Alloreactivity of Allogeneic Mesenchymal Stem/Stromal Cells and Other Cellular Therapies: A Concise Review.

Cellular therapies, deemed live medicine, have brought a wave of new generation biological therapies to treat previously untreatable diseases such as cancers and degenerative diseases like osteoarthritis. These cellular therapies have gained significant recognition in clinical research. The area has been further strengthened with the approval of Chimeric Antigen Receptor added on T cells (CAR-T) therapies by the regulatory authorities USA's Food and Drugs Administration (FDA), European Medical Agency (EMA), the Australian Therapeutic Goods Administration (TGA), and in many countries in 2017 to treat hematological cancers. Another milestone was achieved when allogeneic Mesenchymal Stem Cell- (MSC-) based therapy was approved by the EMA to treat Chrohn's disease in 2018. Allogeneic donor-derived MSC therapies in particular hold great promise and real hope because of their 'off-the shelf' availability and accessibility for patients in need of urgent treatment. So far, thousands of clinical trials have explored the safety and efficacy of both autologous and allogeneic cell therapies, deeming them safe, however with varying degrees of efficacy. In the current pandemic, clinical trials have begun in many parts of the world to treat severe cases of COVID with MSCs. However, the risk of tissue rejection and the development of undesirable effects due to alloreactivity of allogeneic cells are currently not adequately addressed. Therefore, this warrants careful investigation and detailed reporting of such events by clinical researchers. This review aims at discussing the current landscape of approved allogeneic MSCs along with a few other cellular therapies. We explore any possible reactivity reported to inform the readers of any safety concern and on the efficacy of such therapies.

Adaptation to an Amoeba Host Leads to Pseudomonas aeruginosa Isolates with Attenuated Virulence.

The opportunistic pathogen Pseudomonas aeruginosa is ubiquitous in the environment, and in humans, it is capable of causing acute or chronic infections. In the natural environment, predation by bacterivorous protozoa represents a primary threat to bacteria. Here, we determined the impact of long-term exposure of P. aeruginosa to predation pressure. P. aeruginosa persisted when coincubated with the bacterivorous Acanthamoeba castellanii for extended periods and produced genetic and phenotypic variants. Sequencing of late-stage amoeba-adapted P. aeruginosa isolates demonstrated single nucleotide polymorphisms within genes that encode known virulence factors, and this correlated with a reduction in expression of virulence traits. Virulence for the nematode Caenorhabditis elegans was attenuated in late-stage amoeba-adapted P. aeruginosa compared to early-stage amoeba-adapted and nonadapted counterparts. Further, late-stage amoeba-adapted P. aeruginosa showed increased competitive fitness and enhanced survival in amoebae as well as in macrophage and neutrophils. Interestingly, our findings indicate that the selection imposed by amoebae resulted in P. aeruginosa isolates with reduced virulence and enhanced fitness, similar to those recovered from chronic cystic fibrosis infections. Thus, predation by protozoa and long-term colonization of the human host may represent similar environments that select for similar losses of gene function. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute infections in plants and animals, including humans, and chronic infections in immunocompromised and cystic fibrosis patients. This bacterium is commonly found in soils and water, where bacteria are constantly under threat of being consumed by bacterial predators, e.g., protozoa. To escape being killed, bacteria have evolved a suite of mechanisms that protect them from being consumed or digested. Here, we examined the effect of long-term predation on the genotypes and phenotypes expressed by P. aeruginosa. We show that long-term coincubation with protozoa gave rise to mutations that resulted in P. aeruginosa becoming less pathogenic. This is particularly interesting as similar mutations arise in bacteria associated with chronic infections. Importantly, the genetic and phenotypic traits possessed by late-stage amoeba-adapted P. aeruginosa are similar to those observed in isolates obtained from chronic cystic fibrosis infections. This notable overlap in adaptation to different host types suggests similar selection pressures among host cell types as well as similar adaptation strategies.

Effect of interspecific competition on trait variation in Phaeobacter inhibens biofilms.

