Biology subjects

Filler, R.

Publications and source records attributed to Filler, R..

4 recordsLinked to original sources

bioRxiv2026

Mucosal vaccine-elicited IgA is protective against zoonotic Betacoronavirus challenge

Current vaccines for respiratory viruses are primarily administered intramuscularly. Messenger RNA-lipid nanoparticle (LNP)-based intramuscular vaccination for respiratory coronaviruses induces strong systemic IgG antibody responses; they do not consistently elicit IgA in the upper and lower respiratory tracts. Using a synthetic consensus spike protein aimed to broadening immunity against SARS-like viruses, SarbConS, coupled to ferritin nanoparticles co-delivered with mastoparan-7 and an FDA-approved CpG adjuvant, we intranasally boost SARS-CoV-2-immune animals. This intranasal boosting strategy elicits durable mucosal IgA responses in the respiratory tract, along with robust systemic IgG responses, and demonstrates durable protection against SARS-CoV-2 and zoonotic SARS-like viruses from bats and pangolins. Intranasal delivery of mastoparan-7 and CpG with MERS-CoV spike protein similarly elicits MERS-CoV-specific mucosal IgA and protects against MERS-CoV challenge in mice. Moreover, we observe durable protection against these genetically divergent zoonotic SARS-like viral challenges compared to intramuscular mRNA-LNP or unadjuvanted intranasal spike boosters. Intranasal SarbConS-ferritin nanoparticle intranasal vaccination similarly elicited durable mucosal IgA and antigen-specific memory B cell responses in the airways. The protective efficacy of M7-CpG adjuvanted SarbConS ferritin nanoparticle intranasal boosters was abolished in IgA knockout mice, suggesting a requirement for IgA in mediating respiratory mucosal vaccine-mediated protection against coronavirus infection. Altogether, our results demonstrate that respiratory mucosal vaccination can elicit durable and cross-protective mucosal IgA responses against genetically diverse zoonotic coronaviruses with implications for improved mucosal vaccines for highly transmissible respiratory viral pathogens.

immunology↗

bioRxiv2023

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

microbiology↗

bioRxiv2020

Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-{beta} signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

genetics↗

bioRxiv2019

CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. However, after high dose intraperitoneal challenge with MNoV in Cd300lf-/-Stat1-/- mice a single amino acid mutation in the MNoV capsid protein emerged. This substitution did not alter receptor utilization in vitro. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV. Author SummaryHuman norovirus is the leading cause of non-bacterial gastroenteritis causing up to 200,000 deaths each year. How human norovirus enters cells is unknown. Because human norovirus is difficult to grow in the laboratory and in small animals, we use mouse or murine norovirus as a model system. We recently discovered that murine norovirus can use the either CD300ld or CD300lf as a receptor in vitro. We also showed that CD300lf deficient mice were resistant to oral challenge with a single virus strain. Here we determined that CD300lf is essential for infection of diverse murine norovirus strains in cell lines and in mice with normal immune systems demonstrating its the primary physiologic receptor for diverse murine norovirus strains independent of infection route. However, in immunodeficient mice injected with high dose virus directly into the abdominal cavity, we observed a norovirus mutant that enabled CD300lf-independent infection. Finally, we demonstrated that human CD300lf is not the elusive receptor for human norovirus.

microbiology↗