana C. Ribeiro
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Andre C. Palma
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Marcus V. Agrela
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Maria Luiza Moretti
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Andrei C. Sposito
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    Department of Clinical Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Fabrício Bíscaro Pereira
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    Hematology and Hemotherapy Center University of Campinas, Campinas, SP, Brazil
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  • Licio Augusto Velloso
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, Brazil
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  • Marco Aurélio Ramirez Vinolo
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • André Damasio
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    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • José Luiz Proença-Módena
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    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Robson Francisco Carvalho
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    Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
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  • Marcelo A. Mori
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • Daniel Martins-de-Souza
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, BrazilD’Or Institute for Research and Education (IDOR), SP, BrazilInstituto Nacional de Biomarcadores em Neuropsiquiatria, Conselho Nacional de Desenvolvimento Científico e Tecnológico, SP, Brazil
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  • Helder I. Nakaya
    Affiliations
    Department of Clinical and Toxicological analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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  • Alessandro S. Farias
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • Pedro Manoel M. Moraes-Vieira
    Correspondence
    Corresponding Author and Lead Contact: Prof. Pedro Manoel Mendes Moraes Vieira. Rua Monteiro Lobato, 255, Bl H, Instituto de Biologia, Universidade de Campinas, Campinas, Brazil, 13083-862.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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    • Highlights

    • ●
      Elevated glucose levels regulate viral replication and cytokine production in monocytes
    • ●
      Glycolysis sustains CoV-2-induced monocyte response and viral replication
    • ●
      mtROS/HIF-1α is necessary for CoV-2 replication and monocyte cytokine production
    • ●
      Monocyte-derived cytokines drive T cell dysfunction and lung epithelial death.

    Summary

    COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes/macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.
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    SARS-CoV-2 infection induces robust, neutralizing antibody responses, stable for at least 3 months

    Ania Wajnberg, Fatima Amanat, Adolfo Firpo, Deena Altman, Mark Bailey, Mayce Mansour, Meagan McMahon, Philip Meade, Damodara Rao Mendu, Kimberly Muellers, Daniel Stadlbauer, Kimberly Stone, Shirin Strohmeier, Judith Aberg, David Reich, Florian Krammer, Carlos Cordon-Cardo
    doi: https://doi.org/10.1101/2020.07.14.20151126
    This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    Abstract

    SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 19,860 individuals screened at Mount Sinai Health System in New York City. We also show that titers are stable for at least a period approximating three months, and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses and that these titers are stable for at least the near-term future.

    Competing Interest Statement

    Mount Sinai has licensed serological assays to commercial entities and has filed for patent protection for serological assays.

    Funding Statement

    This work was partially supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract HHSN272201400008C (FK), Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (FK), and the generous support of the JPB foundation, the Open Philanthropy Project (#2020-215611) and other philanthropic donations.

    Author Declarations

    I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
    Yes

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    COVID-19 May Manifest in the Mouth in Some Patients

    You can add enanthem, or a rash inside the body, such as in the mouth, to the ever-lengthening list of symptoms with which COVID-19 patients can present, researchers in Spain suggested.
    Six of 21 patients with an exterior skin rash also had these lesions, which seemed to appear about 2 weeks after symptom onset, reported Juan Jimenez-Cauhe, MD, of Hospital Universitario Ramon y Cajal in Madrid, and colleagues, in a research letter in JAMA Dermatology.

    Skin rashes and other lesions have been described in prior research among patients with severe COVID-19 infection, but the authors noted that “whether these manifestations are directly related to COVID-19 remains unclear, since both viral infections and adverse drug reactions are frequent causes of exanthem” or rashes occurring on the outside of the body.
    They also noted how prior research found erythematovesicular and petechial patterns were most commonly associated with viral infections.
    But patients with confirmed or suspected COVID-19 are often not examined for enanthem, since the oral cavity is not examined due to safety concerns, they noted.
    Researchers examined 21 consecutive patients from a tertiary care hospital in Spain with skin rash who both tested positive for SARS-CoV-2 via real-time reverse transcriptase polymerase chain reaction (real RT-PCR) testing, and required a dermatology consult from March 30 to April 8. Patients with skin rash had their oral cavities examined.
    Notably, the mean range of time between symptom onset and the appearance of lesions was 12.3 days, with a range of -2 to 24. No drug intake or laboratory findings were associated with any type of enanthem.
    The six patients with enanthem ranged in age from 40 to 69, and four of six were women. Specifically, the authors noted no enanthem was observed in patients with urticarial or typical maculopapular rashes.
    Enanthem was located on the palate in all patients, and three of six were macular with petechiae, while two were petechial and one was macular. No patient had an erythematovesicular enanthem, the authors noted. They also said the latency was shorter in patients with petechial enanthem versus macular lesions with petechiae appearance.
    The authors noted that five of six patients had petechiae as part of the enanthem, which is consistent with prior research. Also, two patients with petechial lesions developed them “2 days before and 2 days after” the onset of COVID-19 symptoms, meaning an association with drug intake was “unlikely.”
    The authors acknowledged the small number of cases in their series, but still concluded that “the presence of enanthem is a strong clue that suggests a viral etiology rather than a drug reaction, especially when a petechial pattern is observed.”