Interspecific competition between bacteria shapes community dynamics, causing evolutionary changes that affect life history traits. Here, we studied the role of interspecific competition on the generation of trait diversity using a two-species model system of marine, surface-associated bacteria. Bacterial biofilms of Phaeobacter inhibens were established alone or in competition with Pseudoalteromonas tunicata and phenotypic traits of dispersal cells were assessed during biofilm development. P. inhibens dispersal isolates from competition biofilms displayed less phenotypic variation, were superior competitors, were less susceptible to predation, and reached higher planktonic biomass than isolates from noncompetition biofilms. Moreover, the maintenance of competitive ability exhibited by individual dispersal isolates from competition biofilms did not result in an obvious reduction (measured as a negative trait correlation) in other traits, but was rather positively correlated with planktonic growth. However, where negative correlations between traits were found, they were exhibited by individuals derived from noncompetitive biofilms, whose populations also had a higher degree of trait variation than those from biofilms experiencing competition. Our observations indicate that interspecific competition during biofilm formation is important for maintaining both competitive ability and affects variation in ecologically relevant traits. Given that most bacteria in biofilms exist in diverse, multispecies communities, an understanding of how bacteria respond to biotic factors such as interspecific competition is critical for understanding the dynamics of bacterial populations in both ecological and evolutionary time.

Interactions of Vibrio spp. with Zooplankton.

Members of the genus Vibrio are known to interact with phyto- and zooplankton in aquatic environments. These interactions have been proven to protect the bacterium from various environmental stresses, serve as a nutrient source, facilitate exchange of DNA, and to serve as vectors of disease transmission. This review highlights the impact of Vibrio-zooplankton interactions at the ecosystem scale and the importance of studies focusing on a wide range of Vibrio-zooplankton interactions. The current knowledge on chitin utilization (i.e., chemotaxis, attachment, and degradation) and the role of these factors in attachment to nonchitinous zooplankton is also presented.

Draft Genome Sequence of Shewanella sp. Strain CP20.

Shewanella sp. CP20 is a marine bacterium that survives ingestion by Tetrahymena pyriformis and is expelled from the protozoan within membrane-bound vacuoles, where the bacterial cells show long-term survival. Here, we report the draft genome sequence of Shewanella sp. CP20 and discuss the potential mechanisms facilitating intraprotozoan survival.

The rise of pathogens: predation as a factor driving the evolution of human pathogens in the environment.

Bacteria in the environment must survive predation from bacteriophage, heterotrophic protists, and predatory bacteria. This selective pressure has resulted in the evolution of a variety of defense mechanisms, which can also function as virulence factors. Here we discuss the potential dual function of some of the mechanisms, which protect against heterotrophic protists, and how predation pressure leads to the evolution of pathogenicity. This is in accordance with the coincidental evolution hypothesis, which suggests that virulence factors arose as a response to other selective pressures, for example, predation rather than for virulence per se. In this review we discuss some of those environmental factors that may be associated with the rise of pathogens in the marine environment. In particular, we will discuss the role of heterotrophic protists in the evolution of virulence factors in marine bacteria. Finally, we will discuss the implications for expansion of current pathogens and emergence of new pathogens.

Environmental reservoirs and mechanisms of persistence of Vibrio cholerae.

It is now well accepted that Vibrio cholerae, the causative agent of the water-borne disease cholera, is acquired from environmental sources where it persists between outbreaks of the disease. Recent advances in molecular technology have demonstrated that this bacterium can be detected in areas where it has not previously been isolated, indicating a much broader, global distribution of this bacterium outside of endemic regions. The environmental persistence of V. cholerae in the aquatic environment can be attributed to multiple intra- and interspecific strategies such as responsive gene regulation and biofilm formation on biotic and abiotic surfaces, as well as interactions with a multitude of other organisms. This review will discuss some of the mechanisms that enable the persistence of this bacterium in the environment. In particular, we will discuss how V. cholerae can survive stressors such as starvation, temperature, and salinity fluctuations as well as how the organism persists under constant predation by heterotrophic protists.