Vomocytosis

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Vomocytosis (sometimes called non-lytic expulsion) is the cellular process by phagocytes expel live organisms that they have engulfed without destroying the organism. Vomocytosis is one of many methods used by cells to expel internal materials into their external environment, yet it is distinct in that both the engulfed organism and host cell remain undamaged by expulsion. As engulfed organisms are released without being destroyed, vomocytosis has been hypothesized to be utilized by pathogens as an escape mechanism from the immune system. The exact mechanisms, as well as the repertoire of cells that utilize this mechanism, are currently unknown, yet interest in this unique cellular process is driving continued research with the hopes of elucidating these unknowns.

Contents

Discovery

Timelapse movie showing the fungus Cryptococcus neoformans (shown in green in the first frame) being expelled from a chicken macrophage via non-lytic expulsion or vomocytosis.

Vomocytosis was first reported in 2006 [1] [2] by two groups, working simultaneously in the UK and the US, based on time-lapse microscopy footage characterising the interaction between macrophages and the human fungal pathogen Cryptococcus neoformans . Subsequently, this process has also been seen with other fungal pathogens such as Candida albicans [3] and Candida krusei . [4] It has also been speculated [5] that the process may be related to the expulsion of bacterial pathogens such as Mycobacterium marinum [6] from host cells. Vomocytosis has been observed in phagocytic cells from mice, humans and birds, [7] as well as being directly observed in zebrafish [8] and indirectly detected (via flow cytometry) in mice. [9] Amoebae exhibit a similar process to vomocytosis whereby phagosomal material that cannot be digested is exocytosed. Cryptococci are exocytosed from amoebae via this mechanism but inhibition of the constitutive pathway demonstrated that cryptococci could also be expelled via vomocytosis. [10]

Mechanism

A full understanding of the mechanisms involved in vomocytosis is not currently known, yet advances in research have driven initial mechanistic descriptions and crucial steps involved in the process. Research has shown vomocytosis does not occur when pathogens are dead or when engulfed materials are non-living, indicating the survival of phagosomal cargo may be crucial for triggering or enhancing vomocytosis. [11] [12] Additionally, the phagosomal pH may play important roles in vomocytosis efficacy as research has demonstrated vomocytosis rates drop as phagocytes become more acidic and vomocytosis is increased by the addition of weak bases to phagocytes. [11] [12] The membrane composition and cellular state are implicated in vomocytosis as vomocytosis has been shown to decrease with membrane permiability and increase in states of autophagy. [11] Furthermore, inflammatory signals such as Type I interferons, which are produced in response to viral infections, are known to enhance vomocytosis. [12] [13] [14] The impacts of these described forces on inducing vomocytosis are still being elaborated, and it is likely that they are variable based on other unknown external and internal factors.

Just as in standard exocytosis, rearrangements of the actin cytoskeleton within the host cell are crucial for allowing vomocytosis to occur. [15] In contrast to standard exocytosis, the engulfed pathogen is not lysed by internal components of the host cell, and the vesicle is brought close to the cellular membrane where it can fuse and release the pathogen cargo. [11] Annexin A2, a membrane-bound protein, helps regulate vomocytosis and promote the fusing of vesicles to the plasma membranes. [11] [12] In annexin A2 deficient cell lines, rates of vomocytosis were decreased. [11] Furthermore, screens of macrophage kinase inhibitors revealed signaling pathways linked to vomocytosis. [16] ERK5, involved in the MAPK signaling pathway that communicates surface signals to cellular DNA, was shown to suppress vomocytosis. [16] Additional signaling pathways involved in vomocytosis have yet to be determined. Furthermore, different morphologies of vomocytosis have been documented [17] and it is possible that the underlying cellular mechanism may vary between them.

