Taylor Tillery

The persistent evolution of SARS-CoV-2 has led to the emergence of antigenically distinct Omicron subvariants exhibiting increased transmissibility, immune evasion, and altered pathogenicity. Among these, recent subvariants such as JN.1, KP.3.1.1, and LB.1 possess unique antigenic and virological features, underscoring the need for continued surveillance and therapeutic evaluation. As vaccines and commercial monoclonal antibodies show reduced effectiveness against these variants, the role of direct-acting antivirals, such as Nirmatrelvir, targeting conserved viral elements like the main protease inhibitor, becomes increasingly crucial. In this study, we investigated the replication kinetics, host immune responses, and therapeutic susceptibility of three recently circulating Omicron subvariants in the K18-hACE2 transgenic mouse model, using the SARS-CoV-2 parent WA1/2020 strain as a reference. Omicron subvariants exhibited a marked temporal shift in viral infection kinetics characterized by an early lung viral titer peak (~7–8 Log PFU) at 2 days post-infection (dpi), followed by a decline (1–3 Log PFU) by 4 dpi. Pulmonary cytokine and chemokine responses (GM-CSF, TNF-α, IL-1β, IL-6) showed an earlier increase in subvariant-infected mice compared to a gradual response in WA1/2020 infection. Notably, Nirmatrelvir treatment led to significant reductions in lung viral titers in subvariant-infected mice compared to WA1/2020, surpassing its efficacy against the parent strain. These findings highlight that infection with Omicron subvariants yields a broad dynamic range in viral burden with minimum variability, while retaining a prominent therapeutic response to Nirmatrelvir. This study provides insights into the emerging subvariants’ pathogenesis and therapeutic responsiveness, reinforcing the importance of continued variant monitoring and the development of effective countermeasures.

Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of Thbs1 is sufficient to prevent HSC inflammaging. Our results demonstrate that suppression of HSC inflammaging prevents aging-associated defects in hematopoietic activity including loss of HSC self-renewal, myeloid-biased HSC differentiation, and anemia. Our findings indicate that suppression of HSC inflammaging may also prolong overall systemic health span.