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Article ; Online: Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination.

Suberi, Alexandra / Grun, Molly K / Mao, Tianyang / Israelow, Benjamin / Reschke, Melanie / Grundler, Julian / Akhtar, Laiba / Lee, Teresa / Shin, Kwangsoo / Piotrowski-Daspit, Alexandra S / Homer, Robert J / Iwasaki, Akiko / Suh, Hee-Won / Saltzman, W Mark

Science translational medicine

2023 Volume 15, Issue 709, Page(s) eabq0603

Abstract: An inhalable platform for messenger RNA (mRNA) therapeutics would enable minimally invasive and lung-targeted delivery for a host of pulmonary diseases. Development of lung-targeted mRNA therapeutics has been limited by poor transfection efficiency and ... ...

Abstract	An inhalable platform for messenger RNA (mRNA) therapeutics would enable minimally invasive and lung-targeted delivery for a host of pulmonary diseases. Development of lung-targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here, we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-
MeSH term(s)	Animals ; Mice ; Polymers ; RNA, Messenger/genetics ; COVID-19/prevention & control ; Lung ; Vaccination ; Nanoparticles
Chemical Substances	Polymers ; RNA, Messenger
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abq0603
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Article: Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2.

Israelow, Benjamin / Mao, Tianyang / Klein, Jonathan / Song, Eric / Menasche, Bridget / Omer, Saad B / Iwasaki, Akiko

bioRxiv : the preprint server for biology

2021

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 160 million infections and more than 3 million deaths worldwide. While effective vaccines are currently being deployed, the adaptive immune determinants which promote viral ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 160 million infections and more than 3 million deaths worldwide. While effective vaccines are currently being deployed, the adaptive immune determinants which promote viral clearance and confer protection remain poorly defined. Using mouse models of SARS-CoV-2, we demonstrate that both humoral and cellular adaptive immunity contributes to viral clearance in the setting of primary infection. Furthermore, we find that either convalescent mice, or mice that receive mRNA vaccination are protected from both homologous infection and infection with a variant of concern, B.1.351. Additionally, we find this protection to be largely mediated by antibody response and not cellular immunity. These results highlight the One-sentence summary: Defining the roles of humoral and cellular adaptive immunity in viral clearance and protection from SARS-CoV-2 and a variant of concern.
Language	English
Publishing date	2021-05-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.05.19.444825
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Article ; Online: Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2.

Israelow, Benjamin / Mao, Tianyang / Klein, Jonathan / Song, Eric / Menasche, Bridget / Omer, Saad B / Iwasaki, Akiko

Science immunology

2021 Volume 6, Issue 64, Page(s) eabl4509

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 160 million infections and more than 3 million deaths worldwide. Although effective vaccines are currently being deployed, the adaptive immune determinants that promote ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 160 million infections and more than 3 million deaths worldwide. Although effective vaccines are currently being deployed, the adaptive immune determinants that promote viral clearance and confer protection remain poorly defined. Using mouse models of SARS-CoV-2, we demonstrate that both humoral and cellular adaptive immunity contribute to viral clearance in the setting of primary infection. Furthermore, we find that either convalescent mice or mice that receive mRNA vaccination are protected from both homologous infection and infection with a variant of concern, B.1.351. In addition, we find that this protection is largely mediated by antibody response and not cellular immunity. These results highlight the in vivo protective capacity of antibodies generated to both vaccine and natural infection.
MeSH term(s)	Animals ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; COVID-19 Vaccines/pharmacology ; Chlorocebus aethiops ; Disease Models, Animal ; Female ; Immunity, Cellular ; Immunity, Humoral ; Male ; Mice ; Mice, Knockout ; SARS-CoV-2/immunology ; Vero Cells
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2021-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abl4509
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Thesis ; Online: Utilizing miR-122 to examine hepatitis C virus-host interactions

Goldman-Israelow, Benjamin

2014

Abstract: The relationship between hepatitis C virus (HCV) and the liver specific microRNA miR- 122 is unusual. While most miRNAs inhibit translation when bound to their targets, miR- 122 increases HCV protein expression by binding to its RNA genome to enhance RNA ...

