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Tsang, D.

Publications and source records attributed to Tsang, D..

2 recordsLinked to original sources

Intra- and inter-species interactions drive early phases of invasion in mice gut microbiota

The stability and dynamics of ecological communities are dictated by interaction networks typically quantified at the level of species.1-10 But how such networks are influenced by intra-species variation (ISV) is poorly understood.11-14 Here, we use ~500,000 chromosomal barcodes to track high-resolution intra-species clonal lineages of Escherichia coli invading mice gut with the increasing complexity of gut microbiome: germ-free, antibiotic-perturbed, and innate microbiota. By co-clustering the dynamics of intra-species clonal lineages and those of gut bacteria from 16S rRNA profiling, we show the emergence of complex time-dependent interactions between E. coli clones and resident gut bacteria. With a new approach, dynamic covariance mapping (DCM), we differentiate three phases of invasion in susceptible communities: 1) initial loss of community stability as E. coli enters; 2) recolonization of some gut bacteria; and 3) recovery of stability with E. coli coexisting with resident bacteria in a quasi-steady state. Comparison of the dynamics, stability and fitness from experimental replicates and different cohorts suggest that phase 1 is driven by mutations in E. coli before colonization, while phase 3 is by de novo mutations. Our results highlight the transient nature of interaction networks in microbiomes driven by the persistent coupling of ecological and evolutionary dynamics. One-Sentence SummaryHigh-resolution lineage tracking and dynamic covariance mapping (DCM) define three distinct phases during early gut microbiome invasion.

evolutionary biology↗

A dual role for CRTH2 in acute lung injury

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid-onset respiratory failure following acute lung injury (ALI). The high mortality rate and rising incidence of ARDS due to COVID-19 make it an important research priority. Here we sought to investigate the role of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) in ARDS. CRTH2 is a G protein-coupled receptor best studied in the context of type 2 immunity, but it also exerts effects on neutrophilic inflammation. To evaluate its role in mouse models of ARDS, we first examined its expression pattern on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that CRTH2 expression on extravasated lung neutrophils promotes cell survival, as genetic deletion of CRTH2 and pharmacologic inhibition of CRTH2 using fevipiprant both led to increased apoptosis in vitro. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. In line with the pro-inflammatory effects of CRTH2 in vitro, we observed improvement of lung injury in CRTH2-deficient mice in terms of vascular leak, weight loss and survival after LPS administration. However, neutrophilic inflammation was elevated, not suppressed in the CRTH2 KO. This finding indicated a second mechanism offsetting the pro-survival effect of CRTH2 on neutrophils. Bulk RNAseq of lung tissue indicated impairments in type 2 immune signaling in the CRTH2 KO, and qPCR and ELISA confirmed downregulation of IL-4, which is known to suppress neutrophilic inflammation. Thus, CRTH2 may play a dual role in ALI, directly promoting neutrophil cell survival, but indirectly suppressing neutrophil effector function via IL-4.

immunology↗