Biology subjects

Smith, T. C.

Publications and source records attributed to Smith, T. C..

13 recordsLinked to original sources

bioRxiv2026

Human-wildlife conflict shows shared spatial predictors across ecological and geographic contexts

Human-wildlife conflict (HWC) is a global challenge for biodiversity conservation, food security, and human well-being. Effective management towards human-wildlife coexistence, recognized as a priority in Target 4 of the Kunming-Montreal Global Biodiversity Framework, requires understanding the drivers of HWC. However, the strong influence of local human and ecological context means that most HWC research focuses on individual case studies, limiting transferability of patterns across contexts. Here, we link local contexts and transferable drivers by testing whether HWC exhibits an intermediate level of organization, in which local predictor profiles are structured by broader ecological, geographic, and taxonomic contexts. After compiling ~11,000 conflict incidents, we construct and compare random forest models across 29 mammalian HWC scenarios spanning diverse species, conflict types, biomes, and continents to identify contexts in which predictor profiles converge. While predictors varied among individual conflicts, HWC scenarios were organized by shared context: conflicts occurring within the same biome tended to have similar predictor profiles, with continent and taxonomic group providing additional structure. Proximity to protected areas was the most consistently important predictor of HWC globally. The likelihood of conflict increased with human population density across nearly all scales and contexts, while distance to roads was also an important predictor in many contexts. Together, these results demonstrate an intermediate level of organization in HWC that reconciles case-specific variation with broader patterns across biomes, continents, and taxonomic groups. This framework provides a basis for scaling mitigation strategies beyond individual case studies while avoiding one-size-fits-all approaches.

ecology↗

bioRxiv2025

Increased proportion of growth-arrested bacilli in acidic pH adaptation promotes Mycobacterium tuberculosis treatment survival

The ability of Mycobacterium tuberculosis (Mtb) to adapt its growth behavior in response to host environments promotes survival against immune and drug stressors. However, how these behaviors shift at the single-cell level remains poorly understood. Here, we show that Mtb adapts to acidic conditions by increasing the proportion of bacteria in a growth-arrested state, rather than uniformly slowing the growth rate of the entire population. This non-growing subpopulation exhibits greater tolerance to ethambutol. Clinical strains displayed higher proportions of growth-arrested cells under both neutral and acidic conditions, suggesting that growth arrest serves as a bet-hedging strategy during infection. Though the PhoPR two-component system contributes to regulating this non-growing state, we show that it is a partial regulator of the non-growing bacterial subpopulation and that additional transcriptional regulators are involved. Our study demonstrates that non-growing subpopulations of Mtb provide fitness benefits and are an active adaptation to environmental cues and not a passive consequence of stressors.

microbiology↗

bioRxiv2025

Pneumolysin-dependent and independent non-canonical autophagy processes mediate host defense against pneumococcal infection

Streptococcus pneumoniae is an opportunistic pathogen responsible for life-threatening diseases including pneumonia and meningitis. The host defense against pneumococci relies heavily on macrophages, which can effectively internalize and degrade bacteria. Recent studies have implicated both canonical and non-canonical autophagy-related processes in bacterial clearance, but the precise pathways mediating defense against S. pneumoniae remain unknown. Here, we utilize a well-established zebrafish larval infection model to investigate the role of autophagy in host defense against pneumococci in vivo. Using a transgenic macroautophagy/autophagy reporter line, we found the autophagy marker Map1lc3/Lc3 being recruited to pneumococci-containing vesicles upon bacterial internalization by zebrafish macrophages. The genetic inhibition of core autophagy gene atg5 led to loss of the Lc3 associations and their impaired acidification, significantly delaying bacterial clearance. This Lc3 recruitment is partially mediated by LC3-associated phagocytosis (LAP), as knockdown of cyba and rubcn moderately reduced Lc3 association with phagosomes and diminished pneumococcal degradation. Interestingly, we observed no involvement of xenophagy components in S. pneumoniae-infected macrophages, suggesting the activation of another non-canonical autophagy pathway, distinct from LAP, targeting pneumococci-containing phagosomes. Instead, we found that the pneumococcal pore-forming toxin pneumolysin induces ROS-independent CASM pathways, one of which is abolished by knockdown of tecpr1a indicating the involvement of sphingomyelin-Tecpr1-induced LC3 lipidation (STIL). Collectively, our observations shed new light on the host immune response against S. pneumoniae, demonstrating that several distinct non-canonical autophagy pathways mediate bacterial degradation by macrophages and providing potential targets for the development of novel therapies to combat pneumococcal infections.

