Search

The influenza virus (IAV) is a major cause of respiratory disease, with significant infection increases in pandemic years. Vaccines are a mainstay of IAV prevention, but are complicated by consideration of IAV’s vast strain diversity, manufacturing and vaccine uptake limitations. While antivirals may be used for treatment of IAV, they are most effective in early stages of the infection and several virus strains have become drug resistant. Therefore, there is a need for advances in IAV treatment, especially host-directed, personalized therapeutics.Given the spatial dynamics of IAV infection and the relationship between viral spatial distribution and disease severity, a spatial approach is necessary to expand our understanding of IAV pathogenesis. We used spatial metabolomics to address this issue. Spatial metabolomics combines liquid chromatography-tandem mass spectrometry of metabolites extracted from systematic organ sections, 3D models and computational techniques, to develop spatial models of metabolite location and their role in organ function and disease pathogenesis. In this project, we analyzed plasma and systematically sectioned lung tissue samples from uninfected or infected mice. Spatial mapping of sites of metabolic perturbations revealed significantly lower metabolic perturbation in the trachea compared to other lung tissue sites. Using random forest machine learning, we identified metabolites that responded differently in each lung position based on infection, including specific amino acids, lipids and lipid-like molecules, and nucleosides. These results support the implementation of spatial metabolomics to understand metabolic changes upon IAV infection and to identify candidate pathways to be targeted for IAV therapeutics.ImportanceThe influenza virus is a major health concern. Over 1 billion people become infected annually despite the wide distribution of vaccines, and antiviral agents are insufficient to address current clinical needs. In this study, we used spatial metabolomics to understand changes in the lung and plasma metabolome of mice infected with influenza A virus, compared to uninfected controls. We determined metabolites altered by infection in specific lung tissue sites and distinguished metabolites perturbed by infection between lung tissue and plasma samples. Our findings highlight the importance of a spatial approach to understanding the intersection between lung metabolome, viral infection and disease severity. Ultimately, this approach will expand our understanding of respiratory disease pathogenesis and guide the development of novel host-directed therapeutics.

Workplace chemical exposures are a major source of occupational injury. Although over half of these are skin exposures, exposomics research often focuses on chemical levels in the air or in worker biofluids such as blood and urine. Until now, one limitation has been the lack of methods to quantitatively measure surface chemical transfer. Outside the realm of harmful chemicals, the small molecules we leave behind on surfaces can also reveal important aspects of human behavior. In this study, we developed a swab-based quantitative approach to determine small molecule concentrations across common surfaces. We demonstrate its utility using one drug, cyclobenzaprine, and two human-derived metabolites, carnitine and phenylacetylglutamine, on four common surfaces: linoleum flooring, plastified laboratory workbench, metal and Plexiglass. This approach enabled linear small molecule recovery and quantification of molecule abundance on workplace built environment surfaces. Overall, this method paves the way for future quantitative exposomics studies.

Cutaneous leishmaniasis (CL) is the most common disease form caused by a Leishmania parasite infection and considered a neglected tropical disease (NTD), affecting 700,000 to 1.2 million new cases per year in the world. Leishmania major is one of several different species of the Leishmania genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can provide knowledge of new targets for host-targeted drug development. In this study, tissue samples were collected from mice infected in the ear or footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including selected glycerophosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200–799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800–899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through host metabolism and may lead to new curative measures against infection with Leishmania.

Summary ParagraphAmong the biomolecules at the center of human health and molecular biology is a system of molecules that defines the human phenotype known as the metabolome. Through an untargeted metabolomic analysis of fecal samples from human individuals from Africa and the Americas—the birthplace and the last continental expansion of our species, respectively—we present the characterization of the core human fecal metabolome. The majority of detected metabolite features were ubiquitous across populations, despite any geographic, dietary, or behavioral differences. Such shared metabolite features included hyocholic acid and cholesterol. However, any characterization of the core human fecal metabolome is insufficient without exploring the influence of industrialization. Here, we show chemical differences along an industrialization gradient, where the degree of industrialization correlates with metabolomic changes. We identified differential metabolite features like leucyl-leucine dipeptides and urobilin as major metabolic correlates of these behavioral shifts. Our results indicate that industrialization significantly influences the human fecal metabolome, but diverse human lifestyles and behavior still maintain a core human fecal metabolome. This study represents the first characterization of the core human fecal metabolome through untargeted analyses of populations along an industrialization gradient.

