Biology subjects

Solomon, S. L.

Publications and source records attributed to Solomon, S. L..

5 recordsLinked to original sources

bioRxiv2026

Bacterial surface display enables lysis-independent joint host-pathogen single-cell profiling

Heterogeneity in host-pathogen interactions arises from variation in both host cell state and pathogen state, yet most single-cell methods capture these features separately. Joint profiling is limited by fundamental technical mismatches between host- and pathogen-derived material, particularly differences in cell wall structure, lysis requirements, and molecular abundance. Here we introduce a lysis-independent strategy that enables unified measurement of intracellular bacterial presence and state alongside host single-cell profiles. We repurpose bacterial surface display to encode promoter activity and bacterial identity as antibody-detectable signals, rendering bacterial features compatible with existing antibody-based single-cell assays. This approach is modular across promoters, epitope tags, display scaffolds, and bacterial species, including Escherichia coli and Mycobacterium tuberculosis. Surface-displayed reporters are detectable during intracellular infection and can be read out by flow cytometry and droplet-based single-cell RNA sequencing without pathogen-specific lysis optimization or pre-sorting on pathogen signal. Applying this method to infected macrophages, we link heterogeneous bacterial uptake to heterogeneous expression of phagocytosis-associated host programs. This strategy enables scalable, joint host-pathogen single-cell measurements and expands the range of pathogens and states accessible to high-throughput single-cell analysis.

bioengineering↗

bioRxiv2025

Physiological mechanisms underlying coral acclimatization capacity to novel, multi-stressor conditions

Reef-building corals are under pressure to acclimatize and/or adapt to multiple co-occurring stressors, including climate change and declines in water quality. However, their capacity to do so is largely unknown. Yet, some corals naturally persist in habitats with multi-stressor conditions which can provide crucial insight into coral adaptive capacity under future ocean conditions. To assess the role of phenotypic plasticity and local adaptation in coral acclimatory responses to novel conditions, we reciprocally transplanted two coral species (Siderastrea siderea, branching Porites) between a multi-stressor, highly variable inland bay and a more stable fringing reef, and measured key phenotypic traits after 0, 4, and 12 months. Reef-origin corals demonstrated high plasticity when transplanted to the bay, as both species maintained high survival and calcification, and matched bay natives phenotypic traits. Yet, both species had reduced photosynthesis-to-respiration ratios, highlighting the risk of metabolic tradeoffs unless compensated for through increased heterotrophy. Conversely, bay-origin corals had enhanced photosynthetic performance but lower calcification on the reef. Reaction norms provided stronger evidence for environmental specialization in bay-origin than reef-origin corals, which could limit their use as stress-tolerant source corals for reef restoration. Overall, our findings suggest multi-stressor variability may promote specialized genotypes, rather than increased phenotypic plasticity.

ecology↗

bioRxiv2024

Protease shaving of Mycobacterium tuberculosis facilitates vaccine antigen discovery anddelivery of novel cargoes to the Mtb surface

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of infectious disease death and lacks a vaccine capable of protecting adults from pulmonary TB. Studies have shown that Mtb uses a variety of mechanisms to evade host immunity. Secreted Mtb proteins such as Type VII secretion system substrates have been characterized for their ability to modulate anti-Mtb immunity; however, studies of other pathogens such as Salmonella Typhi and Staphylococcus aureus have revealed that outer membrane proteins can also interact with the innate and adaptive immune system. The Mtb outer membrane proteome has received relatively less attention due to limited techniques available to interrogate this compartment. We filled this gap by deploying protease shaving and quantitative mass spectrometry to identify Mtb outer membrane proteins which serve as nodes in the Mtb-host interaction network. These analyses revealed several novel Mtb proteins on the Mtb surface largely derived from the PE/PPE class of Mtb proteins, including PPE18, a component of a leading Mtb vaccine candidate. We next exploited the localization of PPE18 to decorate the Mtb surface with heterologous proteins and deliver these surface-engineered Mtb to the phagosome. Together, these studies reveal potential novel targets for new Mtb vaccines as well as facilitate new approaches to study difficult to study cellular compartments during infection.

microbiology↗

bioRxiv2021

Single-cell analysis reveals the subthreshold TLR response to Mycobacterium tuberculosis infection

Mycobacterium tuberculosis (Mtb) infection remains one of society's greatest human health challenges. Recognition of pathogens such as Mtb by phagocytes via pattern recognition receptors (PRRs) is critical for immune defense. Phagocytes and other innate immune cells must successfully discriminate between pathogen infection or noisy signals derived from transient non-pathogenic exposures to pattern recognition receptor ligands. Previous studies have underscored the importance of toll-like receptor 2 (TLR2) in the recognition of Mtb, and other studies have demonstrated that toll-like receptor 4 (TLR4) exhibits sigmoidal dynamics in inflammatory protein production in response to soluble ligands. How these dynamics extend to TLR2 in response to Mtb or soluble TLR2 ligands is not known. Here, we address a challenging question essential to the pathogenesis of tuberculosis (TB) disease: What is the quality of the early innate response to Mtb infection at low multiplicity of infection and how does the response to soluble TLR2 ligand stimulation reflect the intact pathogen response? Using soluble TLR2 ligands, we demonstrate that inflammatory protein production in response to TLR2 stimulation similarly follows sigmoidal activation. We further show that inflammatory protein production following Mtb infection operates in this subthreshold regime and cannot be attributed to irreversible disruption of inflammatory signaling pathways in Mtb-infected cells. Using highly sensitive assays to interrogate signaling in Mtb-infected primary human macrophages, we further show that Mtb infection results in limited phosphorylation of p38, a key regulator of inflammatory pathways. We further demonstrate that this poor activation is not driven by irreversible inhibition of p38 signaling by Mtb. Lastly, we demonstrate that the quality of canonical inflammatory signal input is decoupled from the ability to control Mtb growth. Together, these data demonstrate that pathways downstream of TLR signaling are differentially activated following Mtb infection and that barriers to activation of these pathways may contribute to functional partitioning of the inflammatory state of Mtb infected cells. Importantly, these studies provide a roadmap to dissect heterogeneous innate responses to Mtb infection as well as provide a tractable experimental system to simulate the early innate immune response to paucibacillary infection in humans.

immunology↗

bioRxiv2020

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

Macrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or undetectable levels of IL-10 independent of activation or stimulation condition. To nominate candidate regulators of this IL-10 response, we leverage unbiased single-cell mRNA sequencing to identify transcriptional networks associated with GM-CSF-derived cells. Using these data, we identify oxidative signaling pathways as upregulated in GM-CSF derived cells and demonstrate that scavenging of oxidative radicals can enhance IL-10 production in these cells. Collectively, these data underscore the complexity of monocyte-derived macrophage state over time and highlight a dominant role for GM-CSF in tuning macrophage inflammatory phenotype, metabolic state, and plasticity.

immunology↗