
Maureen Donlin, Ph.D.
Research Professor
Studies on the cell wall integrity signaling pathway in the human fungal pathogen Cryptococcus neoformans
Research Interests
The human fungal pathogen, Cryptococcus neoformans, is the focus of research in our laboratory. One arm of our research is to understand how C. neoformans regulates and remodels its cell wall in response to stress and antifungal therapies. A second arm of our research is to identify novel small molecules that can inhibit growth of the fungus and potentially be developed into new anti-fungal therapies.
Recent Publications
Chromosome-level subgenome-aware de novo assembly provides insight into genome divergence after hybridization
Chromosome-level subgenome-aware de novo assembly provides insight into genome divergence after hybridization
Interspecies hybridization is prevalent in various eukaryotic lineages and plays important roles in phenotypic diversification, adaptation, and speciation. To better understand the changes that occurred in the different subgenomes of a hybrid species and how they facilitate adaptation, we have completed chromosome-level de novo assemblies of all chromosomes for a recently formed hybrid yeast, strain CBS380, using Oxford Nanopore Technologies’ MinION long-read sequencing. We characterize the genome and compare it with its parent species, and , and other genomes to better understand genome evolution after a relatively recent hybridization event. We observe multiple recombination events between the subgenomes in each chromosome, followed by loss of heterozygosity (LOH) in nine chromosome pairs. In addition to maintaining nearly all gene content and synteny from its parental genomes, has acquired many genes from other yeast species, primarily through the introgression of , such as those involved in the maltose metabolism. Finally, the patterns of recombination and LOH suggest an allotetraploid origin of The gene acquisition and rapid LOH in the hybrid genome probably facilitated its adaptation to maltose brewing environments and mitigated the maladaptive effect of hybridization. This paper describes the first in-depth study using long-read sequencing technology of an hybrid genome, which may serve as an excellent reference for future studies of this important yeast and other yeast strains.
T-Cell Expression of CXCL13 is Associated with Immunotherapy Response in a Sex-Dependent Manner in Patients with Lung Cancer
T-Cell Expression of CXCL13 is Associated with Immunotherapy Response in a Sex-Dependent Manner in Patients with Lung Cancer
Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets. We found that the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has recently been shown to correlate with T-cell tumor specificity, is expressed at greater levels in T cells isolated from female compared with male patients. Furthermore, increased CXCL13 expression was associated with response to PD1-targeting immunotherapy in female but not male patients. These findings suggest that there are sex-based differences in T-cell function required for response to anti-PD1 therapy in lung cancer that may need to be considered during patient treatment decisions. See related Spotlight by Cruz-Hinojoza and Stromnes, p. 952.
Single-cell analysis of peripheral CD8 T cell responses in patients receiving checkpoint blockade immunotherapy for cancer
Single-cell analysis of peripheral CD8 T cell responses in patients receiving checkpoint blockade immunotherapy for cancer
Checkpoint blockade immunotherapy has become a first-line treatment option for cancer patients, with success in increasingly diverse cancer types. Still, many patients do not experience durable responses and the reasons for clinical success versus failure remain largely undefined. Investigation of immune responses within the tumor microenvironment can be highly informative but access to tumor tissue is not always available, highlighting the need to identify biomarkers in the blood that correlate with clinical success. Here, we used single-cell RNA sequencing coupled with T cell receptor sequencing to define CD8 T cell responses in peripheral blood of two patients with melanoma before and after immunotherapy with either anti-PD-1 (nivolumab) alone or the combination of anti-PD-1 and CTLA-4 (ipilimumab). Both treatment regimens increased transcripts associated with cytolytic effector function and decreased transcripts associated with naive T cells. These responses were further evaluated at the protein level and extended to a total of 53 patients with various cancer types. Unexpectedly, the induction of CD8 T cell responses associated with cytolytic function was variable and did not predict therapeutic success in this larger patient cohort. Rather, a decrease in the frequency of T cells with a naive-like phenotype was consistently observed after immunotherapy and correlated with prolonged patient survival. In contrast, a more detailed clonotypic analysis of emerging and expanding CD8 T cells in the blood revealed that a majority of individual T cell clones responding to immunotherapy acquired a transcriptional profile consistent with cytolytic effector function. These results suggest that responses to checkpoint blockade immunotherapy are evident and traceable in patients’ blood, with outcomes predicted by the simultaneous loss of naive-like CD8 T cells and the expansion of mostly rare and diverse cytotoxic CD8 T cell clones.
Reply to Itoh et al., “Potential Use of Iron-Limiting Therapy against Cryptococcus neoformans and Effects of Caspofungin on the Host Immune System”
Reply to Itoh et al., “Potential Use of Iron-Limiting Therapy against Cryptococcus neoformans and Effects of Caspofungin on the Host Immune System”
Metal coordinating inhibitors of Rift Valley fever virus replication
Metal coordinating inhibitors of Rift Valley fever virus replication
Rift Valley fever virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the order Bunyavirales, whose replication depends on the enzymatic activity of the viral L protein. Screening for RVFV inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 47 novel RVFV inhibitors with selective indexes from 1.1-103 and 50% effective concentrations of 1.2-56 μM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against a second Bunyavirus, La Crosse Virus (LACV), and the flavivirus Zika (ZIKV). These data indicate that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes should be investigated in the future to determine their mechanism(s) of action allowing further development as therapeutics for RVFV and LACV, and these chemotypes should be evaluated for activity against related pathogens, including Hantaan virus, severe fever with thrombocytopenia syndrome virus, Crimean-Congo hemorrhagic fever virus.