Biology subjects

Murray, K. A.

Publications and source records attributed to Murray, K. A..

12 recordsLinked to original sources

bioRxiv2026

TCF1lo CD8 T cells proliferate and persist autonomously in tumors

Cancers develop in humans over months to years, and tumor-specific CD8 T cells (TST) can interact with cancer cells throughout tumorigenesis. Nevertheless, the long-term population dynamics of TST, especially within progressing tumors, are not well understood. A paradigm first established in chronic viral infection and applied to tumors describes a population hierarchy among exhausted T cells. Progenitor/stem-like exhausted T cells, which express the transcription factor T cell factor 1 (TCF1), maintain the population through self-renewal and by giving rise to terminally differentiated TCF1lo progeny. This has led to a focus on TCF1hi T cells, and though TCF1lo CD8 T cells are the predominant tumor-infiltrating/tumor-reactive subtype in patients, they have been largely overlooked. We leveraged our autochthonous liver cancer model to analyze TST differentiation and proliferation throughout tumorigenesis. Dual EdU/BrdU labeling studies revealed that throughout tumorigenesis, a subset of TCF1lo TST in the liver stochastically entered and exited cell cycle, and at later time points there was no evidence of a TCF1hi progenitor-like population. Moreover, TCF1-knockout TST proliferated and persisted robustly in tumors. Using liver cancer and melanoma models, we showed that tumor-resident TCF1lo TST proliferate and persist autonomously, even when new TST influx into tumors is inhibited. The prevailing notion is that only TCF1hi TST self-renew but we now demonstrate, using a clinically relevant mouse cancer model, that TCF1lo TST stochastically proliferate to achieve long-term population maintenance. Future studies to understand and harness this mechanism to improve T cell persistence in tumors could lead to novel immunotherapies for patients with cancer. SYNOPSISWe show that tumor-specific T cells with little/no expression of TCF1, previously considered incapable of self-renewal, can proliferate stochastically and persist long-term. As TCF1lo CD8 T cells are often the predominant tumor-reactive T cells found in tumors, future studies should be aimed at reprogramming these proliferating T cells within tumors.

immunology↗

bioRxiv2025

Pre-division TCF1 drop determines long-term CD8 T cell fates

T Cell Factor 1 (TCF1) is a master transcription factor controlling T cell development and peripheral T cell differentiation during infection, cancer, and autoimmunity. TCF1 is highly expressed in naive CD8 T cells but must be downregulated as T cells proliferate to become effectors. If and how TCF1 plays a role during T cell priming prior to cell cycle entry is unknown. Surprisingly, we found that TCF1 expression is rapidly downregulated within hours after antigen encounter in both murine and human CD8 T cells, even before T cells enter cell cycle. TCF1 then rebounds to high levels upon cell cycle entry, ultimately declining again with proliferation and effector differentiation. This rapid pre-division drop and rebound occurs in diverse settings, including infection and cancer. The magnitude of the pre-division TCF1 drop is modulated by TCR signal strength and inflammatory cytokines and strikingly, regulates long-term effector and memory fates. Paired transcriptomic and epigenetic analyses revealed that TCF1-regulated chromatin regions were remodeled within hours following antigen encounter, activating effector and inflammatory cytokine signaling modules and poising T cells for effector differentiation. Remarkably, transient siRNA-mediated TCF1 downmodulation during the pre-division priming phase was sufficient to induce long-term population effector skewing. We have uncovered a novel mechanism whereby pre-division dynamic TCF1 regulation determines long-term CD8 T cell fate commitment, potentially serving as a critical checkpoint regulating T cell responses in infection, cancer, and autoimmunity.

immunology↗

bioRxiv2025

MDR1 promotes CD8 T cell persistence in tumors and protects against cytotoxic chemotherapy

