Biology subjects

Mucker, E. M.

Publications and source records attributed to Mucker, E. M..

3 recordsLinked to original sources

bioRxiv2025

Stability and characterization of infectious monkeypox virus extracellular virions in vitro2and vivo; implications for transmission, pathogenesis and treatment

Abstract/SummaryPoxviruses exist as multiple infectious morphogenic forms commonly simplified as mature virions (MV) and extracellular virions (EV). The roles of morphogenic subtypes as related to disease and transmission are enigmatic as EVs can exist both as cell associated (CEV) or released particles (rCEV) each with potentially unique biochemical properties impacting stability and infectivity. In vitro analysis of prototypical poxviruses is commonly utilized to infer larger conclusions about the in vivo function of all EV-like particles. Here we show that infectious EV of MPXV and VACV strains are stable for [≥] 14 weeks and are more sensitive to human or non-human primate complement compared to rabbit-derived complement. We also characterize the levels of EV produced during MPXV infection in NHPs and found temporal differences in production that may influence spread. Also, we present data characterizing and contrasting the EV from monkeypox (MPXV) and vaccinia virus (VACV) strains. Specifically, we quantified infectious EV quantities produced by different cultured cell lines and characterized the infectious properties and composition of the released (extracellular) virions. We conclude that A33 neutralizable cell associated-like virions (CEV-like), a form of EV, can significantly increase, depending on the strain of VACV or MPXV and the cell lines from which they were released. Based on the outcomes of our studies, the importance of understanding specific orthopoxvirus EV roles in a host-specific manner, as it relates to pathogenesis, stability, and transmission, is warranted and requires further study.

microbiology↗

bioRxiv2025

In vitro and in vivo Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxvirus and African Swine Fever Virus Replication

Poxviruses are double-stranded DNA viruses including relevant zoonotic pathogens with high morbidity. Although African swine fever virus (ASFV) belongs to the Asfarviridae family and is not strictly classified as a member of the Poxviridae, both fall within the same class of Pokkesviricetes that replicate in the cytoplasm, and some poxviruses pose potential biological warfare threats. Among compounds targeting these viruses, acyclic nucleoside phosphonate prodrugs are nucleoside analogues inhibitors of viral DNA polymerases that have been identified as promising agents. However, some limitations related to their toxicity and the rapid emergence of resistance highlight the need for new antiviral molecules. In this study, the new nucleoside analogue LAVR-289 was shown to effectively inhibit the viral replication by intervening early in the viral replication step, targeting a specific domain of the poxvirus DNA polymerase. Using monkeypox virus models, the subcutaneous or oral administration of LAVR-289 demonstrates protective efficacy in infected animal models without toxicity or behavioral modification. The stability in vivo, long shelf-life and efficacy make LAVR-289 a promising candidate for further development and stockpiling as a medical countermeasure against dsDNA virus outbreaks. Its broad-spectrum efficacy is a real asset in a context of recurrent viral epidemics, risk of bioterrorism and emergence of resistance strains in the population. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug targeting viral DNA polymerases. C_LIO_LILAVR-289 displays antiviral activity against dsDNA viruses, ASFV and poxviruses. C_LIO_LIFirst report of in vivo evaluation of LAVR-289 against MPXV by subcutaneous and oral administration. C_LIO_LILAVR-289 reduces clinical signs and increase survival in animal models. C_LI

microbiology↗

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↗