Maria McCavitt-Malvido

Gladstone Institutes

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Mélanie Ott

Gladstone Institutes

Taha Y. Taha

Gladstone Institutes

Mauricio Montaño

Gladstone Institutes

Irene P. Chen

Gladstone Institutes

Nevan J. Krogan

Gladstone Institutes

G.J. Correy

University of California, San Francisco

Manasi P. Jogalekar

UCSF Helen Diller Family Comprehensive Cancer Center

Patrick C. O’Leary

UCSF Helen Diller Family Comprehensive Cancer Center

Morgan E. Diolaiti

University of California, San Francisco

Alan Ashworth

UCSF Helen Diller Family Comprehensive Cancer Center

Cooperative Institutions

University of California, San Francisco

Gladstone Institutes

Quantitative BioSciences

University of California, Berkeley

Mapp Biopharmaceutical (United States)

University of California System

QB3

Universidad Católica de Santa Fe

UCSF Helen Diller Family Comprehensive Cancer Center

Chan Zuckerberg Initiative (United States)

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The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

Rahul K. Suryawanshi Priyadarshini Jaishankar G.J. Correy Moira Rachman Patrick C. O’Leary

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication in vivo by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an in vivo model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.

Viral life cycle

10.7554/elife.103484

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Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Erin A. Kuang Robert W. Cross Maria McCavitt-Malvido Dafna M. Abelson Viktoriya Borisevich

Abstract Intravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.

Ebolavirus

Intramuscular injection

10.1101/2022.01.06.475142

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Citations (3)

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Rahul K. Suryawanshi Priyadarshini Jaishankar G.J. Correy Moira Rachman Patrick C. O’Leary

10.1101/2024.08.08.606661

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Citations (4)

Previous exposure to Spike-providing parental strains confers neutralizing immunity to XBB lineage and other SARS-CoV-2 recombinants in the context of vaccination

Figshare (2023)

Rahul K. Suryawanshi Taha Y. Taha Maria McCavitt-Malvido Inês Silva Mir M. Khalid

The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as “Deltacron.” We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.

Lineage (genetic)

spike protein

10.6084/m9.figshare.24420590

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Author response: The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

Rahul K. Suryawanshi Priyadarshini Jaishankar G.J. Correy Moira Rachman Patrick C. O’Leary

10.7554/elife.103484.1.sa4

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NF-κB inhibitor alpha controls SARS-CoV-2 infection in ACE2-overexpressing human airway organoids

Scientific Reports (2024)

Camille R. Simoneau Peiyi Chen Galen Xing Jennifer M. Hayashi Irene P. Chen

Abstract As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that recapitulate the cell-intrinsic response to arising viral variants are needed. Here we describe an adult stem cell-derived human airway organoid model overexpressing the ACE2 receptor (ACE2-OE) that supports robust viral replication while maintaining 3D architecture and cellular diversity of the airway epithelium. ACE2-OE organoids were infected with SARS-CoV-2 variants and subjected to single-cell RNA-sequencing. Interferon-lambda was upregulated in cells with low-level infection while the NF-kB inhibitor alpha gene (encoding IkBa) was consistently upregulated in infected cells, and its expression positively correlated with infection levels. Confocal microscopy showed more IkBa expression in infected than bystander cells, but found concurrent nuclear translocation of NF-kB that IkBa usually prevents. Overexpressing a nondegradable IkBa mutant reduced NF-kB translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and underscore that the strength of the NF-kB feedback loop in infected cells controls viral replication.

Organoid

HEK 293 cells

10.1038/s41598-024-66003-2

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Citations (5)

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication and pathogenesisin vivo

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Taha Y. Taha Rahul K. Suryawanshi Irene P. Chen G.J. Correy Patrick C. O’Leary

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the therapeutic potential of Mac1 inhibition, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site. While substitution to alanine (N40A) reduced catalytic activity by ~10-fold, mutations to aspartic acid (N40D) reduced activity by ~100-fold relative to wildtype. Importantly, the N40A mutation rendered Mac1 unstable

Pathogenesis

Replication

Viral Pathogenesis

10.1101/2023.04.18.537104

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Citations (1)

Mild SARS-CoV-2 infection results in long-lasting microbiota instability

mBio (2023)

Vaibhav Upadhyay Rahul K. Suryawanshi Preston Tasoff Maria McCavitt-Malvido Renuka Kumar

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2-positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls. These results were confirmed and extended in the K18-humanized angiotensin-converting enzyme 2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the USA), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in

2019-20 coronavirus outbreak

Pandemic

10.1128/mbio.00889-23

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Citations (24)

Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Mir M. Khalid Irene P. Chen Frank S Soveg Taha Y. Taha Takako Tabata

The open reading frame 8 (ORF8), an accessory protein of SARS-CoV-2, is prone to deletions and mutations across different viral variants, which was first described in several Singapore variants. The reason why viral evolution favors loss or inactivation of ORF8 is not fully understood, although the effects of ORF8 on inflammation, immune evasion, and disease severity have been described. Here we show using clinical ORF8 deficient viral isolates, virus like particles (VLPs) and viral replicons that ORF8 expression dampens viral particle production. ORF8 physically interacts with the viral Spike protein and induces Golgi fragmentation, overall contributing to less virus particle production. Using systematic ORF8 deletions, we mapped the particle reducing function to its N terminal signal peptide. Interestingly, this part of ORF8 is severely truncated in the recent XBB.1.5 variant, and when restored, suppresses viral particle production in the context of the entire viral genome. Collectively, our data support the model that evolutionary pressure exists to delete ORF8 sequence and expression across SARS-CoV-2 variants to fully enable viral particle production.

10.1101/2024.03.05.583578

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Citations (1)

Previous exposure to Spike-providing parental strains confers neutralizing immunity to XBB lineage and other SARS-CoV-2 recombinants in the context of vaccination

Emerging Microbes & Infections (2023)

Rahul K. Suryawanshi Taha Y. Taha Maria McCavitt-Malvido Inês Silva Mir M. Khalid

The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as "Deltacron." We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.

Lineage (genetic)

Antigenic variation

10.1080/22221751.2023.2270071

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Citations (3)