Multidrug transporters, including multidrug resistance-1 (MDR1), are recognized chiefly for effluxing chemotherapeutic drugs out of tumor cells. However, they are also expressed in many normal cells and tissues, including lymphocytes, but their physiological role is less well-understood. Here, we investigated the role of MDR1 in tumor-specific CD8 T cells (TST), which are critical in antitumor immunity and key targets of immunotherapies. Using a clinically-relevant genetic liver cancer mouse model, we investigated the efflux dynamics of TST as they underwent activation, proliferation, and differentiation to dysfunctional states in tumor-bearing hosts. Surprisingly, we found that late-stage/terminally dysfunctional TST had the highest efflux capacity in both murine and human liver tumors. TST upregulated transcription of Abcb1a, encoding MDR1. We used CRISPR/Cas9 to generate MDR1-deficient TST, which persisted poorly in tumor-bearing mice as compared to MDR1-sufficient TST. MDR1 expression improved TST viability and reduced reactive oxygen species accumulation. Loss of MDR1 made T cells more susceptible to cytotoxic chemotherapy-induced cell death. Our findings demonstrate a role for MDR1 in regulating TST persistence and oxidative stress, with implications for antitumor T cell therapies in patients and immune regulation following cytotoxic chemotherapy.

immunology↗

bioRxiv2024

Lineage-specific trait variation generates widespread, contemporaneous coexistence and competitive exclusion dynamics in an invasive, multihost wildlife parasite

Invasive and highly virulent parasites are emerging worldwide, transported to new locations and into novel hosts by anthropogenic activities. Multiple introduction events lead to interactions amongst genetically dissimilar genotypes that can result in either competitive exclusion, coexistence, or cycling through a combination of the two. Here, we report how intra-lineage trait variation of the multihost amphibian parasite Batrachochytrium dendrobatidis drives contrasting outcomes of inter-lineage interactions on two continents, Europe and Africa. Through field surveys, competition experiments and mathematical modelling we show that interactions between the same two lineages in the two continents and in different hosts demonstrate both ends of the exclusion/coexistence continuum. Trait variation in one of the two predominating lineages, BdGPL, is responsible for these contrasting outcomes: In Europe, BdGPL is highly competitive and has constrained the distribution of the other, BdCAPE, to two locations. In Africa, BdGPL and BdCAPE can mutually invade host populations when the other lineage is already resident, potentially leading to coinfections and recombination. That these contrasting outcomes are prolonged and contemporaneous for the same two lineages shows that epidemiological models of invasive parasites need to account for trait variation both within and across lineages.

ecology↗

bioRxiv2024

Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control

BackgroundImmune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however only a subset of patients with certain types of cancer achieves durable remissions. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically-relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiate in mice with early sporadic lesions as compared to late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, reprogram TST and impact liver cancer progression. MethodsMice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early pre-cancerous lesions that inevitably progress to established liver cancer. We assessed the immunophenotype and function of TAG-specific CD8 T cells in mice with early and late liver lesions. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression. ResultsIn mice with early lesions, a subset of TST were PD1+ TCF1+ TOX- and could produce IFN{gamma}, while TST present in mice with late liver cancers were PD1+ TCF1lo/- TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were TCF1+ TOX- TST and polyfunctional cytokine producers. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy. ConclusionVaccination, but not ICB, generated a population of progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high-risk of cancer recurrence, immunization may be the most effective strategy. What is already known on this topicImmunotherapy, including immune checkpoint blockade and cancer vaccines, fails to induce long-term remissions in most patients with cancer. What this study addsHosts with early lesions but not hosts with advanced cancer retain a progenitor TCF1+ TST population. This population can be reprogrammed and therapeutically exploited by vaccination, but not ICB, to block tumor progression. How this study might affect research, practice, or policyFor people at high-risk of cancer progression, vaccination administered when a responsive progenitor TST population is present may be the optimal immunotherapy to induce long-lasting progression-free survival.

cancer biology↗

bioRxiv2023

The impact of late Pleistocene mammal extinctions on pathogen richness in extant hosts.

