Within relatively large beings such as us humans, communication is essential. Our individual human cells are like us humans: better together. To come together to form one functioning human, they have to constantly discuss with one another what has to happen next. For example: 'increase heart rate'. 'Heart rate increased' - 'feel nervous!' 'Move legs to run from the nervous feeling'. 'Sweat, it's getting warm'. And so on, and so forth.
This type of intercellular communication is also essential for a functioning immune system. In comparison to the size of a single cell, we humans are pretty big. So, when one cell detects an incoming microbial invader, it has to send messages all across the body to alert its comrades to the threat.
For a while now, scientists have known about three major types of intercellular communication. Firstly, cells that are directly in contact with each other can send messages between their membranes, in a manner similar to holding hands. Secondly, cells that aren't physically touching each other, but are in the same neighbourhood, can send messages to each other via secreted molecules (such as cytokines and chemokines, which are especially important for the immune system and can help trigger an immune response). These molecules act in a manner similar to like yelling across a field to your friend - they work well, but only when the distance is not too far. Thirdly, if cells are really far from each other - say one is in your brain and other in your leg - hormones can be used to communicate. These hormones travel longer distances through your bloodstream to reach their distant targets, kind of like a long distance telephone call.
However, in recent years, a new type of communication has been identified: tiny blips of fat in the bloodstream, that can contain additional and more subtle signals within - including a diverse array of proteins, lipids, and even nucleic acids like RNA. These sophisticated carriers look like tiny, simplified mini-cells that deliver their contents directly to target cells, accomplishing a marvelously sophisticated method of "small talk".
And what are these messengers? They have been given the scientifically sexy name, 'extracellular vesicles' - EVs for short.
EVs are practically oozing out of us humans. They are in our tissues, in the spaces between our cells, in our blood, and even in human urine and milk. Judging from the recent scientific literature, it looks like pretty much every type of human cell, from immune cells to cancer cells, can make EVs. These little blips of fat are formed within the cell, or bud off from the cell membrane, and then go on their merry way through - and even out of - our bodies.
Amongst EVs, there is a great diversity in size, what they look like, and what they carry. In general, though, they are made up of a fatty envelope that acts like a preservative to protect the messages within. This is important, because those messages contained within EVs can have impressive effects on the immune system. They may trigger the receiver cells to send out more local signals, in the form of chemokines or cytokines, to spread the news of a dangerous intruder. On the other hand, if the EVs are carrying anti-inflammatory information, they can tell the receiver cells to stay calm, and not over-react to the threat, thus maintaining a healthy balance in your immune system.
Underlining the importance of EVs in informing the immune system, many different microbes manipulate this long-distance mailing system of the body. For example, several different types of viruses, including Hepatitis C and Epstein-Barr virus, manipulate the type and amount of EVs released by the cells they infect. For example, when Epstein-Barr virus infects human cells, EVs released by those cells start to send out copies of a viral RNA to surrounding cells. Upon entering those surrounded, uninfected cells, this viral RNA specifically targets a specific human protein that is necessary for mounting a sufficient inflammatory response to the virus. As a result, the human immune system is suppressed and the virus can better stay hidden.
The interactions between EVs and viruses go even further - sometimes it is even difficult to say where the line between us (EVs) and the microbial invaders (viruses) should be drawn, as I wrote about in this Microbial Mondays article. But in any case, we can be sure that these little blips of fat swirling through our body carry information - and that EVs add a new layer of complexity to our beautifully regulated immune response, as well as our interactions and co-evolution with those microbes that infect us.
Until next week, I challenge you to make like an EV: send a letter!
~ Alex
This Microbial Mondays article was inspired by the following review article:
van der Grein, S. G. & Nolte-’t Hoen, E. N. M. ‘Small talk’ in the innate immune system via RNA-containing extracellular vesicles. Front. Immunol. 5, 1–8 (2014).