Today, more than a billion people—one-sixth of the world’s population—are suffering from neglected tropical diseases. Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected tropical diseases caused by protozoan parasites belonging to the genera Trypanosoma and Leishmania. About half a million people living in tropical and subtropical regions of the world are at risk of contracting one of these three infections. Kinetoplastids have complex life cycles with different morphologies and unique physiological requirements at each life cycle stage. This review covers the latest findings on metabolic pathways impacting disease pathogenesis of kinetoplastids within the mammalian host. Nutrient availability is a key factor shaping in vivo parasite metabolism; thus, kinetoplastids display significant metabolic flexibility. Proteomic and transcriptomic profiles show that intracellular trypanosomatids are able to switch to an energy-efficient metabolism within the mammalian host system. Host metabolic changes can also favor parasite persistence, and contribute to symptom development, in a location-specific fashion. Ultimately, targeted and untargeted metabolomics studies have been a valuable approach to elucidate the specific biochemical pathways affected by infection within the host, leading to translational drug development and diagnostic insights.

Each year 700,000 to 1.2 million new cases of cutaneous leishmaniasis (CL) are reported and yet CL remains one of thirteen diseases classified as neglected tropical diseases (NTDs). Leishmania major is one of several different species of that same genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can lead to new drug targets. In this study, samples were collected from mice infected in the ear and footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including select phosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200-799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800-899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through the host metabolism and may lead to new curative measures against infection with Leishmania.Author summaryCutaneous leishmaniasis (CL) is one of thirteen neglected tropical diseases in the world today. It is an infectious disease with a wide distribution spanning five continents, with increasing distribution expected due to climate change. CL manifests as skin lesions and ulcers that are disabling and stigmatized. With the current treatment options being limited, studying host-pathogen metabolism can uncover mechanisms of disease pathogenesis that may lead to new curative measures against infection. In this paper we used untargeted metabolomics to address molecular-level changes occurring in vivo in experimental skin lesions of Leishmania major. Distinct global metabolic profiles were observed. Total phosphocholines (PCs) and those in the lower m/z ranges were significantly higher at the site of the skin lesion in the ear. In addition, specific PCs as well as PCs of varied m/z ranges were also affected at healthy-appearing lesion-adjacent sites, indicating that infection-induced metabolic perturbations are not restricted to the lesion site. Ultimately, these results provide essential clues to the metabolic pathways affected by CL.

Soil covers most of Earth’s continental surface and is fundamental to life-sustaining processes such as agriculture. Given its rich biodiversity, soil is also a major source for natural product drug discovery from soil microorganisms. However, the study of the soil small molecule profile has been challenging due to the complexity and heterogeneity of this matrix. In this study, we implemented high-resolution liquid chromatography–tandem mass spectrometry and large-scale data analysis tools such as molecular networking to characterize the relative contributions of city, state and regional processes on backyard soil metabolite composition, in 188 soil samples collected from 14 USA States, representing five USA climate regions. We observed that region, state and city of collection all influence the overall soil metabolite profile. However, many metabolites were only detected in unique sites, indicating that uniquely local phenomena also influence the backyard soil environment, with both human-derived and naturally-produced (plant-derived, microbially-derived) metabolites identified. Overall, these findings are helping to define the processes that shape the backyard soil metabolite composition, while also highlighting the need for expanded metabolomic studies of this complex environment.

Chemical cartography of experimental gastrointestinal Chagas disease identifies previously-unknown mechanisms of disease tolerance., Chagas disease (CD) is a parasitic disease caused by Trypanosoma cruzi protozoa, presenting with cardiomyopathy, megaesophagus, and/or megacolon. To determine the mechanisms of gastrointestinal (GI) CD tissue tropism, we systematically characterized the spatial localization of infection-induced metabolic and microbiome alterations, in a mouse model of CD. Notably, the impact of the transition between acute and persistent infection differed between tissue sites, with sustained large-scale effects of infection in the esophagus and large intestine, providing a potential mechanism for the tropism of CD within the GI tract. Infection affected acylcarnitine metabolism; carnitine supplementation prevented acute-stage CD mortality without affecting parasite burden by mitigating infection-induced metabolic disturbances and reducing cardiac strain. Overall, results identified a previously-unknown mechanism of disease tolerance in CD, with potential for new therapeutic regimen development. More broadly, results highlight the potential of spatially resolved metabolomics to provide insight into disease pathogenesis and infectious disease drug development.