AI-guided discovery of the invariant host response to viral pandemics

ABSTRACTWe sought to define the host immune response, a.k.a, the “cytokine storm” that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a ‘seed’ gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

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Recombinant Viruses for Cancer Therapy

Biomedicines ◽

10.3390/biomedicines6040094 ◽

2018 ◽

Vol 6 (4) ◽

pp. 94 ◽

Cited By ~ 11

Author(s):

Daria Chulpanova ◽

Valeriya Solovyeva ◽

Kristina Kitaeva ◽

Stephen Dunham ◽

Svetlana Khaiboullina ◽

...

Keyword(s):

Immune Response ◽

Cancer Therapy ◽

Immune Surveillance ◽

Oncolytic Viruses ◽

Host Cells ◽

Therapeutic Goals ◽

Recombinant Viruses ◽

Wide Range ◽

Anti Cancer ◽

Specific Antigens

Recombinant viruses are novel therapeutic agents that can be utilized for treatment of various diseases, including cancers. Recombinant viruses can be engineered to express foreign transgenes and have a broad tropism allowing gene expression in a wide range of host cells. They can be selected or designed for specific therapeutic goals; for example, recombinant viruses could be used to stimulate host immune response against tumor-specific antigens and therefore overcome the ability of the tumor to evade the host’s immune surveillance. Alternatively, recombinant viruses could express immunomodulatory genes which stimulate an anti-cancer immune response. Oncolytic viruses can replicate specifically in tumor cells and induce toxic effects leading to cell lysis and apoptosis. However, each of these approaches face certain difficulties that must be resolved to achieve maximum therapeutic efficacy. In this review we discuss actively developing approaches for cancer therapy based on recombinant viruses, problems that need to be overcome, and possible prospects for further development of recombinant virus based therapy.

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Antibody response to SARS-CoV-2 infection and BNT162b2 vaccine in Israel

10.1101/2021.07.07.21259499 ◽

2021 ◽

Author(s):

Guy Shapira ◽

Ramzia Abu Hamad ◽

Chen Weiner ◽

Nir Rainy ◽

Reut Sorek-Abramovich ◽

...

Keyword(s):

Immune Response ◽

Viral Entry ◽

Neutralizing Antibodies ◽

Host Cells ◽

Spike Protein ◽

Igg Antibodies ◽

Age And Gender ◽

Specific Igg ◽

And Gender ◽

Specific Igg Antibodies

Neutralizing antibodies targeting the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) block viral entry to host cells, preventing disease and further spread of the pathogen. The presence of SARS-CoV-2 antibodies in serum is a reliable indicator of infection, used epidemiologically to estimate the prevalence of infection and clinically as a measurement of an antigen-specific immune response. In this study, we analyzed serum Spike protein-specific IgG antibodies from 26,170 samples, including convalescent individuals who had coronavirus disease 2019 (COVID-19) and recipients of the BNT162b2 vaccine. We find distinct serological patterns in COVID-19 convalescent and vaccinated individuals, correlated with age and gender and the presence symptoms.

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SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

10.1101/2020.07.31.228486 ◽

2020 ◽

Cited By ~ 6

Author(s):

Marco Mandolesi ◽

Daniel J Sheward ◽

Leo Hanke ◽

Junjie Ma ◽

Pradeepa Pushparaj ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Host Cells ◽

High Dose ◽

Protein Subunit ◽

High Dose Regimen ◽

Antibody Titers ◽

Protein Immunization

The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

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Prospective Artificial Intelligence to Dissect the Dengue Immune Response and Discover Therapeutics

Frontiers in Immunology ◽

10.3389/fimmu.2021.574411 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eriberto N. Natali ◽

Lmar M. Babrak ◽

Enkelejda Miho

Keyword(s):