    Disclosures
    Jimenez-Cauhe and co-authors disclosed no relevant relationships with industry.
    Primary Source
    JAMA Dermatology
    Source Reference: Jimenez-Cauhe J, et al “Enanthem in patients with COVID-19 and skin rash” JAMA Dermatol 2020; DOI: 10.1001/jamadermatol.2020.2550.

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    Merck taps Novocure cancer-fighting electric fields for Keytruda combo study

    Merck’s mainstay cancer fighter Keytruda is being evaluated in combination with dozens of different drugs, to find any headway against the disease. Now, the Big Pharma has signed up to test the PD-1 antibody alongside Novocure’s bioelectric treatment as well.
    The two companies plan to launch a phase 2 study in advanced or metastatic non-small cell lung cancer, putting the drug-plus-device regimen forward as a potential first-line treatment.
    Novocure’s Tumor Treating Fields apply specific frequencies of electricity designed to disrupt cell division within a tumor, slowing down the cancer’s growth and causing the cells to die, without applying heat or harming healthy cells.
    “Multiple preclinical studies suggest that the use of Tumor Treating Fields together with anti-PD-1 therapy can potentially augment the immune response resulting in improved tumor control,” said Novocure’s executive chairman, William Doyle.

    In May 2019, Novocure received an humanitarian device approval from the FDA for its use against mesothelioma—as an add-on to Eli Lilly’s combination treatment of Alimta and cisplatin chemotherapy—making it the first new treatment option for the lung disease in 15 years.
    That approval was also the company’s first outside of brain cancer, following a 2011 green light in glioblastoma when given with temozolomide chemotherapy, surgery and radiation. Currently, Novocure is also studying the use of its Tumor Treating Fields in liver, ovarian and pancreatic cancer, as well as in brain metastases.
    The new pilot study with Merck aims to enroll about 66 NSCLC patients in the U.S. and launch before the end of this year, while tracking responses to the therapy combination and survival out to one year.

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    South Korea approves human trials of Celltrion’s COVID-19 antibody drug

    South Korea on Friday approved an early stage clinical trial of Celltrion Inc’s experimental COVID-19 treatment drug, making it the country’s first such antibody drug to be tested on humans.

    Drugmakers worldwide are scrambling to develop vaccines and treatments for the flu-like illness caused by the novel coronavirus that has infected nearly 14 million people and killed more than 580,000 globally.
    Celltrion’s antibody treatment is directed against the surface of the virus and designed to block it from locking on to human cells.
    The company plans to enrol 32 healthy volunteers in collaboration with a local hospital for Phase I study of the drug, which demonstrated an up to 100-fold reduction in viral load in animal tests.
    Celltrion said overseas human trials of its treatment will begin soon across Europe, including the UK, which will be followed by global second and third trials in patients with mild and moderate symptoms.
    It anticipates primary results from these studies by the end of this year and aims to commercialize the drug by early 2021, it said.
    “Our human trials are conducted globally, so we will be able to export for sure, but will offer it to patients abroad only after securing domestic supplies for South Korea,” Kee Woo-sung, its chief executive officer, told Reuters.
    Its antibody treatment was developed after it was identified from a blood sample taken from one of the first South Korean patients who recovered from COVID-19 in February.
    He said drugmakers should make prices for their COVID-19 treatments affordable to help end the pandemic, adding prices of its drug will be cheaper than that of Gilead Sciences Inc’s antiviral drug remdesivir.
    In June, Gilead priced its COVID-19 treatment remdesivir at $2,340 per patient for developed nations.
    Other companies developing potential COVID-19 treatments include Eli Lilly and Co, Regeneron Pharmaceuticals Inc and AbbVie.