Many species of large mammals were driven to extinction during the late Pleistocene and early Holocene (approx. 10,000 - 50,000 years ago), with cascading effects on the physical structure of ecosystems and the dispersal of seeds, nutrients, and microbes. However, it remains uncertain whether the parasites associated with these extinct hosts also disappeared or persisted in surviving (extant) mammals. We hypothesize that if some parasites endured, extant mammals sharing their ranges with phylogenetically similar extinct mammals would have a greater pathogen richness than expected based on current levels of host diversity. We find that the inclusion of variables related to these extinctions account for an additional 5% of deviance when modelling per-host viral and bacterial richness, compared to models run without these variables. Partial dependence plots show a positive correlation between the number of extinct mammals lost and per-host viral and bacterial richness (p < 0.001 and p = 0.03, respectively). Additionally, decreasing phylogenetic distance between the extinct and extant species is associated with an increasing viral richness (p < 0.001). We discuss four mechanisms that may be driving these patterns and highlight future research to distinguish between them. Next, we use the models and IUCN range maps to identify geographic regions where viral and bacterial richness differs due to the inclusion of extinction variables. Notably, the richness of both pathogen types is increased in South America (viruses: +6.8%; bacteria: +3.1%) and decreased in Africa (viruses: -2.6%; bacteria: -13.6%), two continents known to have high and low levels of historical mammal extinctions, respectively. Viral richness is also elevated in North America (+8.6%), Europe (+5.1%), Oceania (+3.3%), and Asia (+2.3%). These results support the inclusion of extinction variables in future models of pathogen richness and may allow for improved targeting of future surveillance efforts.

paleontology↗

bioRxiv2022

Climatic niche evolution of infectious diseases driving amphibian declines

Climate change and infectious diseases continue to drive global amphibian population declines, contributing to one of the greatest vertebrate extinctions of the Anthropocene. Currently around 16% amphibian species across the world are affected by four pathogens - Batrachochytrium dendrobatidis (Bd), B. salamandrivorans (Bsal), Ranavirus and Perkinsea. A climatic context behind the dispersal of some of these diseases is hypothesized. However, the interplay between niche conservatism (NC) and climatic niche evolution (CNE), essential to understand disease evolution and dispersal, has so far received little attention. Here we show that the impacts of amphibian pathogens are intensifying as their climatic niches evolve. NC-based analyses suggest that niches of these diseases overlap, especially in Europe and East/southeast Asia (ESEA), and that all four pathogens will continue to devastate amphibians through seasonality shifts and range expansions, penetrating deeper into temperate regions and global amphibian diversity hotspots. Bd will spread over diversity-rich mountain ranges and ranaviruses will overwhelm lowlands. CNE-based analyses suggest that the earliest lineages of these diseases originated in colder regions and that some lineages subsequently evolved towards warmer climatic niches. We caution that quiescent, warm-adapted strains are likely to become widespread and novel ranaviruses adapted to local climatic conditions and new hosts are likely to emerge. These results portend the dangers of introducing pathogens into new regions given their ability to adapt to changing climate scenarios. In a climatic background conducive to most of these diseases, frequent monitoring, enhanced biosecurity measures and policy reforms are needed for disease control and mitigation.

evolutionary biology↗

bioRxiv2021

Taxonomic classification methods reveal a new subgenus in the paramyxovirus subfamily Orthoparamyxovirinae

As part of a broad One Health surveillance effort to detect novel viruses in wildlife and people, we report several paramyxoviruses sequenced primarily from bats during 2013 and 2014 in Brazil and Malaysia, including seven from which we recovered full-length genomes. Of these, six represent the first full-length paramyxovirus genomes sequenced from the Americas, including two sequences which are the first full-length bat morbillivirus genomes published to date. Our findings add to the vast number of viral sequences in public repositories that have been increasing considerably in recent years due to the rising accessibility of metagenomics. Taxonomic classification of these sequences in the absence of phenotypic data has been a significant challenge, particularly in the paramyxovirus subfamily Orthoparamyxovirinae, where the rate of discovery of novel sequences has been substantial. Using pairwise amino acid sequence classification (PASC), we describe a novel genus within this subfamily tentatively named Jeishaanvirus, which we propose should include as subgenera Jeilongvirus, Shaanvirus, and a novel South American subgenus Cadivirus. We also highlight inconsistencies in the classification of Tupaia virus and Mojiang virus using the same demarcation criteria and show that members of the proposed subgenus Shaanvirus are paraphyletic. Importantly, this study underscores the critical importance of sequence length in PASC analysis as well as the importance of biological characteristics such as genome organization in the taxonomic classification of viral sequences.

