The Ebola virus acts fast. The course of infection, from exposure to recovery, or death, can take as little as two weeks. That may not leave enough time for the immune system to mount an effective response.

The goal of some anti-viral therapies, therefore, is to buy more and give the immune system a leg up on the virus. A new study demonstrates a way to do that, by reducing the ability of the virus to exit a host cell and spread. The work showed that blocking a calcium-signaling pathway could inhibit not only the Ebola virus, but also Marburg, Lassa and Junin viruses, all sources of deadly infections.

They conducted initial experiments using non-infectious viral-like particles, or VLPs, the production of which is orchestrated by the virus’ matrix protein and which bud from cells in a similar manner to the infectious virus. This allows for the observation of host-virus interactions without using dangerous live viruses.

Calcium signaling is a key regulator of many cell processes, and earlier studies by these authors had suggested that calcium was needed by these and other viruses. The researchers followed up by examining how cellular calcium levels responded when VLPs were being produced in cells. They found that virus matrix proteins triggered significant upticks in calcium levels, which were prevented when the researchers introduced a mutated version of a gene that encodes a calcium channel called ORAI1 into the host cells.

Next they looked directly at VLP production in normal cultured cells or cells with a mutation in ORAI1. Production of Ebola, Marburg, Lassa and Junin VLPs were all significantly lowered, as much as 100-fold, in the ORAI1 mutant cells, an indication that hemorrhagic fever virus budding relies on the ORAI1-dependent calcium signaling.

Further studies implicated another protein upstream from ORAI1, called STIM1, as also required to form VLPs. Suppressing expression of STIM1 in cultured cells caused VLP production to decline.

To see whether they could pharmacologically block VLP production in normal cells, the Penn researchers used three different ORAI1 inhibitors. Each substantially inhibited production of Ebola and Marburg VLPs.

http://www.upenn.edu/pennnews/news/penn-study-blocks-ebola-virus-budding-regulating-calcium-signaling