Ciudad, T. | bioRxiv Science

bioRxiv2026

Sequential infection reprograms the immune landscape to shape future responses

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naive CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naive and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

immunology↗

bioRxiv2024

The histone variant H2A.Z is required for efficient transcription-coupled NER and to maintain genome integrity in UV challenged yeast cells.

The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblock and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z enables proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation. Author summaryThe genome of living organisms is constantly challenged by intrinsic and extrinsic DNA damaging agents. The resulting DNA lesions must be readily repaired to maintain genome integrity. This is particularly important for bulky DNA lesions, such as those produced by UV light, as they will block the progress of elongating RNA polymerases on transcribed genes. These DNA lesions are repaired by a specific pathway called transcription-coupled nucleotide excision repair (TC-NER), the dysfunction of which is associated with severe human diseases. In this work, we used budding yeast as a eukaryotic model organism to perform a genetic screen for new TC-NER factors. We discovered that the HTZ1 gene, encoding the histone variant H2A.Z, is required for efficient DNA repair by TC-NER. Our molecular and genetic analyses showed that in the absence of H2A.Z, RNA polymerases persist on damaged DNA, causing interference with DNA replication and genome instability. Our findings further highlight the importance of chromatin plasticity for the maintenance of genome integrity.

genetics↗