Immune Response ◽

Neutralizing Antibodies ◽

High Throughput Sequencing ◽

Host Cells ◽

Multiple Infections ◽

Complex Data ◽

Denv Serotypes ◽

T Cell Immune Responses ◽

Efficacious Vaccine ◽

Sequential Infection

Dengue virus (DENV) poses a serious threat to global health as the causative agent of dengue fever. The virus is endemic in more than 128 countries resulting in approximately 390 million infection cases each year. Currently, there is no approved therapeutic for treatment nor a fully efficacious vaccine. The development of therapeutics is confounded and hampered by the complexity of the immune response to DENV, in particular to sequential infection with different DENV serotypes (DENV1–5). Researchers have shown that the DENV envelope (E) antigen is primarily responsible for the interaction and subsequent invasion of host cells for all serotypes and can elicit neutralizing antibodies in humans. The advent of high-throughput sequencing and the rapid advancements in computational analysis of complex data, has provided tools for the deconvolution of the DENV immune response. Several types of complex statistical analyses, machine learning models and complex visualizations can be applied to begin answering questions about the B- and T-cell immune responses to multiple infections, antibody-dependent enhancement, identification of novel therapeutics and advance vaccine research.

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Interleukin-17A (IL-17A): the silent amplifier of COVID-19

10.22541/au.161826946.65721162/v1 ◽

2021 ◽

Author(s):

Francesco Maione ◽

Gian Casillo ◽

Federica Raucci ◽

Mariarosaria Bucci

Keyword(s):

Immune Response ◽

Disease Progression ◽

Clinical Outcomes ◽

Disease Severity ◽

Systemic Inflammation ◽

Therapeutic Strategies ◽

Cytokine Storm ◽

Interleukin 17A ◽

Potential Link ◽

Per Se

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated levels of interleukin-17A (IL-17A) and disease severity and progression. Considering that per se IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, this cytokine can represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this “unique” cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy.

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Role of poly (ADP) ribose polymerase-1 inhibition by nicotinamide as a possible additive treatment to modulate host immune response and prevention of cytokine storm in COVID-19

Indian Journal of Medical Sciences ◽

10.25259/ijms_29_2020 ◽

2020 ◽

Vol 72 ◽

pp. 25-28 ◽

Cited By ~ 6

Author(s):

Mukul Arvind Gharote

Keyword(s):

Immune Response ◽

Lung Injury ◽

Parp Inhibitor ◽

Lung Parenchyma ◽

Chinese Patients ◽

High Dose ◽

Cytokine Storm ◽

Ventilator Induced Lung Injury ◽

Patients At Risk ◽

Macrophage Colony

COVID-19 is rapidly spreading contagious disease spreading across the world. Patients at risk are elderly people and those with comorbidity. Early studies done on Chinese patients who suggest cytokine storm to be responsible for lung injury. We need to understand the mechanism of modulating such robust response of immunity and resultant cytokine storm. We suggest nicotinamide, a potential poly ADP ribose polymerase (PARP) inhibitor, as a supportive treatment for the prevention of cytokine storm from injuring the lung parenchyma. Nicotinamide supplementation albeit at high dose may modulate outcome in COVID-19. Nicotinamide was used previously to reduce ventilator-induced lung injury and lung injury due to hypoxia. Nicotinamide congeners are used to treat chronic lung disease like tuberculosis. Certainly, nicotinamide is effective pharmacotherapy in lung injury – whether acute or chronic. Other measures used in treating COVID-19 are focusing on targeting interleukin-6 – a cytokine responsible for mayhem, while few are targeting granulocyte-macrophage colony- stimulating factor. We suggest targeting PARP in addition to other measures to block cytokines. By inhibiting PARP course of COVID-19 may be altered. Understanding the pathophysiology of acute lung injury is crucial. PARP plays a pivotal role on cytokine release in response to any lung injury ranging from viral infection to hypoxia. Various antiviral defenses and immune response need to be studied in detail.

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Circulating Exosomes Are Strongly Involved in SARS-CoV-2 Infection

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.632290 ◽

2021 ◽

Vol 8 ◽

Author(s):

Elettra Barberis ◽

Virginia V. Vanella ◽

Marco Falasca ◽

Valeria Caneapero ◽

Giuseppe Cappellano ◽

...