immunology↗

bioRxiv2024

Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action

Treatments for tuberculosis remain lengthy, motivating a search for new drugs with novel mechanisms of action. However, it remains challenging to elucidate the direct targets of a drug, and even more so, to determine which disrupted cellular processes lead to bacterial killing. We developed a computational tool, DECIPHAER (DEcoding Cross-modal Information of PHarmacologies via AutoEncodeRs), to select the important correlated transcriptional and morphological responses of Mycobacterium tuberculosis to drug treatments. By finding a reduced feature space from these measurements, DECIPHAER highlighted essential features of Mtb cellular damage such as phosphosugar stress and inhibition of translation and DNA replication. After training, DECIPHAER provides cell-death-relevant insight into single-modal datasets, enabling interrogation of drug treatment responses for which transcriptional data are unavailable. Using morphological data alone with DECIPHAER, we discovered that respiration inhibition by the poly-pharmacological drugs, SQ109 and BM212, can influence cell death more than their effects on the cell wall. This study demonstrates that DECIPHAER can extract the critical shared information from multi-modal measurements to identify cell death-relevant mechanisms of TB drugs.

microbiology↗

bioRxiv2024

Do fungi look like macroparasites? Quantifying the patterns and mechanisms of aggregation for host-fungal parasite relationships

Most hosts contain few parasites, whereas few hosts contain many. This pattern, known as aggregation, is well-documented in macroparasites where parasite intensity distribution among hosts affects host-parasite dynamics. Infection intensity also drives fungal disease dynamics, but we lack a basic understanding of host-fungal aggregation patterns, how they compare to macroparasites, and if they reflect biological processes. To address these gaps, we characterized aggregation of the fungal pathogen Batrachochytrium dendrobatidis (Bd) in amphibian hosts. Utilizing the slope of Taylors Power Law, we found Bd intensity distributions were more aggregated than macroparasites, conforming closely to lognormal distributions. We observed that Bd aggregation patterns are strongly correlated with known biological processes operating in amphibian populations, such as epizoological phase--invasion, post-invasion, and enzootic--and intensity-dependent disease mortality. Using intensity-dependent mathematical models, we found evidence of evolution of host resistance based on aggregation shifts in systems persisting with Bd following disease-induced declines. Our results show that Bd aggregation is highly conserved across disparate systems and is distinct from aggregation patterns in macroparasites, and contains signatures of potential biological processes of amphibian-Bd systems. Our work lays a foundation to unite host-fungal dynamics under a common theoretical framework and inform future modeling approaches that may elucidate host-fungus interactions.

ecology↗

bioRxiv2023

Evolutionary rescue and reintroduction of resistant frogs allows recovery in the presence of a lethal fungal disease