Abstract	The relationship between hepatitis C virus (HCV) and the liver specific microRNA miR- 122 is unusual. While most miRNAs inhibit translation when bound to their targets, miR- 122 increases HCV protein expression by binding to its RNA genome to enhance RNA stability and replication. Developing a cell system that supports the HCV lifecycle took almost 10 years of research. Huh-7 cells, which are one of the only cell lines found to support the entire HCV lifecycle, are also one of the only cell lines found to express miR-122. We hypothesized that insufficient miR-122 expression in most other hepatocyte derived cell lines was the reason they could not support HCV replication. Indeed, when we engineered HepG2 cells to express miR-122, HCV replication was greatly enhanced. We went on to show that HepG2 cells overexpressing both the missing entry factor CD81 in addition to miR-122 supported the entire HCV lifecycle. We found a striking difference in these cells' ability to sustain HCV infection and spread when compared to Huh-7 and Huh-7.5 cells, which was accompanied by robust antiviral and proinflammatory response reminiscent of HCV infections in vivo. Furthermore, blocking RIG-I like receptor and IFN-λ signaling pathways promoted HCV infection and spread in these cells. These studies further solidify the importance of IFN-λ in the hepatic response to HCV infection and revealed non-redundant roles of RIG-I and MDA5 in HCV recognition and antiviral response. Finally, we set out to better understand how miR-122 inhibition influences HCV replication over time and if HCV can develop resistance to miR-122 inhibition. We found a single nucleotide change at position 28 (G28A) of the HCV genome, which falls between the two miR-122 seed- binding sites, and enhanced HCV replication in cells with low miR-122 activity. Naturally occurring HCV isolates encoding an A at nucleotide 28 were similarly resistant to miR- 122 inhibition, indicating that subtle differences in viral sequence, even outside the seed-binding site, greatly influence HCV's requirement for miR-122. These studies provide insight into the interaction between miR-122 and HCV, and have important implications for the development of anti-miR-122-based HCV drugs. Taken together, these studies demonstrate how manipulation of miR-122 can reveal new and important information about HCV host-cell interactions.
Keywords	Microbiology\|Virology\|Immunology
Subject code	570 ; 360
Language	ENG
Publishing date	2014-01-01 00:00:01.0
Publisher	Icahn School of Medicine at Mount Sinai
Publishing country	us
Document type	Thesis ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses.

Mao, Tianyang / Israelow, Benjamin / Suberi, Alexandra / Zhou, Liqun / Reschke, Melanie / Peña-Hernández, Mario A / Dong, Huiping / Homer, Robert J / Saltzman, W Mark / Iwasaki, Akiko

bioRxiv : the preprint server for biology

2022

Abstract: As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor ... ...

Abstract	As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin. One-sentence summary: Broad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.
Language	English
Publishing date	2022-01-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.01.24.477597
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Article: Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination.

bioRxiv : the preprint server for biology

2022

Abstract: An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle- ... ...

Abstract	An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge. One-sentence summary: Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.
Language	English
Publishing date	2022-03-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.03.22.485401
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Article ; Online: Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.

Mao, Tianyang / Israelow, Benjamin / Peña-Hernández, Mario A / Suberi, Alexandra / Zhou, Liqun / Luyten, Sophia / Reschke, Melanie / Dong, Huiping / Homer, Robert J / Saltzman, W Mark / Iwasaki, Akiko

Science (New York, N.Y.)

2022 Volume 378, Issue 6622, Page(s) eabo2523

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the ... ...