Keyword(s):

Immune Response ◽

Disease Severity ◽

Area Under The Curve ◽

Multiple Organ ◽

Host Cells ◽

Diagnostic Feature ◽

The Novel ◽

Proteomic Approach ◽

Novel Coronavirus ◽

First Time

Knowledge of the host response to the novel coronavirus SARS-CoV-2 remains limited, hindering the understanding of COVID-19 pathogenesis and the development of therapeutic strategies. During the course of a viral infection, host cells release exosomes and other extracellular vesicles carrying viral and host components that can modulate the immune response. The present study used a shotgun proteomic approach to map the host circulating exosomes’ response to SARS-CoV-2 infection. We investigated how SARS-CoV-2 infection modulates exosome content, exosomes’ involvement in disease progression, and the potential use of plasma exosomes as biomarkers of disease severity. A proteomic analysis of patient-derived exosomes identified several molecules involved in the immune response, inflammation, and activation of the coagulation and complement pathways, which are the main mechanisms of COVID-19–associated tissue damage and multiple organ dysfunctions. In addition, several potential biomarkers—such as fibrinogen, fibronectin, complement C1r subcomponent and serum amyloid P-component—were shown to have a diagnostic feature presenting an area under the curve (AUC) of almost 1. Proteins correlating with disease severity were also detected. Moreover, for the first time, we identified the presence of SARS-CoV-2 RNA in the exosomal cargo, which suggests that the virus might use the endocytosis route to spread infection. Our findings indicate circulating exosomes’ significant contribution to several processes—such as inflammation, coagulation, and immunomodulation—during SARS-CoV-2 infection. The study’s data are available via ProteomeXchange with the identifier PXD021144.

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Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19)

Microbiology Australia ◽

10.1071/ma21013 ◽

2021 ◽

Vol 42 (1) ◽

pp. 47

Author(s):

Erik De Clercq

Keyword(s):

Protease Inhibitors ◽

Host Cells ◽

High Dose ◽

Cytokine Storm ◽

Efficacy And Safety ◽

Virus Adsorption ◽

The Us ◽

Safety Studies ◽

Us Fda ◽

Very High

Compared with vaccines, antivirals for curbing COVID-19 (SARS-CoV-2 infection) have been developed at a much lower pace. Favipiravir has proven efficacious (in hamsters) but only at a very high dose which may not be feasible in humans. Remdesivir is the sole antiviral approved by the US FDA, but it has not been extensively evaluated for its safety. EIDD-1931 and EIDD-2801 have not been evaluated clinically. Mpro (protease) inhibitors likewise need to be subjected to clinical efficacy and safety studies. Remdesivir is a C-nucleoside and this class of compounds should be further evaluated. Polyanionic substances interfering with virus adsorption to the host cells have not been explored. They may possibly be administered by inhalation. Corticosteroids (such as dexamethasone), while virus-stimulating rather than inhibitory, may counteract the ‘cytokine storm’. Combination of (two or more of) the compounds mentioned above may offer an increased benefit through a synergistic interaction.

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SARS-CoV-2 variants: A double-edged sword?

Experimental Biology and Medicine ◽

10.1177/15353702211014146 ◽

2021 ◽

pp. 153537022110141

Author(s):

Manasi P Jogalekar ◽

Anurag Veerabathini ◽

Prakash Gangadaran

Keyword(s):

Immune Response ◽

Disease Severity ◽

Vaccine Efficacy ◽

Neutralizing Antibodies ◽

Viral Evolution ◽

Herd Immunity ◽

Spike Protein ◽

Local Strains ◽

Risk Of Death ◽

Main Target

Since the worldwide emergence of the COVID-19 outbreak, there have been international concerns about the possible viral evolution into variants with underlying mutations that may contribute to their increased transmissibility, disease severity, risk of death, and their potential escape from the immune response or may even lead to its extinction. Rigorous surveillance has revealed the variants harboring mutations in the spike protein, the main target of neutralizing antibodies generated through vaccination or herd immunity. In this review, we have highlighted major SARS-CoV-2 variants as well as other local strains along with their specific mutations, suspected changes in their characteristics, and their impact on the current pandemic and vaccine efficacy. We have also emphasized the need to develop widely protective interventions to curb further transmission of variants.

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