Biology subjects

Mickelson, C. K.

Publications and source records attributed to Mickelson, C. K..

4 recordsLinked to original sources

bioRxiv2026

A mammalian fibroblast zoo reveals barriers to cross-species virus replication and differential regulation of antiviral immunity

Virus zoonosis represents a continual threat to humans. Viruses emerge in humans directly or indirectly through interactions with mammals. However, our understanding of virus-host susceptibility across the diversity of mammals is limited and experimental model systems are restricted to a very small set of model organisms. Mammals are highly diverse and different habitats, lifestyles, diets, and exposures to different pathogens have driven substantial genetic diversity. We generated a library of primary fibroblasts across 86 mammalian species and used these cells to build an atlas of virus-host susceptibility across a panel of arboviruses that infect diverse mammals including humans. Perturbing the innate immune system revealed some virus-host pairs where restriction is controlled by the immune system and others where there is an incompatibility with host factors. Transcriptomic profiling of the library in response to virus sensing mimicked by poly(I:C) or antiviral signaling with type I interferon reveals a core set of conserved genes that respond as well as substantial species- and order-specific responses. Together these data provide a comparative atlas of innate immune responses across mammals and offer a window into how these systems have evolved across animals.

immunology↗

bioRxiv2025

Intrinsic OASL expression licenses interferon induction during influenza A virus infection

Effective control of viral infection requires rapid induction of the innate immune response, especially the type I and type III interferon (IFN) systems. Despite the critical role of IFN induction in host defense, numerous studies have established that most cells fail to produce IFNs in response to viral stimuli. The specific factors that govern cellular heterogeneity in IFN induction potential during infection are not understood. To identify specific host factors that license some cells but not others to mount an IFN response to viral infection, we developed an approach for analyzing temporal scRNA-seq data of influenza A virus (IAV)-infected cells. This approach identified the expression of several interferon stimulated genes (ISGs) within pre-infection cells as correlates of IFN induction potential of those cells, post-infection. Validation experiments confirmed that intrinsic expression of the ISG OASL is essential for robust IFNL induction during IAV infection. Altogether, our findings reveal an important role for IFN-independent, intrinsic expression of ISGs in promoting IFN induction and provide new insights into the mechanisms that regulate cell-to-cell heterogeneity in innate immune activation.

immunology↗

bioRxiv2024

Mammalian ZAP and KHNYN independently restrict CpG-enriched avian viruses

Zoonotic viruses are an omnipresent threat to global health. Influenza A virus (IAV) transmits between birds, livestock, and humans. Proviral host factors involved in the cross-species interface are well known. Less is known about antiviral mechanisms that suppress IAV zoonoses. We observed CpG dinucleotide depletion in human IAV relative to avian IAV. Notably, human ZAP selectively depletes CpG-enriched viral RNAs with its cofactor KHNYN. ZAP is conserved in tetrapods but we uncovered that avian species lack KHNYN. We found that chicken ZAP may not affect IAV (PR8) or CpG enriched IAV (PR8CG). Human ZAP or KHNYN independently restricted CpG-enriched IAV PR8CG by overexpression in chicken cells and by combined knockout in human cells. Additionally, mammalian ZAP-L and KHNYN also independently restricted an avian retrovirus (ROSV). Curiously, platypus KHNYN, the most divergent from eutherian mammals, was also capable of independent restriction of multiple diverse viruses. We suggest that some mammalian KHNYN can act as a bona fide restriction factor with cell-autonomous activity. Furthermore, we speculate that through repeated contact between avian viruses and mammalian hosts, protein changes may accompany CpG-biased mutations or reassortment to evade mammalian ZAP and KHNYN.

microbiology↗

bioRxiv2021

Nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing antibodies target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with HAd5 expressing the nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and k18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral antigens, even if they are not a target of neutralizing antibodies, to broaden epitope coverage and immune effector mechanisms.

immunology↗