Paracytophagy
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Paracytophagy () is the cellular process whereby a cell engulfs a protrusion which extends from a neighboring cell. This protrusion may contain material which is actively transferred between the cells. The process of paracytophagy was first described as a crucial step during cell-to-cell spread of the intracellular bacterial pathogen ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the ho ...
'', and is also commonly observed in ''
Shigella flexneri ''Shigella flexneri'' is a species of Gram-negative bacteria in the genus ''Shigella'' that can cause diarrhea in humans. Several different serogroups of ''Shigella'' are described; ''S. flexneri'' belongs to group ''B''. ''S. flexneri'' infect ...
''. Paracytophagy allows these intracellular pathogens to spread directly from cell to cell, thus escaping
immune In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization. Innate and adaptive ...
detection and destruction. Studies of this process have contributed significantly to our understanding of the role of the
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
in
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
cells.


Actin cytoskeleton

Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
is one of the main cytoskeletal proteins in eukaryotic cells. The polymerization of actin filaments is responsible for the formation of
pseudopods A pseudopod or pseudopodium (: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filaments and ...
,
filopodia Filopodia (: filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lamellipod ...
and
lamellipodia The lamellipodium (: lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional act ...
during
cell motility Motility is the ability of an organism to move independently using metabolism, metabolic energy. This biological concept encompasses movement at various levels, from whole organisms to cells and subcellular components. Motility is observed in ...
. Cells actively build actin microfilaments that push the cell membrane towards the direction of advance.Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.


Nucleation factors and the Arp2/3 complex

Nucleation factors are enhancers of actin polymerization and contribute to the formation of the trimeric polymerization nucleus. This is a structure required to initiate the process of actin filament polymerization in a stable and efficient way. Nucleation factors such as
WASP A wasp is any insect of the narrow-waisted suborder Apocrita of the order Hymenoptera which is neither a bee nor an ant; this excludes the broad-waisted sawflies (Symphyta), which look somewhat like wasps, but are in a separate suborder ...
(Wiskott-Aldrich syndrome protein) help to form the seven-protein Arp2/3 nucleation complex, which resembles two actin monomers and therefore allows for easier formation of the polymerization nucleus. Arp2/3 is able to cap the trailing ("minus") end of the actin filament, allowing for faster polymerization at the "plus" end. It can also bind to the side of existing filaments to promote filament branching.Cellular Microbiology, 2nd Ed., edited by Pascale Cossart, Patrice Boquet, and Staffan Normark and Rino Rappuoli.Washington, DC: ASM Press; 2005.


WASP analogs used by pathogens for intracellular motility

Certain intracellular pathogens such as the bacterial species ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the ho ...
'' and ''
Shigella flexneri ''Shigella flexneri'' is a species of Gram-negative bacteria in the genus ''Shigella'' that can cause diarrhea in humans. Several different serogroups of ''Shigella'' are described; ''S. flexneri'' belongs to group ''B''. ''S. flexneri'' infect ...
'' can manipulate host cell actin polymerization to move through the cytosol and spread to neighboring cells (see below). Studies of these bacteria, especially of ''Listeria''
Actin assembly-inducing protein The Actin assembly-inducing protein (ActA) is a protein encoded and used by '' Listeria monocytogenes'' to propel itself through a mammalian host cell. ActA is a bacterial surface protein comprising a membrane-spanning region. In a mammalian cell ...
(ActA), have resulted in further understanding of the actions of WASP.
ActA Acta or ACTA may refer to: Institutions * Anti-Counterfeiting Trade Agreement, an intellectual property trade agreement * Administrative Council for Terminal Attachments, a standards organization for terminal equipment such as registered jacks * A ...
is a nucleation promoting factor that mimics WASP. It is expressed polarized to the posterior end of the bacterium, allowing Arp2/3-mediated actin nucleation. This pushes the bacterium in the anterior direction, leaving a trailing "comet tail" of actin. In the case of ''Shigella'', which also moves using an actin comet tail, the bacterial factor recruits host cell WASPs in order to promote actin nucleation.


