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Page 91 Rutter et al. Extracell Vesicles Circ Nucleic Acids 2023;4:90-106 https://dx.doi.org/10.20517/evcna.2023.04

microparticles; ~100-1,000 nm in diameter) bud directly from the plasma membrane of living cells. Lastly,
exosomes (~30-150 nm in diameter) form inside living cells as a result of membrane invaginations into the
lumen of a late endosome; they are released after the fusion of a late endosome with the plasma
[3]
membrane . Overlapping size ranges and protein markers among these classes of vesicles make it extremely
difficult to classify isolated EVs as exosomes, microvesicles or ABs. In the absence of direct observations of
biogenesis or highly specific markers, EVs are more often categorized according to physical characteristics,
such as size, buoyant density or biochemical composition .
[4]

Once released from a cell, these extracellular organelles provide a protective environment for the long-
distance delivery of proteins, lipids, nucleic acids and other bioactive compounds. EVs exert their effects on
recipient cells through interactions with surface receptors or the transfer of EV cargo through membrane
[2]
fusion or endocytosis . This form of long-distance communication is not limited to cells within an
[5]
organism or of the same species but can occur across species and even kingdoms .
The ability of EVs to transfer molecules across kingdoms is particularly important during infectious
diseases, where both the host and pathogen secrete vesicles in an effort to promote or subvert immunity,
[6]
respectively . In mammals, various cell types release EVs in response to stress and disease. Vesicles released
under these conditions are capable of mediating coagulation, promoting or suppressing inflammation and
[6-8]
modulating adaptive immune responses through the transfer of antigens . In some cases, they may even
directly inhibit the growth and spread of invading microbes .
[9]
Pathogens, such as viruses, bacteria, fungi and protozoan parasites, also utilize EVs during infections, either
releasing their own vesicles or inducing host cells to secrete EVs containing pathogen-derived
molecules [10,11] . These vesicles can be a two-edged sword. On the one hand, components of pathogen-derived
EVs are often recognized by the host as pathogen-associated molecular patterns and inadvertently trigger
immune responses [10,11] . On the other hand, pathogen-derived EVs can contain toxins and molecules with
immunity-modulating properties that enhance pathogen survival, infectivity and spread [10,11] .

EVs can also benefit pathogens in ways that do not directly interfere with the host immune system. For
example, both bacteria and single-celled fungi produce vesicles that enhance the formation of biofilms and
increase antibiotic resistance [12-14] . Moreover, highly virulent strains of bacteria can stimulate less virulent
strains to heightened states of infectivity through an EV-mediated exchange of virulence factors, including
proteins and genetic material [15-17] .

While the overwhelming majority of research into host- and pathogen-derived EVs concerns human
diseases, the tit-for-tat exchange of vesicles during infections is by no means limited to mammalian systems
of pathology. EVs also play a prominent role in plant pathosystems. Electron microscopy studies have
revealed the presence of exosome-like vesicles secreted underneath sites of pathogen attack and around
invading fungal tissues [18-21] . Many of these vesicles are clearly generated by the plant, but other EVs may be
pathogen-derived . Isolated plant EVs are enriched for proteins involved in stress and defense responses
[21]
and secreted in greater abundance in response to stress hormones and bacterial infections . Plant EVs have
[22]
also been shown to have direct, cytotoxic effects on fungal spores [23,24] .
In turn, plant-pathogenic bacteria and fungi produce their own EVs loaded with cytotoxic compounds and
immunity-modulating virulence factors . While research into these pathogen-derived EVs has been
[25]
limited, there is a growing recognition of their importance for understanding and better managing plant
diseases. This is particularly true of EVs produced by phytopathogenic fungi, owing to the massive