Vast alteration of the biosphere by humans is causing a sixth mass extinction, driven in part by an increase in emerging infectious diseases. The emergence of the lethal fungal pathogen (Batrachochytrium dendrobatidis; "Bd") has devastated global amphibian biodiversity, with hundreds of species experiencing declines or extinctions. With no broadly applicable methods available to reverse these impacts in the wild, the future of many amphibians appears grim. The once-common mountain yellow-legged (MYL) frog is emblematic of amphibians threatened by Bd. Although most MYL frog populations are extirpated following disease outbreaks, some persist and eventually recover. Frogs in these recovering populations have increased resistance against Bd infection, consistent with evolution of resistant genotypes and/or acquired immunity. We conducted a 15-year landscape-scale reintroduction study and show that frogs collected from recovering populations and reintroduced to vacant habitats can reestablish populations despite the presence of Bd. In addition, results from viability modeling suggest that many reintroduced populations have a low probability of extinction over 50 years. To better understand the role of evolution in frog resistance, we compared the genomes of MYL frogs from Bd-naive and recovering populations. We found substantial differences between these categories, including changes in immune function loci that may confer increased resistance, consistent with evolutionary changes in response to Bd exposure. These results provide a rare example of how reintroduction of resistant individuals can allow the landscape-scale recovery of disease-impacted species. This example has broad implications for the many taxa worldwide that are threatened with extinction by novel pathogens. Significance StatementUnderstanding how species persist despite accelerating global change is critical for the conservation of biodiversity. Emerging infectious diseases can have particularly devastating impacts, and few options exist to reverse these effects. We used large-scale reintroductions of disease-resistant individuals in an effort to recover a once-common frog species driven to near-extinction by a disease that has decimated amphibian biodiversity. Introduction of resistant frogs allowed reestablishment of viable populations in the presence of disease. In addition, resistance may be at least partially the result of natural selection at specific immune function genes, which show evidence for selection in recovering populations. The evolution of resistance and reintroduction of resistant individuals could play an important role in biodiversity conservation in our rapidly changing world.

ecology↗

bioRxiv2022

Novel synergies and isolate specificities in the drug interactions landscape of Mycobacterium abscessus

Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotic lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured approximately 230 pairwise drug interactions among 22 antibiotics and identified 71 synergistic pairs, 54 antagonistic pairs, and four potentiator-antibiotics not previously reported. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in lab reference strain ATCC19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed highly strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.

microbiology↗

bioRxiv2021

Effectiveness of antifungal treatments during chytridiomycosis epizootics in populations of an endangered frog

The recently-emerged amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has had an unprecedented impact on global amphibian populations, and highlights the urgent need to develop effective mitigation strategies against this pathogen. We conducted field antifungal treatment experiments in populations of the endangered mountain yellow-legged frog during or immediately after Bd-caused mass die-off events. The objective of the treatments was to reduce Bd infection intensity ("load") and in doing so alter frog-Bd dynamics and increase the probability of frog population persistence despite ongoing Bd infection. Experiments included treatment of early life stages (tadpoles and subadults) with the antifungal drug itraconazole, treatment of adults with itraconazole, and augmentation of the skin microbiome of subadults with Janthinobacterium lividum, a commensal bacterium with antifungal properties. All itraconazole treatments caused immediate reductions in Bd load, and produced longer-term effects that differed between life stages. In experiments focused on early life stages, Bd load was reduced in the two months immediately following treatment and was associated with increased survival of subadults. However, Bd load and frog survival returned to pre-treatment levels in less than one year, and treatment had no effect on population persistence. In adults, treatment reduced Bd load and increased frog survival over the three-year post-treatment period, consistent with frogs having developed an effective adaptive immune response against Bd. Despite this protracted period of reduced impacts of Bd on adults, recruitment of new individuals into the adult population was limited and the population eventually declined to near-extirpation. In the microbiome augmentation experiment, bathing frogs in a J. lividum solution after Bd load reduction with itraconazole increased concentrations of this bacterium on frogs, but concentrations declined to baseline levels within one month and did not have a protective effect against Bd infection. Collectively, these results suggest that Bd mitigation efforts focused on frog populations that have recently declined due to Bd emergence are ineffective in causing long-term changes in frog-Bd dynamics and increasing population persistence, due largely to the inability of early life stages to mount an effective immune response against Bd and resulting high susceptibility. This results in repeated recruitment failure and a low probability of population persistence in the face of ongoing Bd infection.

ecology↗

bioRxiv2021

A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis

The identification and validation of a small molecules targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecules targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here we studied the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis (Mtb). After screening ~200 compounds, we focused on two inhibitors active against both exponentially replicating and hypoxia-induced drug-tolerant Mtb that form part of a four-compound structure-activity series. The compound with negligible activity revealed potential false positive targets not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirmed that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings showed that ABPP identifies the targets most likely relevant to a compounds antibacterial activity.

