Intracellular delivery is a key step in biological research and has enabled decades of biomedical discoveries. It is also becoming increasingly important in industrial and medical applications ranging from biomanufacture to cell-based therapies. Here, we review techniques for membrane disruption-based intracellular delivery from 1911 until the present. These methods achieve rapid, direct, and universal delivery of almost any cargo molecule or material that can be dispersed in solution. We start by covering the motivations for intracellular delivery and the challenges associated with the different cargo types—small molecules, proteins/peptides, nucleic acids, synthetic nanomaterials, and large cargo. The review then presents a broad comparison of delivery strategies followed by an analysis of membrane disruption mechanisms and the biology of the cell response. We cover mechanical, electrical, thermal, optical, and chemical strategies of membrane disruption with a particular emphasis on their applications a...

/pdf/intracellular-delivery-by-membrane-disruption-mechanisms-1r7lisc9lz.pdf

Intracellular Delivery by Membrane Disruption: Mechanisms, Strategies, and Concepts.

SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae, group A and B streptococci, Staphylococcus aureus, Escherichia coli, and Mycobacterium tuberculosis. PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

One key aspect of S. aureus virulence lies in its ability to target the host cell membrane with a large number of membrane-damaging toxins and peptides. In this review, we describe the hemolysins, the bi-component leukocidins, which include the Panton Valentine Leukocidin, LukAB/GH, LukED and the cytolytic peptides (Phenol Soluble Modulins). While at first glance, all these factors might appear redundant, it is now clear that some of these factors play specific roles in certain S. aureus life stages and diseases or target specific cell types or species. Here, we present an update of the literature on toxins receptors and their cell type and species specificities. Furthermore, we review epidemiological studies and animal models illustrating a role of these membrane-damaging factors in various diseases. Finally, we emphasize the interplay of these factors with the host immune system and highlight all their non-lytic functions.

/pdf/staphylococcus-aureus-hemolysins-bi-component-leukocidins-2mqpbigo3d.pdf

Staphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: a redundant arsenal of membrane-damaging virulence factors?

// Andrey V. Shubin 1,2,3,* , Ilya V. Demidyuk 1,* , Alexey A. Komissarov 1 , Lola M. Rafieva 1 and Sergey V. Kostrov 1 1 Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia 2 Laboratory of Chemical Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia 3 Laboratory of Biologically Active Nanostructures, N.F. Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia * These authors contributed equally to this work Correspondence to: Andrey V. Shubin, email: // Keywords : regulated cell death, vacuolization, microbial toxins, viruses Received : February 27, 2016 Accepted : June 06, 2016 Published : June 17, 2016 Abstract Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

/pdf/cytoplasmic-vacuolization-in-cell-death-and-survival-102f8qnal7.pdf

Cytoplasmic vacuolization in cell death and survival.

Listeriolysin O: the Swiss army knife of Listeria

Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium.

FLASH Mechanisms Track MECHANISMS OF FLASH RADIOTHERAPY SPARING OF NORMAL TISSUE AS INFORMED BY RNA-SEQ TRANSCRIPTOME ANALYSES

Pore-forming toxins (PFT) comprise a large, structurally heterogeneous group of bacterial protein toxins. Nucleated target cells mount complex responses which allow them to survive moderate membrane damage by PFT. Autophagy has recently been implicated in responses to various PFT, but how this process is triggered is not known, and the significance of the phenomenon is not understood. Here, we show that S. aureus α-toxin, Vibrio cholerae cytolysin, streptolysin O and E. coli haemolysin activate two pathways leading to autophagy. The first pathway is triggered via AMP-activated protein kinase (AMPK). AMPK is a major energy sensor which induces autophagy by inhibiting the target of rapamycin complex 1 (TORC1) in response to a drop of the cellular ATP/AMP-ratio, as is also observed in response to membrane perforation. The second pathway is activated by the conserved eIF2α-kinase GCN2, which causes global translational arrest and promotes autophagy in response to starvation. The latter could be accounted for by impaired amino acid transport into target cells. Notably, PKR, an eIF2α-kinase which has been implicated in autophagy induction during viral infection, was also activated upon membrane perforation, and evidence was obtained that phosphorylation of eIF2α is required for the accumulation of autophagosomes in α-toxin-treated cells. Treatment with 3-methyl-adenine inhibited autophagy and disrupted the ability of cells to recover from sublethal attack by S. aureus α-toxin. We propose that PFT induce pro-autophagic signals through membrane perforation–dependent nutrient and energy depletion, and that an important function of autophagy in this context is to maintain metabolic homoeostasis.

/pdf/pro-autophagic-signal-induction-by-bacterial-pore-forming-2frtavow72.pdf

Pro-autophagic signal induction by bacterial pore-forming toxins

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Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium.

FLASH Mechanisms Track MECHANISMS OF FLASH RADIOTHERAPY SPARING OF NORMAL TISSUE AS INFORMED BY RNA-SEQ TRANSCRIPTOME ANALYSES

Pro-autophagic signal induction by bacterial pore-forming toxins