Biology subjects

Ignacio, M. A.

Publications and source records attributed to Ignacio, M. A..

3 recordsLinked to original sources

bioRxiv2024

Mpox mRNA-1769 Vaccine Inhibits Orthopoxvirus Replication at Intranasal, Intrarectal, and Cutaneous Sites of Inoculation

The increasing incidence of mpox in Africa and the recent global outbreak with evidence of sexual transmission have stimulated interest in new vaccines and therapeutics. Our previous study demonstrated that mice immunized twice with a quadrivalent lipid nanoparticle vaccine comprising four monkeypox virus mRNAs raised neutralizing antibodies and antigen-specific T cells and were protected against a lethal intranasal challenge with vaccinia virus. Here we extended these findings by using live animal imaging to demonstrate that the mRNA vaccine greatly reduced virus replication and spread from an intranasal site of inoculation and prevented detectable replication at intrarectal and cutaneous inoculation sites. Moreover, considerable protection was achieved with a single vaccination and a booster vaccination enhanced protection for at least 4 months. Protection was related to the amount of mRNA inoculated, which correlated with neutralizing antibody levels. The role of antibody in protection was demonstrated by passive transfer of immune serum pre- or post-challenge to immunocompetent and immunodeficient mice lacking mature B and T cells and therefore unable to mount an adaptive response. These findings provide insights into the mechanism and extent of mRNA vaccine induced protection of orthopoxviruses and support clinical testing.

microbiology↗

bioRxiv2023

Inhibition of SARS-CoV-2 Infection in Human Airway Epithelium with a Xeno-Nucleic Acid Aptamer

BackgroundSARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. MethodsHere, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. ResultsWe demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. ConclusionsTogether, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

microbiology↗

bioRxiv2023

Mucus physically restricts influenza A viral particle access to the epithelium

Prior work suggests influenza A virus (IAV) crosses the airway mucus barrier in a sialic acid-dependent manner through the actions of the viral envelope glycoproteins, hemagglutinin and neuraminidase. However, host and viral factors that influence how efficiently mucus traps IAV remain poorly defined. In this work, we assessed how the physicochemical properties of mucus influence its ability to effectively capture IAV using fluorescence video microscopy and multiple particle tracking. We found an airway mucus gel layer must be produced with virus-sized pores to physically constrain IAV. While sialic acid binding by IAV may improve mucus trapping efficiency, sialic acid binding preference was found to have little impact on IAV mobility and the fraction of viral particles expected to penetrate the mucus barrier. Further, we demonstrate synthetic polymeric hydrogels engineered with mucus-like architecture are similarly protective against IAV infection despite their lack of sialic acid decoy receptors. Together, this work provides new insights on mucus barrier function toward IAV with important implications on innate host defense and interspecies transmission.

microbiology↗