Exchange of cellular material between adjacent cells

Cells can exchange material through various mechanisms, such as by secreting proteins, releasing
extracellular vesicle This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
s such as exosomes or
microvesicles Microvesicles (ectosomes, or microparticles) are a type of extracellular vesicle (EV) that are released from the cell membrane. In multicellular organisms, microvesicles and other EVs are found both in tissues (in the interstitial space between ...
, or more directly engulfing pieces of adjacent cells. In one example,
filopodia Filopodia (: filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lamellipod ...
-like protrusions, or tunneling nanotubes directed toward neighboring cells in a culture of rat PC12 cells have been shown to facilitate transport of organelles through transient membrane fusion. In another example, during bone marrow homing, cells of the surrounding bone engulf pieces of bone marrow hematopoietic cells. These osteoblasts make contact with hematopoietic stem-progenitor cells through membrane nanotubes, and pieces of the donor cells are transferred over time to various endocytic compartments of the target osteoblasts. A distinct process known as
trogocytosis Trogocytosis (; ''gnaw'') is when a cell nibbles another cell. It is a process whereby lymphocytes ( B, T and NK cells) conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. Th ...
, the exchange of lipid rafts or membrane patches between immune cells, can facilitate response to foreign stimuli. Moreover, exosomes have been shown to deliver not only antigens for
cross-presentation Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present ''extracellular'' antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, th ...
, but also MHCII and co-stimulatory molecules for lymphocyte T activation. In non-immune cells, it has been demonstrated that mitochondria can be exchanged intercellularly to rescue metabolically non-viable cells lacking mitochondria. Mitochondrial transfer has also been observed in cancer cells.


Argosomes and melanosomes

Argosomes are derived from basolateral epithelial membranes and allow communication between adjacent cells. They were first described in ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
'', where they act as a vehicle for the spread of molecules through the epithelia of imaginal discs. Melanosomes are also transferred by filopodia from melanocytes to keratinocytes. This transfer involves a classic filopodial forming pathway, with Cdc42 and WASP as key factors. Argosomes,
melanosome A melanosome is an organelle found in animal cells and is the site for synthesis, storage and transport of melanin, the most common light-absorbing pigment found in the animal kingdom. Melanosomes are responsible for color and photoprotectio ...
s, and other examples of epithelial transfer have been compared with the process of paracytophagy, all of which can be viewed as special cases of intercellular material transfer between epithelial cells.


Role in the life cycle of intracellular pathogens

The two main examples of paracytophagy are the modes of cell-cell transmission of ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the ho ...
'' and ''
Shigella flexneri ''Shigella flexneri'' is a species of Gram-negative bacteria in the genus ''Shigella'' that can cause diarrhea in humans. Several different serogroups of ''Shigella'' are described; ''S. flexneri'' belongs to group ''B''. ''S. flexneri'' infect ...
''. In the case of ''Listeria'', the process was first described in detail using
electron microscopy An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
and video microscopy. The following is a description of the process of cell-cell transmission of ''Listeria monocytogenes'', primarily based on Robbins ''et al''. (1999):


Early events

In an already infected "donor" cell, the ''Listeria'' bacterium expresses
ActA Acta or ACTA may refer to: Institutions * Anti-Counterfeiting Trade Agreement, an intellectual property trade agreement * Administrative Council for Terminal Attachments, a standards organization for terminal equipment such as registered jacks * A ...
, which results in formation of the
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
comet tail and movement of the bacterium throughout the
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
. When the bacterium encounters the donor
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
, it will either ricochet off it or adhere to it and begin to push outwards, distending the membrane and forming a protrusion of 3-18 μm. The close interaction between the bacterium and the host cell membrane is thought to depend on
Ezrin Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the ''EZR'' gene. Structure The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contains an ...
, a member of the ERM family of membrane-associated proteins. Ezrin attaches the actin-propelled bacterium to the plasma membrane by
crosslinking Cross-linking may refer to *Cross-link In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers ca ...
the actin comet tail to the membrane, and maintains this interaction throughout the protrusion process.


Invasion of target cell and secondary vacuole formation

As the normal site of infection is the gut
columnar epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of many ...
, cells are packed closely together and a cell protrusion from one cell will easily push into a neighboring "target" cell without rupturing the target cell membrane or the donor protrusion membrane. At this point, the bacterium at the tip of the protrusion will begin to undergo "fitful movement" caused by continuing polymerization of actin at its rear. After 7–15 minutes, the donor cell membrane pinches off and fitful movement ceases for 15–25 minutes due to depletion of ATP. Subsequently, the target membrane pinches off (taking 30–150 seconds) and the secondary
vacuole A vacuole () is a membrane-bound organelle which is present in Plant cell, plant and Fungus, fungal Cell (biology), cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water ...
containing the bacterium forms inside the target cell cytoplasm.


