Biology subjects

Batra, A.

Publications and source records attributed to Batra, A..

4 recordsLinked to original sources

bioRxiv2024

Variation in the response to antibiotics and life-history across the major Pseudomonas aeruginosa clone type (mPact) panel

Pseudomonas aeruginosa is a ubiquitous, opportunistic human pathogen. Since it often expresses multidrug resistance, it is ranked by the World Health Organization among the top 3 high priority pathogens, for which new treatment options are urgently required. An evaluation of new treatments is usually performed experimentally with one of the canonical laboratory strains (e.g., PAO1 or PA14). However, these two strains are unlikely representative of the strains infecting patients, because they have adapted to laboratory conditions and do not capture the enormous genomic diversity of the species. Here, we characterized the major P. aeruginosa clone type (mPact) panel. This panel consists of 20 strains, which reflect the genomic diversity of the species, cover all major clone types, and have both patient and environmental origins. We found significant strain variation in distinct responses towards antibiotics and general growth characteristics. Only few of the measured traits are related, and if so, only for specific antibiotics. Moreover, high levels of resistance were only identified for clinical mPact isolates and could be linked to known AMR (antimicrobial resistance) genes in the sequenced genomes. One strain also produced highly unstable AMR, indicating an evolutionary cost to resistance expression. By linking isolation source, growth, and virulence to life history traits, we further identified specific adaptive strategies for individual mPact strains towards either host processes or degradation pathways. Overall, the mPact panel provides a reasonably sized set of distinct strains, enabling in-depth analysis of new treatment designs or evolutionary dynamics in consideration of the species genomic diversity. ImportanceNew treatment strategies are urgently needed for high risk pathogens such as the opportunistic and often multidrug resistant pathogen Pseudomonas aeruginosa. Here, we characterize the major P. aeruginosa clone type (mPact) panel. It consists of 20 strains with different origins that cover the major clone types of the species as well as its genomic diversity. This mPact panel shows significant variation in (i) resistance against distinct antibiotics, including several last resort antibiotics, (ii) related traits associated with the response to antibiotics, and (iii) general growth characteristics. We further developed a novel approach that integrates information on resistance, growth, virulence, and life-history characteristics, allowing us to demonstrate the presence of distinct adaptive strategies of the strains that focus either on host interaction or resource processing. In conclusion, the mPact panel provides a manageable number of representative strains for this important pathogen for further in-depth analyses of treatment options and evolutionary dynamics.

microbiology↗

bioRxiv2021

High potency of sequential therapy with only beta-lactam antibiotics

Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution- informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only {beta}-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross- resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.

evolutionary biology↗

bioRxiv2020

Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohns disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, plasmablasts, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD.

bioinformatics↗

bioRxiv2020

Maladaptive myelination promotes epileptogenesis in absence epilepsy

Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a+/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a+/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.

neuroscience↗