Biological significance

Research has been devoted to understanding the mechanisms and importance of vomocytosis as it is hypothesized to be linked to many significant biological processes. Vomocytosis plays a role in lateral transfer, a process by which cells transfer engulfed cargo to a neighboring recipient cell, as initial cells expel their cargo undamaged so they can be uptaken by recipient cells. [11] Additionally, vomocytosis is hypothesized to be utilized as an escape mechanism by pathogens as it allows them to evade degradation by macrophages. [11] [12] Since there is no damage to host cells or pathogens during vomocytosis, the immune system is not triggered, which allows for further potential evasion from hosts. More research is necessary to determine whether vomocytosis is initiated by engulfed pathogens for this purpose or by host cells and this is simply an unintentional benefit to pathogens. An additional hypothesis is that vomocytosis may enhance pathogenesis or spread of a pathogen as they are engulfed by macrophages and later expelled in locations that may potentially be different from the site of acute infection. [11] Enhancing our understanding of host-pathogen interactions will clarify our understanding of vomocytosis's role in infection progression. Lastly, vomocytosis has been implicated in tumor response as tumor-associated macrophages (TAMs) are speculated to be able to modulate the tumor microenvironment (TME) via vomocytosis. [18] Better understanding the mechanisms of inducing and regulating vomocytosis will enhance our knowledge of host-pathogen and host-self interactions, allowing for advances in our ability to respond to infections and tumors.

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Phagocytosis</span> Process by which a cell uses its plasma membrane to engulf a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">Neutrophil</span> Most abundant type of granulocytes and the most abundant white blood cell

Neutrophils are a type of white blood cell. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in different animals.

<i>Candida albicans</i> Species of fungus

Candida albicans is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usually a commensal organism, but it can become pathogenic in immunocompromised individuals under a variety of conditions. It is one of the few species of the genus Candida that cause the human infection candidiasis, which results from an overgrowth of the fungus. Candidiasis is, for example, often observed in HIV-infected patients. C. albicans is the most common fungal species isolated from biofilms either formed on (permanent) implanted medical devices or on human tissue. C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata are together responsible for 50–90% of all cases of candidiasis in humans. A mortality rate of 40% has been reported for patients with systemic candidiasis due to C. albicans. By one estimate, invasive candidiasis contracted in a hospital causes 2,800 to 11,200 deaths yearly in the US. Nevertheless, these numbers may not truly reflect the true extent of damage this organism causes, given new studies indicating that C. albicans can cross the blood–brain barrier in mice.

<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<i>Cryptococcus neoformans</i> Species of yeast

Cryptococcus neoformans is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to Filobasidiella neoformans. In its yeast state, it is often found in bird excrement. Cryptococcus neoformans can cause disease in apparently immunocompetent, as well as immunocompromised, hosts.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host.

<span class="mw-page-title-main">Innate immune system</span> One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

<span class="mw-page-title-main">Phagolysosome</span> Cytoplasmic body

In biology, a phagolysosome, or endolysosome, is a cytoplasmic body formed by the fusion of a phagosome with a lysosome in a process that occurs during phagocytosis. Formation of phagolysosomes is essential for the intracellular destruction of microorganisms and pathogens. It takes place when the phagosome's and lysosome's membranes 'collide', at which point the lysosomal contents—including hydrolytic enzymes—are discharged into the phagosome in an explosive manner and digest the particles that the phagosome had ingested. Some products of the digestion are useful materials and are moved into the cytoplasm; others are exported by exocytosis.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

The mannose receptor is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes. It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205).

Pathogenic fungi are fungi that cause disease in humans or other organisms. Although fungi are eukaryotic, many pathogenic fungi are microorganisms. Approximately 300 fungi are known to be pathogenic to humans; their study is called "medical mycology". Fungal infections kill more people than either tuberculosis or malaria—about 2 million people per year.

<span class="mw-page-title-main">Blastoconidium</span>

A blastoconidium is an asexual holoblastic conidia formed through the blowing out or budding process of a yeast cell, which is a type of asexual reproduction that results in a bud arising from a parent cell. The production of a blastoconidium can occur along a true hyphae, pseudohyphae, or a singular yeast cell. The word "conidia" comes from the Greek word konis and eidos, konis meaning dust and eidos meaning like. The term "bud" comes from the Greek word blastos, which means bud. Yeasts such as Candida albicans and Cryptococcus neoformans produce these budded cells known as blastoconidia.

