Biology subjects

Camps, M.

Publications and source records attributed to Camps, M..

4 recordsLinked to original sources

bioRxiv2021

OX40 agonism enhances efficacy of PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Immune checkpoint therapy (ICT) has the potency to eradicate cancer but the mechanisms that determine effective versus non-effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling we examined whether T cell states in the blood circulation could predict responsiveness to a combined ICT, sequentially targeting OX40 costimulatory and PD-1 inhibitory pathways, which effectively eradicated syngeneic mouse tumors. Unbiased assessment of transcriptomic alterations by single-cell RNA sequencing and profiling of cell-surface protein expression by mass cytometry revealed unique activation states for therapy-responsive CD4+ and CD8+ T cells. Effective ICT elicited T cells with dynamic expression of distinct NK cell and chemokine receptors, and these cells were systemically present in lymphoid tissues and in the tumor. Moreover, NK cell receptor-expressing CD8+ T cells were also present in the peripheral blood of immunotherapy-responsive cancer patients. Targeting of the NK cell and chemokine receptors in tumor-bearing mice showed their functional importance for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use of dynamic biomarkers on effector CD4+ and CD8+ T cells to improve cancer immunotherapy.

immunology↗

bioRxiv2021

Genetic interplay between type II topoisomerase enzymes and chromosomal ccdAB toxin-antitoxin in E. coli

Fluoroquinolones are one of the most widely used class of antibiotics. They target two type II topoisomerase enzymes: gyrase and topoisomerase IV. Resistance to these drugs, which is largely caused by mutations in their target enzymes, is on the rise and becoming a serious public health risk. In this work, we analyze the sequences of 352 extraintestinal E. coli clinical isolates to gain insights into the selective pressures shaping the type II topoisomerase mutation landscape in E. coli. We identify both Quinolone Resistance-Determining Region (QRDR) and non-QRDR mutations, outline their mutation trajectories, and show that they are likely driven by different selective pressures. We confirm that ciprofloxacin resistance is specifically and strongly associated with QRDR mutations. By contrast, non-QRDR mutations are associated with the presence of the chromosomal version of ccdAB, a toxin-antitoxin operon, where the toxin CcdB is known to target gyrase. We also find that ccdAB and the evolution of QRDR mutation trajectories are partially incompatible. Finally, we identify partial deletions in CcdB and additional mutations that likely facilitate the compatibility between the presence of the ccdAB operon and QRDR mutations. These "permissive" mutations are all found in ParC (a topoisomerase IV subunit). This, and the fact that CcdB-selected mutations frequently map to topoisomerase IV, strongly suggests that this enzyme (in addition to gyrase) is likely a target for the toxin CcdB in E. coli, although an indirect effect on global supercoiling cannot be excluded. This work opens the door for the use of the presence of ccdB and of the proposed permissive mutations in the genome as genetic markers to assess the risk of quinolone resistance evolution and implies that certain strains may be genetically more refractory to evolving quinolone resistance through mutations in target enzymes.

microbiology↗

bioRxiv2021

Massive export of diazotrophs across the tropical south Pacific Ocean

Diazotrophs are widespread microorganisms that alleviate nitrogen limitation in 60% of our oceans, regulating marine productivity. Yet, their contribution to organic matter export has not been quantified, making an assessment of their impact on the biological carbon pump impossible. Here, we demonstrate that cyanobacterial and non-cyanobacterial diazotrophs are massively exported down to 1000 m-depth in the western subtropical South Pacific Ocean (WTSP), accounting for up to 52-100% of the total particulate nitrogen export fluxes. We further demonstrate that small size unicellular diazotrophs (UCYN, 1-8 {micro}m) are exported more efficiently than filamentous diazotrophs (>100-1000 {micro}m) under the form of large (>50 {micro}m) aggregates linked by an extracellular organic matrix. Beyond the WTSP, our data are supported by analysis of the Tara Oceans metagenomes collected in other ocean basins, showing that diazotrophs are systematically detected in mesopelagic waters when present at the surface. We thus conclude that diazotrophs are key players in carbon sequestration in the ocean and need to be considered in future studies to improve the accuracy of current regional and global estimates of export.

microbiology↗

bioRxiv2018

Functionally redundant forms of extended-spectrum beta-lactamases and aminoglycoside modifying enzymes drive the evolution of two distinct multidrug resistance gene clusters in clinical populations of EXPEC

We evaluate the distribution of genetic markers for antibiotic resistance in 276 genomic sequences of Extraintestinal Pathogenic E. coli from two hospitals on the U.S. West coast. Plasmid-borne genes encoding drug-inactivating enzymes dominate the distribution of aminoglycoside and {beta}-lactam resistance markers. These genes can be assigned based on their distribution to two mutually exclusive complementarity groups (CGs: CG1 and CG2) with each displaying genetic linkage and minimal functional overlap. CG1 includes genes encoding OXA-1 and AAC(6)-Ib-cr, frequently also CTX-M-15, and sometimes AAC(3)-IIe.2, a variant of AAC(3)-IIe; CG2 includes AAC(3)-IId tightly linked to TEM-1, and occasionally also to genes encoding CTX-M-14-like {beta}-lactamases. This binary distribution of aminoglycoside and {beta}-lactamase resistance genes suggests a convergence between two different evolutionary solutions, and results in a ubiquitous functional redundancy in the clinical populations. CG1 and CG2 are largely carried in IncF plasmids, of which we distinguish seven classes based on Rpt-A1 sequence homology. Both CG1 and CG2 genes are found in two different IncF plasmid classes, demonstrating their pervasive mobility across plasmid backbones. Different CG genes and IncF plasmid classes are found in a wide range of MLSTs, highlighting the prevalence of horizontal gene transfer. We also identify at least five clonally expanding MLSTs, which represent high-risk clones: ST131, ST95, ST73, ST127, and ST69. The identification of clonally-expanding types, the discovery of CGs that are ubiquitously spread in diverse clinical strains, and the functional redundancy that these two groups represent have significant implications for monitoring and controlling the spread of resistance.

microbiology↗