Why can’t our immune system fight Ebola when it can easily defeat other diseases?

The long story short

Ebolaviruses produce a viral protein that paralyses a crucial signaling cascade of the immune system, effectively leaving the immune system swinging between insufficient antiviral immune response and overwhelming inflammatory symptoms.

The long story, long

Ok, be prepared — the Magic School bus is going to take an extended trip to the lands of ebolaviruses and viral proteins and the interferon system.

Interferons are what are called cytokines — molecules that cells use to talk to each other. Interferon in particular is like an alert signal, pointing out signs of trouble. A cell that has been exposed to a virus emits interferon to put neighboring cells on the defensive and mark itself for destruction. They also activate immune cells, such as NK cells (a kind of lymphocyte that can kill other cells, similarly to cytotoxic T lymphocytes) and, systemically, they put the body in a state that's conducive to fighting a viral infection, e.g. by raising its temperature. Ever heard of 'flu-like symptoms', which may be caused by just about everything, from a lingering infection through — obviously! — The flu to other viral infections? That's the product of systemic interferon release. Thus, interferons are the primary defensive structure against viral infections.

Ebolaviruses are incredibly efficient. An ebolavirus has seven monocistronic genes (that is, each coding for one protein): the nucleoprotein NP, viral proteins VP35, VP40, VP30 and VP24 (in their order from 3' to 5'), the glycoprotein GP and L, which is an RNA polymerase. It has to make the most of it, so many of these proteins have multiple functions, often depending on polymerism — for instance, VP40 organized into a linear hexamer (looking a little like a zigzag row of six VP40 monomers) forms the viral matrix of the ebolavirus virion, whereas organised as a ring-shaped octamer it acts as a controller of virion replication. The linear hexamer can also act as an antagonist of interferon alpha, beta and gamma signaling through interfering with the tyrosine kinase JAK1. VP35 is also involved with interfering with the interferon system. But it's VP24 that's going to be really interesting.

One of the things, and far from the only that VP24 does is paralyzing interferon signaling, thereby suppressing the immune reaction that would normally be elicited. Here's how.

·         Normally, in the presence of viral infection, a protein named STAT1 is phosphorylated by interferons, causing it to express a ncNLS — a sort of chemical Uber call saying 'hey, pick me up!'. The Uber in this case is called karyopherin alpha (KPNA), a sort of intracellular shuttle protein. It picks up STAT1, and transports it to the nucleus, where it stimulates transcription and getting the whole process going.

·         VP24 hijacks the intracellular Uber. By binding to KPNA, STAT1 can no longer hail the intracellular Uber, KPNA, anymore. So all the interferons that reach the cell do not elicit any response from the cell. They're supposed to phosphorylate STAT1, which they duly do, which then calls itself a KPNA Uber, but the Uber never comes — it's stuck driving around VP24 on an endless journey to nowhere. And so STAT1 does not make it into the nucleus, and gene transcription is not stimulated.

The bottom line is, ebolaviruses as well as MARV are amazing at evading the human immune system, much better than most viruses. They are using a service the cell can't do without — KPNA, the intracellular Uber service — and they are paralysing an essential signal that effectively blinds cells to warning signals from neighbouring cells. Because the idea of interferon signalling is that an alerted cell passes the signal on to neighbouring cells, which in turn use interferon to signal neighbouring cells, and so on, inhibiting it means the body is defenseless. Few other viruses are as good at evading the immune system as filoviruses, and that's the key to their true lethality. Everything else is a side effect. The cell destruction, for instance, is a side effect of glycoprotein GP accumulation, used to burst cells so as to allow viral particles to be released. The gnarly symptoms of DIC, cell destruction, liver damage and all that are just epiphenomena. The true source of filoviruses' lethality is in its ability to circumvent the body's key antiviral defence mechanism.