Mutational meltdown of putative microbial altruists in Streptomyces coelicolor colonies

In colonies of the filamentous multicellular bacterium Streptomyces coelicolor, a subpopulation of cells arises that hyperproduces metabolically costly antibiotics, resulting in a division of labor that increases colony fitness. Because these cells contain large genomic deletions that cause massive reductions to individual fitness, their behavior is similar to altruistic worker castes in social insects or somatic cells in multicellular organisms. To understand these mutant cells’ reproductive and genomic fate after their emergence, we use experimental evolution by serially transferring populations via spore-to-spore transfer for 25 cycles, reflective of the natural mode of bottlenecked transmission for these spore-forming bacteria. We show that in contrast to wild-type cells, putatively altruistic mutant cells continue to decline in fitness during transfer while they lose more fragments from their chromosome ends. In addition, the base-substitution rate in mutants increases roughly 10-fold, possibly due to mutations in genes for DNA replication and repair. Ecological damage, caused by reduced sporulation, coupled with DNA damage due to point mutations and deletions, leads to an inevitable and irreversible type of mutational meltdown in these cells. Taken together, these results suggest the cells arising in the S. coelicolor division of labor are analogous to altruistic reproductively sterile castes of social insects

Generating heterokaryotic cells via bacterial cell-cell fusion

NWOMicrobial Biotechnolog

Platelet alpha-granules contribute to organ-specific pathologies in a mouse model of severe malaria

Cerebral malaria (CM) and malaria-associated acute lung injury/acute respiratory distress syndrome (MA-ALI/ARDS) are among the most severe complications of Plasmodium infection. While these disease manifestations are multifactorial, platelets have been described to play a role in the development of both syndromes in humans1,2 and mice3,4. Although the impact of platelets on malaria has been well-studied, questions remains with regard to their contribution to parasite control and immunopathogenesis. Studies have indicated that platelets can kill Plasmodium-infected red blood cells (iRBCs)5-8. However, there are contrasting reports that platelets do not exert any significant control over parasite growth but rather exacerbate malaria immunopathology3,9-12. In this study, we address the role of platelets in the development of severe malaria in three different mouse models of platelet dysfunction/depletion. We show a key role for platelets, and particularly platelet alpha granules (-granules), in mediating organ-specific pathologies during rodent Plasmodium infection

Effect of ultrapure lipopolysaccharides derived from diverse bacterial species on the modulation of platelet activation

Platelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin IIb3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions

The role of platelets in sepsis

Sepsis, a dysregulated host immune response to an infection, is a major cause of morbidity and death worldwide. In this thesis we studied the contribution of platelets to the immune response during sepsis. Platelets are historically viewed as hemostatic cells, but the work in this thesis (as well as other publications) shows that platelets can also influence host immune responses during infection. In a cohort of 930 European sepsis patients and in 1160 Asian patients with gram negative sepsis, we show that reduced platelet counts are associated with increased mortality. We moreover show that platelets can contribute to the dysregulated host response in sepsis patients, independent of disease severity. In murine models of pneumonia derived sepsis, we also found that low platelet counts (after platelet depletion) increased mortality. Low platelets counts moreover impaired host defense against bacteria en impaired vascular integrity. Using several Knock-out mice and antibodies, we were able to identify that platelets use their receptors Glycoprotein(GP)VI and GPIbα to partly mediate this protective effect. Platelet Toll Like receptor signalling was however not involved. Additionally, the interaction between the coagulation system (specifically thrombin) and platelets can also aid in host defense against gram-negative bacteria. In conclusion, we have shown that platelets can modulate immune responses during sepsis, and from our results it has become clear that platelets are not solely hemostatic cells

Nutrition Phytochemicals Affecting Platelet Signaling and Responsiveness:Implications for Thrombosis and Hemostasis

Cardiovascular disease, in particular due to arterial thrombosis, is a leading cause of mortality and morbidity, with crucial roles of platelets in thrombus formation. For multiple plant-derived phytochemicals found in common dietary components, claims have been made regarding cardiovascular health and antiplatelet activities. Here we present a systematic overview of the published effects of common phytochemicals, applied in vitro or in nutritional intervention studies, on agonist-induced platelet activation properties and platelet signaling pathways. Comparing the phytochemical effects per structural class, we included general phenols: curcuminoids (e.g., curcumin), lignans (honokiol, silybin), phenolic acids (caffeic and chlorogenic acid), derivatives of these (shikimic acid), and stilbenoids (isorhapontigenin, resveratrol). Furthermore, we evaluated the flavonoid polyphenols, including anthocyanidins (delphinidin, malvidin), flavan-3-ols (catechins), flavanones (hesperidin), flavones (apigenin, nobiletin), flavonols (kaempferol, myricetin, quercetin), and isoflavones (daidzein, genistein); and terpenoids including carotenes and limonene; and finally miscellaneous compounds like betalains, indoles, organosulfides (diallyl trisulfide), and phytosterols. We furthermore discuss the implications for selected phytochemicals to interfere in thrombosis and hemostasis, indicating their possible clinical relevance. Lastly, we provide guidance on which compounds are of interest for further platelet-related research