microbiology↗

bioRxiv2021

Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2

The SARS-CoV-2 Nucleoprotein (NCAP) functions in RNA packaging during viral replication and assembly. Computational analysis of its amino acid sequence reveals a central low-complexity domain (LCD) having sequence features akin to LCDs in other proteins known to function in liquid-liquid phase separation. Here we show that in the presence of viral RNA, NCAP, and also its LCD segment alone, form amyloid-like fibrils when undergoing liquid-liquid phase separation. Within the LCD we identified three 6-residue segments that drive amyloid fibril formation. We determined atomic structures for fibrils formed by each of the three identified segments. These structures informed our design of peptide inhibitors of NCAP fibril formation and liquid-liquid phase separation, suggesting a therapeutic route for Covid-19. One Sentence SummaryAtomic structures of amyloid-driving peptide segments from SARS-CoV-2 Nucleoprotein inform the development of Covid-19 therapeutics.

biochemistry↗

bioRxiv2021

Competition in depleting resource environments shapes the thermal response of mosquito population fitness

The temperature-dependencies of life history traits are increasingly being used to predict how climatic warming will affect vector-borne disease dynamics, partially by affecting the abundance dynamics of the vector population. Such predictions generally arise from mathematical models that incorporate the temperature dependence of traits measured under laboratory conditions. These temperature-trait relationships are typically estimated from juvenile populations reared under optimal resource conditions, even though natural populations experience intermittent resource depletion. Using laboratory experiments on the mosquito Aedes aegypti, combined with a stage-structured population model, we show that resource depletion in the juvenile habitat can significantly depress the vectors maximal population growth rate (rm) across the entire temperature range, cause it to peak at a lower temperature, and narrow its thermal niche width. Our results provide compelling evidence for future studies to consider resource depletion when predicting the effects of global change on vector-borne disease transmission, disease vectors and other arthropods.

ecology↗

bioRxiv2020

Poor protection of amphibian evolutionary history reveals opportunities for global protected areas

As habitat loss is a major driver of amphibian population declines, protected areas (PAs) can play a crucial role in amphibian conservation. Documenting how well the global PA network captures the evolutionary history of amphibians can inform conservation prioritisation and action. We conducted a phylogenetic gap analysis to assess the extent to which amphibian phylogenetic diversity (PD) is unprotected by the PA network and compared this to other terrestrial vertebrate groups. 78% of amphibian species and 64% of global amphibian PD remains unprotected, which is higher than corresponding figures for squamates, mammals and birds. Amongst amphibians, salamanders were the least well protected, with 78% of PD unprotected, compared with 64% for caecilians and 63% for frogs. We identify areas that offer the greatest opportunity to capture unprotected amphibian evolutionary history. We could capture an additional 29.4% of amphibian PD, representing 40 billion years of evolutionary history, by protecting an additional 1.9% of global amphibian distributions (1.74% of global land area) and increasing the restrictions in 0.6% of amphibian distributions to match the management objectives of PAs in IUCN categories I or II. Importantly, we found that the spatial distribution of unprotected PD was correlated across all groups, indicating that expanding the PA network to conserve amphibian PD can secure imperilled vertebrate diversity more generally.

evolutionary biology↗

bioRxiv2020

The effect of resource limitation on the temperature dependence of mosquito population fitness

Laboratory-derived temperature dependencies of life history traits are increasingly being used to make mechanistic predictions for how climatic warming will affect vector-borne disease dynamics, partially by affecting abundance dynamics of the vector population. These temperature-trait relationships are typically estimated from populations reared on optimal resource supply, even though natural populations of vectors are expected to experience variation in resource supply, including intermittent resource limitation. Using laboratory experiments on the mosquito Aedes aegypti, a principal arbovirus vector, combined with stage-structured population modelling, we show that low-resource supply significantly depresses the vectors maximal population growth rate across the entire temperature range (22-32{degrees}C) and causes it to peak at a lower temperature than at high-resource supply. This effect is primarily driven by an increase in juvenile mortality and development time, combined with an exaggerated decrease in adult size with temperature at low-resource supply. Our study suggests that projections of vector abundance and disease transmission based on laboratory studies are likely to substantially underestimate how resource supply can modulate the temperature-dependency of population-level fitness through its influence on juvenile survival and development time. Our results provide compelling evidence for future studies to consider resource supply when predicting the effects of climate and habitat change on disease vectors and transmission.

ecology↗