Leah Bernstein - Graduate Student

Defective viral genomes (DVGs) are truncated versions of viral genomes, ubiquitously produced during infection with many RNA viruses, including SARS-CoV-2. DVGs are potent stimulators of antiviral interferon responses and promote persistent viral infection. We identify three conserved recombination hotspots for SARS-CoV-2 DVGs. Among them, hotspot B is the most conserved, with a deletion of ORF7, ORF8, and N from its genome. We observed that DVG-B induced a strong interferon response and inhibited standard viral replication in A549 epithelial cells. Given the important role of alveolar macrophages in antiviral defense, immune regulation, and viral persistence in the lung, understanding how DVGs function in this cell type is critical. However, the immunological effects of DVG-B in macrophages remain poorly defined. Using viral titration, immunofluorescence microscopy, and interferon stimulation assays, we showed that SARS-CoV-2 wild type virus caused a productive infection in THP-1 derived macrophages. However, this infection was much delayed and reduced compared to that in ACE-2 A549 epithelial cells. In macrophages, DVG-B fails to trigger the strong interferon response seen in epithelial cells, as observed by weak interferon and interferon-stimulated gene induction despite intact downstream interferon signaling. This cell-type specific difference may allow macrophages to support SARS-CoV-2 persistence in the lung without triggering a robust antiviral response. Ongoing studies involving immunofluorescence imaging must be performed to better understand and visualize the SARS-CoV-2 infection kinetics within macrophages. This research aims to address a critical gap in knowledge about macrophage function during viral infection, to ultimately improve patient outcomes.

 Feb 12, 2026 @ 12:00 p.m.
 Medical Center | K307 (3-6408)

Kei Brown - Graduate Student

BST2 is a potent mammalian antiviral factor that restricts the viral release and enhances immune recognition of a wide array of enveloped viruses, including SARS-CoV-2. It primarily functions through its secondary structure, which prevents the release of nascent virions by tethering them to the host cell surface. Consequently, many of these enveloped viruses have evolved mechanisms to counteract BST2. The ability to overcome BST2 restriction has proven critical, especially for the successful spread of zoonoses like pandemic HIV-1. Whether or not BST2 also serves as a cross-species barrier for coronaviruses, many of which lie in the bat virus reservoir, remains unknown. We plan to fill this gap in knowledge by using the readily available SARS-CoV-2, a now human-adapted virus that is thought to have arisen in bats.

Our lab has recently identified the Spike as SARS-CoV-2’s main antagonist of human BST2 (hBST2), where it downregulates the protein via lysosomal degradation. Further, we identified an accumulation of mutations in the Spike of recent SARS-CoV-2 VOC that have resulted in improved efficiency of hBST2 downregulation compared to ancestral SARS-CoV-2 strains. Although this indicates evolution to counteract hBST2, whether human and bat BST2 can restrict bat coronaviruses is unknown. Many facets of the bat-human cross-species barrier remain to be assessed and could provide valuable knowledge to inform future therapeutics and identify bat coronaviruses poised to cross this barrier.

Here, we aim to answer if coronavirus antagonists of BST2 are species-specific and if BST2 is a driving factor of coronavirus evolution to address our broader question of BST2’s role in the bat-human cross-species barrier for bat coronaviruses. Thus far, we have found that SARS-CoV-2 Wuhan Spike, an ancestral strain, downregulates bat BST2s more efficiently than SARS-CoV-2 Omicron Spike, a recent VOC, via transfection. We also found that RaTG13 (a bat coronavirus closely related to SARS-CoV-2) Spike appears to downregulate Rhinolophus (bat) BST2s to a greater extent than Pteropus (bat) or human BST2. Unexpectedly, it also seems that HIV-1’s Vpu, a known antagonist of hBST2, may have the ability to antagonize bat BST2s as well.

 Feb 12, 2026 @ 12:30 p.m.
 Medical Center | K307 (3-6408)