Biology subjects

Adams, S. E.

Publications and source records attributed to Adams, S. E..

4 recordsLinked to original sources

bioRxiv2025

Insights into the potential functions of nucleoside diphosphate kinases in Waddlia chondrophila encoded by two ndk paralogs

The Chlamydiota phylum consists of obligate intracellular bacteria, including well-known pathogens and emerging environmental species, with diverse host ranges and metabolic capabilities. Among these bacteria, the gene, which encodes nucleoside diphosphate kinase (ndk), is present in variable copy numbers. While most chlamydial species carry a single copy of ndk, some species have two copies. In W. chondrophila, the two Ndk proteins encoded by ndk paralogs retain conserved kinase motifs but differ in subcellular localization, suggesting divergent functional roles. According to localization studies performed in heterologous expression systems, WcNdk1 is confined to the inclusion and probably supports nucleotide metabolism, while WcNdk2 localizes to the host nucleus, perinuclear space, and Golgi apparatus, suggesting involvement in host interaction. Azidothymidine (AZT), a known Ndk inhibitor, impaired W. chondrophila growth, potentially through inhibition of WcNdk2. However, the lack of genetic tools and the absence of in vitro enzymatic assays currently limit definitive functional conclusions. Our data suggest potential functions for Ndks in W. chondrophila, providing a foundation for future studies on Ndk-mediated interactions between this pathogen and its host.

microbiology↗

bioRxiv2024

Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells

Recent models of infection and experimental inflammation reveal that hematopoietic stem and progenitor cells (HSPCs) can generate a memory of the exposure that heightens the response to subsequent stimulation, a process termed central trained immunity. Inflammation is also a constitutive feature of cancer, including hematologic malignancies. Here, we adapt a translationally relevant model of acute myeloid leukemia (AML) to determine if inflammation in the bone marrow (BM) niche durably reprograms resident healthy HSPCs. To simulate the onset of malignancy along with the associated inflammatory surge as well as the subsequent remission, we generated hematopoietic chimera with healthy HSPCs and HSPCs bearing a doxycycline-responsive oncogene (hMLL-AF9) expression cassette, a validated model of AML. Results show that the exposure to AML blasts in the BM leaves healthy HSPCs during experimental remission with broad transcriptomic, epigenetic changes and enhanced reliance on glycolysis. A heterologous secondary challenge of AML-experienced animals resulted in pronounced gene expression changes in inflammatory and metabolic pathways. These augmented responses coincided with altered chromatin accessibility in AML-experienced HSPCs. Motif analysis of the epigenome in AML trained HSPC points to the involvement of core hematopoietic transcription factors. Altogether, these observations provide first evidence for the durable inflammatory reprogramming of healthy HSPCs in the cancer microenvironment.

cancer biology↗

bioRxiv2024

Dynamic Tracking of Native Polyclonal Hematopoiesis in Adult Mice

Hematopoietic dysfunction has been associated with a reduction in the number of active precursors. However, precursor quantification at homeostasis and under diseased conditions is constrained by the scarcity of available methods. To address this issue, we optimized a method for quantifying a wide range of hematopoietic precursors. Assuming the random induction of a stable label in precursors following a binomial distribution, estimates depend on the inverse correlation between precursor numbers and the variance of precursor labeling among independent samples. Experimentally validated to cover the full dynamic range of hematopoietic precursors in mice (1 to 105), we utilized this approach to demonstrate that thousands of precursors, which emerge after modest expansion during fetal-to-adult transition, contribute to native and perturbed hematopoiesis. We further estimated the number of precursors in a mouse model of Fanconi Anemia, showcasing how repopulation deficits can be classified as autologous (cell proliferation) and non-autologous (lack of precursor). Our results support an accessible and reliable approach for precursor quantification, emphasizing the contemporary perspective that native hematopoiesis is highly polyclonal.

cell biology↗

bioRxiv2021

A novel bivalent DNA vaccine encoding both spike protein receptor-binding domain and nucleocapsid protein of SARS-CoV-2 to elicit T cell and neutralising antibody responses that cross react with variants

Although the efficacy of vaccines targeting SARS-CoV-2 is apparent now that the approved mRNA and adenovirus vector vaccines are in widespread use, the longevity of the protective immune response and its efficacy against emerging variants remains to be determined. We have therefore designed a DNA vaccine encoding both the SARS-CoV-2 spike receptorbinding domain ( RBD) and nucleocapsid proteins, the latter of which is highly conserved amongst beta coronaviruses. The vaccine elicits strong pro-inflammatory CD4+ Th1 and CD8+ T-cell responses to both proteins in mice and rats, with responses being significantly enhanced by fusing the nucleocapsid sequence to a modified Fc domain. We have shown that the vaccine also stimulates high titre antibody responses to RBD in mice that efficiently neutralise in pseudotype and live virus neutralisation assays and show cross reactivity with spike proteins from the variants B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). The vaccine also showed good protection in a viral challenge model in ACE2 receptor transgenic mice. This DNA platform can be easily adapted to target variant proteins and we show that a vaccine variant encoding the Beta variant sequence stimulates cross-reactive humoral and T cell responses. These data support the translation of this DNA vaccine platform into the clinic, thereby offering a particular advantage for rapidly targeting emerging SARS-CoV-2 variants.

immunology↗