<span class="mw-page-title-main">IRGs</span>

Immunity Related Guanosine Triphosphatases or IRGs are proteins activated as part of an early immune response. IRGs have been described in various mammals but are most well characterized in mice. IRG activation in most cases is induced by an immune response and leads to clearance of certain pathogens.

Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory cell. It takes place in the form of Golgi membrane-bound micro-sized vesicles, termed membrane vesicles (MVs).

<span class="mw-page-title-main">Arturo Casadevall</span> Cuban-American scientist

Arturo Casadevall is a Bloomberg Distinguished Professor of Molecular Microbiology & Immunology and Infectious Diseases at the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, and the Alfred and Jill Sommer Professor and Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. He is an internationally recognized expert in infectious disease research, with a focus on fungal and bacterial pathogenesis and basic immunology of antibody structure-function. He was elected a member of the National Academy of Sciences in 2022.

Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.

<span class="mw-page-title-main">Joseph Heitman</span>

Joseph Heitman is an American physician-scientist focused on research in genetics, microbiology, and infectious diseases. He is the James B. Duke Professor and Chair of the Department of Molecular Genetics and Microbiology at Duke University School of Medicine.

References

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  4. ↑ García-Rodas R, González-Camacho F, Rodríguez-Tudela JL, Cuenca-Estrella M, Zaragoza O (June 2011). "The interaction between Candida krusei and murine macrophages results in multiple outcomes, including intracellular survival and escape from killing". Infection and Immunity. 79 (6): 2136–44. doi:10.1128/iai.00044-11. PMC   3125833 . PMID   21422181.
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  9. ↑ Nicola AM, Robertson EJ, Albuquerque P, Derengowski LD, Casadevall A (2011). "Nonlytic exocytosis of Cryptococcus neoformans from macrophages occurs in vivo and is influenced by phagosomal pH". mBio. 2 (4): e00167-11. doi:10.1128/mBio.00167-11. PMC   3150755 . PMID   21828219.
  10. ↑ Watkins RA, Andrews A, Wynn C, Barisch C, King JS, Johnston SA (April 9, 2018). "Cryptococcus neoformans Escape From Dictyostelium Amoeba by Both WASH-Mediated Constitutive Exocytosis and Vomocytosis". Frontiers in Cellular and Infection Microbiology. 8 (108): 108. doi: 10.3389/fcimb.2018.00108 . PMC   5900056 . PMID   29686972.
  11. 1 2 3 4 5 6 7 8 9 Seoane PI, May RC (February 2020). "Vomocytosis: What we know so far". Cellular Microbiology. 22 (2): e13145. doi: 10.1111/cmi.13145 . PMID   31730731. S2CID   208061582.
  12. 1 2 3 4 5 Cruz-Acuña M, Pacifici N, Lewis JS (December 2019). Garsin DA (ed.). "Vomocytosis: Too Much Booze, Base, or Calcium?". mBio. 10 (6): e02526–19, /mbio/10/6/mBio.02526–19.atom. doi:10.1128/mBio.02526-19. PMC   6935858 . PMID   31874916.
  13. ↑ Lundie RJ, Helbig KJ, Pearson JS, Fairfax KA (January 2019). "Fluorescent antibiotics, vomocytosis, vaccine candidates and the inflammasome". Clinical & Translational Immunology. 8 (11): e01083. doi:10.1002/cti2.1083. PMC   6823609 . PMID   31700626.
  14. ↑ Voelz K, Lammas DA, May RC (August 2009). "Cytokine signaling regulates the outcome of intracellular macrophage parasitism by Cryptococcus neoformans". Infection and Immunity. 77 (8): 3450–7. doi:10.1128/iai.00297-09. PMC   2715691 . PMID   19487474.
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