Organisms rely on inducible and constitutive immune defences to combat infection. Constitutive immunity enables a rapid response to infection but may carry a cost for uninfected individuals, leading to the prediction that it will be favoured when infection rates are high. When we exposed populations of Drosophila melanogaster to intense parasitism by the parasitoid wasp Leptopilina boulardi, they evolved resistance by developing a more reactive cellular immune response. Using single-cell RNA sequencing, we found that immune-inducible genes had become constitutively upregulated. This was the result of resistant larvae differentiating precursors of specialized immune cells called lamellocytes that were previously only produced after infection. Therefore, populations evolved resistance by genetically hard-wiring the first steps of an induced immune response to become constitutive.
Unprocessed single cell sequence reads were deposited in the Sequence Read Archive (accession: SRP256887, Bioproject: PRJNA625925). Cell count matrices for all detected genes, cluster identities and processed scRNA-seq results were deposited into Gene Expression Omnibus (accession: GSE148826). The R script used to analyze the scRNA-seq data is available on Github (Repository: dmel_scRNA_hemocyte).
Single cell sequencing reveals that constitutive activation of cellular immunity underlies the evolution of resistance to infectionNCBI Gene Expression Omnibus, GSE148826.
- Alexandre B. Leitão
- Francis M Jiggins
- Alexandre B. Leitão
- Ramesh Arunkumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Bruno Lemaitre, École Polytechnique Fédérale de Lausanne, Switzerland
© 2020, Leitão et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Abiraterone acetate is an effective treatment for metastatic castrate-resistant prostate cancer (mCRPC), but evolution of resistance inevitably leads to progression. We present a pilot study in which abiraterone dosing is guided by evolution-informed mathematical models to delay onset of resistance.
In the study cohort, abiraterone was stopped when PSA was <50% of pretreatment value and resumed when PSA returned to baseline. Results are compared to a contemporaneous cohort who had >50% PSA decline after initial abiraterone administration and met trial eligibility requirements but chose standard of care (SOC) dosing.
17 subjects were enrolled in the adaptive therapy group and 16 in the SOC group. All SOC subjects have progressed, but four patients in the study cohort remain stably cycling (range 53–70 months). The study cohort had significantly improved median time to progression (TTP; 33.5 months; p<0.001) and median overall survival (OS; 58.5 months; hazard ratio, 0.41, 95% confidence interval (CI), 0.20–0.83, p<0.001) compared to 14.3 and 31.3 months in the SOC cohort. On average, study subjects received no abiraterone during 46% of time on trial. Longitudinal trial data demonstrated the competition coefficient ratio (αRS/αSR) of sensitive and resistant populations, a critical factor in intratumoral evolution, was two- to threefold higher than pre-trial estimates. Computer simulations of intratumoral evolutionary dynamics in the four long-term survivors found that, due to the larger value for αRS/αSR, cycled therapy significantly decreased the resistant population. Simulations in subjects who progressed predicted further increases in OS could be achieved with prompt abiraterone withdrawal after achieving 50% PSA reduction.
Incorporation of evolution-based mathematical models into abiraterone monotherapy for mCRPC significantly increases TTP and OS. Computer simulations with updated parameters from longitudinal trial data can estimate intratumoral evolutionary dynamics in each subject and identify strategies to improve outcomes.
Moffitt internal grants and NIH/NCI U54CA143970-05 (Physical Science Oncology Network).
Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398 is the dominant MRSA in European livestock and a growing cause of human infections. Previous studies have identified three categories of MGEs whose presence or absence distinguishes livestock-associated CC398 from a closely related and less antibiotic-resistant human-associated population. Here, we fully characterise the evolutionary dynamics of these MGEs using a collection of 1180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCCmec that carries methicillin, tetracycline, and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCCmec. In contrast, a class of prophages that carry a human immune evasion gene cluster and that are largely absent from livestock-associated CC398 have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA is transmitted to humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, the stable inheritance of resistance-associated MGEs suggests that the impact of ongoing reductions in antibiotic and zinc oxide use in European farms on livestock-associated MRSA will be slow to be realised.