Abstract	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the respiratory mucosa. We developed a vaccine strategy that we call "prime and spike," which leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike). We show that prime and spike induces robust resident memory B and T cell responses, induces immunoglobulin A at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, prime and spike enables the induction of cross-reactive immunity against sarbecoviruses.
MeSH term(s)	Animals ; Mice ; Administration, Intranasal ; Antibodies, Viral ; COVID-19/prevention & control ; COVID-19/transmission ; Immunity, Mucosal ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Vaccination/methods ; COVID-19 Vaccines/administration & dosage ; COVID-19 Vaccines/immunology ; Immunoglobulin A ; Memory B Cells/immunology ; Memory T Cells/immunology ; Immunologic Memory
Chemical Substances	Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; COVID-19 Vaccines ; Immunoglobulin A
Language	English
Publishing date	2022-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abo2523
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Mao, Tianyang / Kim, Jooyoung / Peña-Hernández, Mario A / Valle, Gabrielee / Moriyama, Miyu / Luyten, Sophia / Ott, Isabel M / Gomez-Calvo, Maria Luisa / Gehlhausen, Jeff R / Baker, Emily / Israelow, Benjamin / Slade, Martin / Sharma, Lokesh / Liu, Wei / Ryu, Changwan / Korde, Asawari / Lee, Chris J / Silva Monteiro, Valter / Lucas, Carolina /

Dong, Huiping / Yang, Yi / Gopinath, Smita / Wilen, Craig B / Palm, Noah / Dela Cruz, Charles S / Iwasaki, Akiko

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 18, Page(s) e2319566121

Abstract: Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that ... ...

Abstract	Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2319566121
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Zs.A 1148: Show issues

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Article: A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice.

Mao, Tianyang / Israelow, Benjamin / Lucas, Carolina / Vogels, Chantal B F / Fedorova, Olga / Breban, Mallery I / Menasche, Bridget L / Dong, Huiping / Linehan, Melissa / Wilen, Craig B / Landry, Marie L / Grubaugh, Nathan D / Pyle, Anna M / Iwasaki, Akiko

bioRxiv : the preprint server for biology

2021

Abstract: As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in ...

Abstract	As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral replication in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I) dependent manner. SLR14 demonstrated remarkable protective capacity against lethal SARS-CoV-2 infection when used prophylactically and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity by inducing IFN-I responses in the absence of the adaptive immune system. In the context of infection with variants of concern (VOC), SLR14 conferred broad protection and uncovered an IFN-I resistance gradient across emerging VOC. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and for treatment of chronically infected immunosuppressed patients.
Language	English
Publishing date	2021-06-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.06.16.448754
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Article ; Online: Rapid, reliable, and reproducible cell fusion assay to quantify SARS-Cov-2 spike interaction with hACE2.

Zhao, Min / Su, Pei-Yi / Castro, Danielle A / Tripler, Therese N / Hu, Yingxia / Cook, Matthew / Ko, Albert I / Farhadian, Shelli F / Israelow, Benjamin / Dela Cruz, Charles S / Xiong, Yong / Sutton, Richard E

PLoS pathogens

2021 Volume 17, Issue 6, Page(s) e1009683

Abstract: COVID-19 is a global crisis of unimagined dimensions. Currently, Remedesivir is only fully licensed FDA therapeutic. A major target of the vaccine effort is the SARS-CoV-2 spike-hACE2 interaction, and assessment of efficacy relies on time consuming ... ...

Abstract	COVID-19 is a global crisis of unimagined dimensions. Currently, Remedesivir is only fully licensed FDA therapeutic. A major target of the vaccine effort is the SARS-CoV-2 spike-hACE2 interaction, and assessment of efficacy relies on time consuming neutralization assay. Here, we developed a cell fusion assay based upon spike-hACE2 interaction. The system was tested by transient co-transfection of 293T cells, which demonstrated good correlation with standard spike pseudotyping for inhibition by sera and biologics. Then established stable cell lines were very well behaved and gave even better correlation with pseudotyping results, after a short, overnight co-incubation. Results with the stable cell fusion assay also correlated well with those of a live virus assay. In summary we have established a rapid, reliable, and reproducible cell fusion assay that will serve to complement the other neutralization assays currently in use, is easy to implement in most laboratories, and may serve as the basis for high throughput screens to identify inhibitors of SARS-CoV-2 virus-cell binding and entry.
MeSH term(s)	Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Biological Assay/methods ; COVID-19/blood ; COVID-19/virology ; Cell Fusion ; HEK293 Cells ; Humans ; Receptors, Coronavirus/genetics ; Receptors, Coronavirus/metabolism ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Transfection ; Virus Attachment
Chemical Substances	Receptors, Coronavirus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009683
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