First isolated in the late '70s, EBOV now causes significant epidemics occurring with increasing frequency - the latest in early 2009. It is believed that bats play an important role in the natural replication cycle of these viruses and hence may transmit it to neighboring human and other animal populations. There are currently four 'species' of EBOV recognised which infect humans: Zaire, Sudan, Ivory Coast and Bundibugyo - yet a fifth related virus, EBOV-Reston is known only to infect non-human primates in captivity and domesticated pigs. These viruses which are mainly found throughout Central and Western Africa cause a hemorrhagic fever in humans which most often or not leads to death; EBOV-Zaire (ZEBOV) is the most deadly of all types resulting in at most 90% of those infected to die; the reasons for such high mortality are not known.
We can begin to build up a picture of ZEBOV infection and pathogenesis using a combination of in vitro studies, animal models and clinical work carried out in humans. In animal models EBOV has been shown to replicate to extremely high levels, induce the abundant secretion of inflammatory signalling molecules, cause massive cell death of lymphocytes and a great deal of tissue destruction eventually leading to multi-organ system failure, toxic shock and death. Work carried out on blood samples collected from both human survivors and non-survivors of EBOV outbreaks have showed that lethal infection is associated with a highly deregulated immune response. Extremely high levels of pro-inflammatory cytokines (cell signalling proteins) were detected as well as low levels of circulating T lymphocytes. Yet there was a surprisingly little anti-viral response seen. This all suggests that the EBOV induces a rapid and strong pro-inflammatory immune response without eliciting effective innate and adaptive antiviral defenses resulting in a lethal outcome. Those people which did not develop this lethal immune reaction survived EBOV infection. But how exactly does EBOV do this?
New evidence has been uncovered suggesting that certain ZEBOV components may act like what are known as 'superantigens' (sAg) which may responsible for this damaging deregulation in immune responses.
As the paper explains:
"SAgs are microbial proteins that bind simultaneously to major histocompatibility complex class II molecules and to the T-cell receptor (TCR) V beta region. This “bridge” skews the T-cell repertoire by amplifying specific T- cell V beta subsets, which then are either rapidly deleted by activated cell death or become anergic."
What this means is that maybe ZEBOV proteins are able to bind to our own immune cells through an abnormal mechanism (TCR AND MHCII) which results in those cells going into overdrive and then being selectively killed by our bodies (in order to prevent a runaway immune response) or those cells becoming immunologically unresponsive (anergic). If EBOV did encode a sAg it may be able to vastly eliminate our adaptive immunity.
A major feature mentioned above is the massive levels of cell death in T lymphocyte populations. There are many ways in which EBOV could produce this effect, including up regulation of pro-cell death molecules inside lymphocytes or through an alternative indirect pathway via infection of dendritic cells and macrophages - as it is known EBOV infects these cells. These immune regulatory cells are responsible for controlling the levels of other immune cells produced (they are considered major immunoregulators)- alter their behavior and you alter the number of lymphocytes. The finding the EBOV may encode a superantigen adds to the growing number of ways this virus may inhibit host immune responses.
We can begin to investigate this by looking at the specific types of T cell found within EBOV infected patients - normally you would expect each T cell V region type to found to the same level. sAG activity leads to the loss of specific T cell types without loss of others. Looking at the expression levels of specific V regions of the TCR we can observe whether certain types decrease after being infected with EBOV. This recent report demonstrated just this in infected patients versus non-infected (see above) suggesting that something in EBOV may act as an sAg. This appears to correlate well with a fatal immune response.
Of course we will have to further verify this finding possibly in animal models or cell culture work but we can begin to ask further questions: does this occur in other EBOV species? What protein is causing the sAg activity? Can we somehow inhibit its activity? And, how is it that some patients come to avoid a sAg response?
Leroy EM, Becquart P, Wauquier N, & Baize S (2011). Evidence for ebola virus superantigen activity. Journal of virology, 85 (8), 4041-2 PMID: 21307193
Wauquier N, Becquart P, Padilla C, Baize S, & Leroy EM (2010). Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS neglected tropical diseases, 4 (10) PMID: 20957152