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    Sanofi forges ahead with active ingredients spin-off

    Sanofi is starting preparations for a stock market listing of its active ingredients business as the French drugmaker pushes ahead with a strategy focusing on its more profitable businesses, sources told Reuters.

    CEO Paul Hudson set out a plan in December to boost profits by 2022 by exiting diabetes and cardiovascular research and slashing costs, and said in February that it would create a separate company for the manufacturing of active pharmaceutical ingredients (API), the essential components of a drug.
    Sources said Sanofi could start marketing the API unit to potential individual investors in the autumn while also initiating work on an initial public offering, which could take place in late 2021 if all goes according to plan.
    It had said it would decide by 2022 whether to list the separated business on the Euronext Paris stock exchange.
    Depending on what Sanofi opts to put into the carved-out unit, the API business could be valued at between 1 and 2 billion euros ($1.15-2.3 billion), the sources said.
    France’s state investment bank Bpifrance was involved in discussions and was considering taking a stake, according to several sources.
    France’s state investment bank Bpifrance was involved in discussions and was considering taking a stake, according to several sources.
    Two sources said other institutional investors, in Germany and at a regional level in France, had also been approached and were involved in discussions.
    POLITICALLY SENSITIVE
    The process is likely to be sensitive in the context of the coronavirus pandemic. President Emmanuel Macron has pledged several times to diminish the heavy reliance of France on drugs made outside the country.
    “Sanofi remains committed to executing our IPO on Euronext Paris as planned. We are not reviewing any other financial alternative option,” a group spokesman said in an emailed statement.
    Sanofi’s adviser Rothschild and Bpifrance declined to comment.
    “Separating the API business is extremely complex and will take some time. Sanofi may decide to keep the most profitable parts. Earnings of the standalone API unit will also depend on the supply contracts it would sign with Sanofi,” one of the sources said.
    Sanofi has said it wants to retain a minority stake in the business and become a customer. The new company would rank as the world’s second-biggest API player by sales, behind Switzerland’s Lonza, in a $170 billion market otherwise dominated by manufacturers from India and China.
    “Shaping the future of the API will be one of the first priorities of the management team after the summer break and everyone is well aware the discussions with the employee representatives will be very challenging,” one of the sources said, asking not to be named for confidentiality reasons.
    “It is also seen as a test for (CEO) Hudson as he will have to demonstrate his team can mastermind a complex operation in the current context,” the source said, adding talks with unions would start in September.
    JOBS IN FOCUS
    Sanofi has said the new group would be headquartered in France, operate with at least 3,100 skilled employees and have sales estimated at about 1 billion euros by 2022.
    The business would be established on the back of six of Sanofi’s European API production sites in France, as well as Italy, Germany, Britain and Hungary.
    One of the issues would be defining the status and work contracts of the employees at the new entity, the source said, as Sanofi would only retain around 30% of the new business.
    The relationship between management and unions is already strained following Sanofi’s decision last month to cut up to 1,680 jobs in Europe over the next three years.
    Hudson, who took the reins in September, has taken steps to simplify the business, moving it from a generalist pharmaceutical company towards a leaner player centred around vaccines, rare diseases and oncology.
    Sanofi is also taking a bold approach to tackling COVID-19, the illness caused by the new coronavirus which has killed more than 590,000 globally, being the sole big pharma group pursuing two vaccine candidates using different technologies.
    The company’s balance sheet received a $11.7 billion cash boost in May after Sanofi sold most of its 20.6% stake in U.S. group Regeneron. The money is expected to be spent on innovation and acquisitions.
    Bankers expect bolt-on deals for biotech companies, similar to its purchase last year of Synthorx, a Californian company focused on therapies for patients with cancer and auto-immune disorders.
    A possible sale of Sanofi’s consumer health operation is also being considered.

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    Russia’s R-Pharm signs deal to make UK-developed COVID-19 vaccine

    Russian drugmaker R-Pharm has signed a deal with AstraZeneca for it to manufacture a COVID-19 vaccine being developed by the British pharmaceuticals giant and Oxford University, it said on Friday.

    Following allegations from Britain, Canada and the United States that hackers backed by Russia were trying to steal COVID-19 vaccine and treatment research, the head of Russia’s wealth fund said the deal showed that Moscow has no need to steal anything.
    “We have formalised this plan in the form of signed agreements in the area of production and supply of the vaccine, developed by AstraZeneca and Oxford University, using R-Pharm to fulfil the project,” said R-Pharm’s board chairman, Alexey Repik.

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