microbiology↗

bioRxiv2020

Morphological profiling of tubercule bacilli identifies drug pathways of action

Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here, we utilized the cell-to-cell variation in morphological features of Mycobacterium tuberculosis bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding of Stress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target or secondary bactericidal activities. We observed cell-wall damaging activity induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of bactericidal activity in tubercule bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous. Significance StatementTuberculosis is a leading cause of death in the world and requires treatment with an arduous multidrug regimen. Many new tuberculosis drugs are in development, and the drug development pipeline would benefit from more rapid methods to learn drug mechanism of action and off-target effects. Here, we describe a high throughput imaging method for rapidly classifying drugs into categories based on the primary and secondary cellular damage called Morphological Evaluation and Understanding of drug-Stress (MorphEUS). We anticipate that MorphEUS will assist in rapidly pinpointing causes of cellular death in response to drug treatment in tuberculosis and other bacterial pathogens.

microbiology↗

bioRxiv2017

Staphylococcus aureus Colonization And Familial Transmission Over A One Year Period

Methods177 adults and 86 minors comprising 95 family units were enrolled from two counties in Iowa and followed up for 52 weeks. Random effects logistic regression was used to test the effect of different risk factors on the probability of an individual falling into a different S. aureus colonization categories. Additionally, the frequency of S. aureus colonization events and familial transmission events were calculated.\n\nResultsThe number of positive environmental sites within a participants house was associated with being a persistent carrier compared to being a non-carrier or intermittent carrier. Age, sharing bath towels, and the number of positive environmental sites within a participants house were associated with being a persistent or intermittent carrier. Colonization events per year were 3.95 for adults and 3.04 for minors. Duration of colonization was longest for persistent carriers (92.3 days for adults and 97.8 days for minors), and intermittent carriers had the most colonization events.\n\nConclusionsThe average duration of colonization was significantly different when comparing intermittent carriers and non-carriers. We have also established estimates of the duration of colonization and the frequency of transmission events among family units in a non-healthcare population.

epidemiology↗

bioRxiv2017

The Nasal And Oropharyngeal Microbiomes Of Healthy Livestock Workers

Little information exists on the microbiomes of livestock workers. A cross-sectional, epidemiological study was conducted enrolling 59 participants (26 of which had livestock contact) in Iowa. Participants were enrolled in one of four ways: from an existing prospective cohort study (n=38), from the Iowa Department of Natural Resources Animal Feeding Operations database (n=17), through Iowa county fairs (n=3), and through snowball sampling (n=1). We collected two sets of swabs from the nares and oropharynx of each participant. The first set of swabs was used to assess the microbiome via 16s rRNA sequencing and the second was used to culture S. aureus. We observed livestock workers to have greater diversity in their microbiomes compared to those with no livestock contact. In the nares, there were 26 operational taxonomic units found to be different between livestock workers and non-livestock workers with the greatest difference seen with Streptococcus and Proteobacteria. In the oropharynx, livestock workers with swine exposure were more likely to carry several pathogenic organisms. The results of this study are the first to characterize the livestock worker nasal and oropharyngeal microbiomes.

epidemiology↗

bioRxiv2017

The Oropharynx As A Distinct Colonization Site For Staphylococcus aureus In The Community

BackgroundS. aureus is a frequent cause of hospital and community associated infections and colonization is known to increase the risk of infection, with the nares considered the most important colonization site.\n\nMethodsWe compared the prevalence of nasal and oropharyngeal carriage in a yearlong, prospective cohort study of people from the community as well as assessed risk factors for nares-only and oropharynx-only colonization.\n\nResultsColonization at both anatomical sites was correlated; however, oropharynx only carriage occurred and oropharyngeal swabs were more sensitive than nasal swabs at detecting carriage (77.27% and 72.725 respectively). Non-Caucasian race, having a greater number of people living in your home and more children in your home all significantly increased the odds of oropharynx-only carriage. Having S. aureus present on home environmental sites, exercising in a fitness center, and sharing bath towels all increased the odds of nares-only carriage.\n\nConclusionsOropharyngeal swabs increase the detection of S. aureus colonization in community embers.

epidemiology↗