Biology subjects

Hilbert, Z. A.

Publications and source records attributed to Hilbert, Z. A..

6 recordsLinked to original sources

bioRxiv2024

Distinct routes to thermotolerance in the fungal pathogen Cryptococcus neoformans

Increasing temperatures associated with climate change have the potential for far-reaching impact on human health and disease vectors, including fungal pathogens. Pathogenic fungi occupy a wide range of environments across the world, and their ranges have been slowly expanding in recent decades due, in part, to climate change. Despite these links between increasing temperature and higher prevalence of fungal disease, the direct effects of rising environmental temperatures on the evolution of pathogenic fungi remains unclear. In this study, we investigated how increasing temperatures drive adaptive evolution in the human fungal pathogen Cryptococcus neoformans. First, we performed serial passages of a C. neoformans environmental isolate with gradual changes in temperature over the course of 38 days. Through this approach we identified several distinct thermally adapted isolates with competitive growth advantages over the parental strain at high temperatures. We then characterized the phenotypic and genetic changes acquired in these evolved isolates, which include alteration of cell size, colony morphology, and, notably, antifungal resistance. Our genetic analyses further revealed distinct genes that facilitate thermoadaptation in different populations--identifying new molecular players in the regulation of this trait and revealing that there are multiple independent routes to gaining thermotolerance. These results highlight the remarkable flexibility of fungi to adapt rapidly to new environments and raise pressing questions about the impacts of rising environmental temperatures on the future of infectious diseases and human health.

microbiology↗

bioRxiv2023

Hidden evolutionary constraints dictate the retention of coronavirus accessory genes

Coronaviruses exhibit many mechanisms of genetic innovation, including the acquisition of accessory genes that originate by capture of cellular genes or through duplication of existing viral genes. Accessory genes influence viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) encoding a cellular AKAP7 phosphodiesterase and an inactive native phosphodiesterase, NS2 to model the evolutionary fate of accessory genes. After courses of serial infection, the gene encoding inactive NS2, ORF2, unexpectedly remained intact, suggesting it is under cryptic constraint uncoupled from the function of NS2. In contrast, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. Experimental evolution also led to altered viral replication in a cell type-specific manner and changed the relative proportions of subgenomic viral RNA in plaque-purified viral isolates, revealing additional mechanisms of adaptation. Guided by the retention of ORF2 and similar patterns in related betacoronaviruses, we analyzed ORF8 of SARS-CoV-2, which arose via gene duplication and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution, challenging assumptions on the dynamics of gene loss in virus genomes and extending these findings to viruses currently adapting to humans.

evolutionary biology↗

bioRxiv2023

Genetic Variants That Modify the Neuroendocrine Regulation of Foraging Behavior in C. elegans

The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. The neuroendocrine TGF-beta ligand, DAF-7, regulates diverse behavioral responses of Caenorhabditis elegans to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons and identified common variants in gap-2, encoding a GTPase-Activating Protein homologous to mammalian SynGAP proteins, which modify daf-7 expression cell-non-autonomously and promote exploratory foraging behavior in a DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.

neuroscience↗

bioRxiv2022

Rapid Evolution of Glycan Recognition Receptors Reveals an Axis of Host-Microbe Conflicts at Carbohydrate-Protein Interfaces

Detection of microbial pathogens is a primary function of many mammalian immune proteins. This can be accomplished through the recognition of diverse microbial-produced macromolecules including proteins, nucleic acids and carbohydrates. Many pathogens subvert host defenses by rapidly changing these structures to avoid detection, placing strong selective pressures on host immune proteins that repeatedly adapt to remain effective. Signatures of rapid evolution have been identified in numerous host immunity proteins involved in the detection of pathogenic protein substrates, but whether the same signals can be observed in host proteins engaged in interactions with other pathogen-derived molecules has received much less attention. This focus on protein-protein interfaces has largely obscured the study of fungi as contributors to host-pathogen evolutionary conflicts, despite their importance as a formidable class of vertebrate pathogens. Here, we provide evidence that many mammalian immune receptors involved in the detection of microbial glycans have been subject to recurrent positive selection. Notably, we find that rapidly evolving sites in these genes primarily cluster in key functional domains involved in carbohydrate recognition. Further, we identified convergent patterns of substitution in distinct primate populations at a site in the Melanin Lectin gene that has been associated with increased risk of invasive fungal disease. Our results also highlight the power of evolutionary analyses to reveal uncharacterized interfaces of host-pathogen conflict by identifying genes, such as CLEC12A, with strong signals of positive selection across multiple mammalian lineages. These results suggest that the realm of interfaces shaped by host-microbe conflicts extends beyond the world of host-viral protein-protein interactions and into the world of microbial glycans and fungi.

evolutionary biology↗

bioRxiv2020

Conflicts with diarrheal pathogens trigger rapid evolution of an intestinal signaling axis

The pathogenesis of infectious diarrheal diseases is largely attributed to enterotoxin proteins that disrupt intestinal water absorption, causing severe dehydration. Despite profound health consequences, the impacts of diarrhea-causing microbes on the evolutionary history of host species are largely unknown. We investigated patterns of genetic variation in mammalian Guanylate Cyclase-C (GC-C), an intestinal receptor frequently targeted by bacterial enterotoxins, to determine how hosts might adapt in response to diarrheal infections. Under normal conditions, GC-C interacts with endogenous guanylin peptides to promote water secretion in the intestine, but signaling can be hijacked by bacterially-encoded heat-stable enterotoxins (STa) during infection, which leads to overstimulation of GC-C and diarrhea. Phylogenetic analysis in mammals revealed evidence of recurrent positive selection in the GC-C ligand-binding domain in primates and bats, consistent with selective pressures to evade interactions with STa. Using in vitro assays and transgenic intestinal organoids to model STa-mediated diarrhea, we show that GC-C diversification in these lineages results in substantial variation in toxin susceptibility. In bats, we observe a unique pattern of compensatory coevolution in the endogenous GC-C ligand uroguanylin, reflecting intense bouts of positive selection at the receptor-ligand interface. These findings demonstrate control of water physiology as a previously unrecognized interface for genetic conflict and reveal diarrheal pathogens as a source of selective pressure among diverse mammals.

evolutionary biology↗

bioRxiv2018

A sexually dimorphic neuroendocrine cascade acts through shared sensory neurons to regulate behavior in C. elegans

ABSTRACT\n\nSexually dimorphic behaviors are observed in species across the animal kingdom, however the relative contributions of sex-specific and sex-shared nervous systems to such behaviors are not fully understood. Building on our previous work which described the sexually dimorphic expression of a neuroendocrine ligand, DAF-7, and its role in behavioral decision-making in C. elegans (Hilbert and Kim, 2017), we show here that sex-specific expression of daf-7 is regulated by another neuroendocrine ligand, Pigment Dispersing Factor (PDF-1), which has previously been implicated in regulating male-specific behavior (Barrios et al., 2012). Our analysis revealed that PDF-1 acts sex- and cell-specifically in the ASJ neurons to regulate the expression of daf-7 and we show that differences in the expression of the PDFR-1 receptor account for the sex-specific effects of this pathway. Our data suggest that modulation of the sex-shared nervous system by neuroendocrine signaling pathways can play a role in shaping sexually dimorphic behaviors.

neuroscience↗