Secondary vacuole breakdown and target cell infection

Within 5 minutes, the target cell becomes infected when the secondary vacuole begins to acidify and the inner (donor cell-derived) membrane breaks down through the action of bacterial phospholipases (PI-PLC and PC-PLC). Shortly thereafter, the outer membrane breaks down as a result of the actions of the bacterial protein listeriolysin O which punctures the vacuolar membrane. A cloud of residual donor cell-derived actin persists around the bacterium for up to 30 minutes. The bacterial
metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...
Mpl cleaves ActA in a pH-dependent fashion while the bacterium is still within the acidified secondary vacuole, but new ActA
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...
is not required as pre-existing ActA mRNA can be utilized to
translate Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
new ActA protein. The bacterium regains motility and the infection proceeds.


Impact on disease

The most severe symptoms of
Listeriosis Listeriosis is a bacterial infection most commonly caused by '' Listeria monocytogenes'', although '' L. ivanovii'' and '' L. grayi'' have been reported in certain cases. Listeriosis can cause severe illness, including severe sepsis, me ...
result from involvement of the central nervous system (CNS). These severe and often fatal symptoms include
meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasion ...
, rhombencephalitis, and
encephalitis Encephalitis is inflammation of the Human brain, brain. The severity can be variable with symptoms including reduction or alteration in consciousness, aphasia, headache, fever, confusion, a stiff neck, and vomiting. Complications may include se ...
. These forms of disease are a direct result of ''Listeria'' pathogenicity mechanisms at the cellular level. Listerial infection involving the CNS can occur via three known routes: through the blood, through intracellular delivery, or through neuronal intracellular spread. Paracytophagous cell to cell spread offers ''Listeria'' access to the CNS by the latter two mechanisms.


Paracytophagy in CNS infection by ''Listeria''

In peripheral tissues, ''Listeria'' can invade cells such as
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
and
dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
from infected
endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
via the paracytophagous mode of invasion. Using these phagocytic cells as vectors, ''Listeria'' travels throughout the nerves and reaches tissues usually inaccessible to other bacterial pathogens. Similar to the mechanism seen in
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
, infected leukocytes in the blood cross the blood brain barrier and transport ''Listeria'' into the CNS. Once in the CNS, cell to cell spreading causes associated damage leading to brain encephalitis and bacterial meningitis. ''Listeria'' uses phagocytic leukocytes as a “
Trojan Horse In Greek mythology, the Trojan Horse () was a wooden horse said to have been used by the Greeks during the Trojan War to enter the city of Troy and win the war. The Trojan Horse is not mentioned in Homer, Homer's ''Iliad'', with the poem ending ...
to gain access to a greater range of target cells. In one study, mice treated with
gentamicin Gentamicin is an aminoglycoside antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis amo ...
via
infusion pump An infusion pump infuses fluids, medication or nutrients into a patient's circulatory system. It is generally used intravenously, although subcutaneous, arterial and epidural infusions are occasionally used. Infusion pumps can administer ...
displayed CNS and brain involvement during infection with ''Listeria'', indicating that the population of bacteria responsible for severe pathogenesis resided within cells and was protected from the circulating
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
. Macrophages infected with ''Listeria'' pass the infection on to neurons more easily through paracytophagy than through extracellular invasion by free bacteria. The mechanism which specifically targets these infected cells to the CNS is currently not known. This Trojan horse function is also observed and thought to be important in early stages of infection where gut-to-
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
infection is mediated by infected dendritic cells. A second mechanism of reaching the brain tissue is achieved through intra-axonal transport. In this mechanism, ''Listeria'' travels along the nerves to the brain, resulting in encephalitis or transverse myelitis. In rats, the
dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...
can be infected directly by ''Listeria'', and the bacteria can move in retrograde as well as anterograde direction through the nerve cells. The specific mechanisms involved in brain disease are not yet known, but paracytophagy is thought to have some role. Bacteria have not been shown to infect neuronal cells directly in an efficient manner, and the previously described macrophage hand-off is thought to be necessary for this mode of spread.


See also

The process of paracytophagy is considered distinct from similar but unrelated processes such as
phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...
and
trogocytosis Trogocytosis (; ''gnaw'') is when a cell nibbles another cell. It is a process whereby lymphocytes ( B, T and NK cells) conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. Th ...
. Some related concepts include: *
Membrane nanotubes A tunneling nanotube (TNT) or membrane nanotube is a term that has been applied to cytoskeletal protrusions that extend from the plasma membrane which enable different animal cells to connect over long distances, sometimes over 100 μm between c ...
*
Intercellular signaling In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryot ...


References

{{Reflist, 2 Cell biology