Immune Response
The typical immune response to Ebola infection is characterized by an impaired innate immune response, abnormal and deleterious cytokine secretion profiles of innate and adaptive immune cells, and significant apoptosis of lymphocytes. It is important to note that the nature of the immune response to Ebola is intimately associated with the disease pathology. By suppressing certain parts of the immune system and causing an inappropriate activation of others, Ebola deals rapid, severe and typically fatal damage to the host while avoiding its own destruction by the immune system.
Innate immunity
The response of the innate immune system to Ebola infection is an important determinant of the outcome of infection/disease, because an appropriate innate immune response is necessary for activation of proper adaptive immunity that leads to control and clearance of the virus, and also because innate immune mechanisms are believed to be responsible for a significant portion of Ebola pathology. Ebola virus infects and replicates in dendritic cells, monocytes, and macrophages, particularly in the early stages of infection, and impairs their development and in certain cases can change their functioning in order to contribute to its own spread.
Dendritic cells infected with Ebola exhibit general suppression of cytokine secretion; in particular, secretion of IFNa, an important immunomodulatory and antiviral cytokine, is eliminated. Suppression of IFNa secretion is believed to significantly contribute to the defects in activating adaptive immunity that are observed in later stages of Ebola infection/disease. DCs infected with Ebola also exhibit defects in their ability to stimulate T cells, and impaired response to other interferon-inducing stimuli. The molecule responsible for the inactivation of IFN-a production is the viral protein weighing 35kDa, known as VP35. VP35 is believed to interfere with gene transcription of important immune factors. Because inactivated Ebola can also lead to impairment of IFN-a production, it is believed that Ebola structurally expresses VP35 before it enters a cell and replicates. |
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Monocytes and macrophages infected with Ebola also exhibit defects in IFNa secretion, and changes in the secretion of other cytokines. In particular, infected monocytes/macrophages were observed to secrete increased levels of IL-1b, IL-6, Il-8, and TNF-a, as well as RANTES, MIP-1a, and monocyte chemotactic protein-1. Since monocytes and macrophages are motile cells, they can also serve to transport Ebola virus to other parts of the body, such as the lymph nodes, lungs, spleen, and liver.
Infected dendritic cells, monocytes, and macrophages have also been observed to upregulate expression and secretion of tissue factor (TF), which is thought to be responsible for the development of disseminated intravascular coagulation (DIC) through overactivation of the clotting system and formation of microthrombi on the microvascular endothelia. DIC is thought to be an important factor in the necroses and organ failures observed in the later stages of Ebola disease.
It is important to consider both the typical dysfunctions of the innate responses to Ebola, as well as the types of innate responses that would be most advantageous to control of Ebola infection when examining the adaptive responses to the virus, because of the profound influence (which can be beneficial or detrimental) that innate immunity has on adaptive immunity, and the implications thereof for treatment, control, and ultimately vaccination against the virus.
Adaptive immunity
It is widely held that robust innate and adaptive responses are both necessary for control and clearance of Ebola infection. The profound impact Ebola infection has on innate immunity has been described above, and those factors in conjunction with specific impairment of the branches of adaptive immunity are important determinants in the pathology of Ebola infection, particularly in the intermediate and end stages of the disease. Early presence of specific anti-Ebola antibodies, and proper functioning of helper and cytotoxic T cells in coordinating cytokine release and antibody switching and clearing Ebola-infected cells are the factors most strongly correlated with increased likelihood of survival from Ebola infection.
Ebola has not been observed to infect T or B lymphocytes. However, Ebola infection leads to significant apoptosis of T lymphocytes, evidence for which is provided by the increased levels of Fas, FasL, perforin, IFN-y, and sometimes CD28 in infected individuals, and the disappearance of CD3, CD8, and T-cell receptor mRNA in later stages of infection. It is important to note that in fatal cases, the levels of these factors continued to rise until death, suggesting relentless cytotoxic killing of T cells. This killing is possibly mediated by infected monocytes and macrophages, both of which are capable of producing both membrane and soluble Fas ligand. One study found that IL-2 and IL-4 mRNA were barely or never detected in the peripheral blood mononuclear cells of either human survivors or fatalities, presumably due to the impact of Ebola infection on T-cell activation, proliferation, and survival.
Because of the significant effect Ebola has on T cells, it is expected that B cell functioning (specifically, production of antibody) would be impaired. This has been observed to be the case, as the typically observed humoral response to Ebola is not very robust, and is characterized by low anti-Ebola IgG and no anti-Ebola IgM in most fatal cases. This is potentially due to impaired B-cell activation as a result of reduced T cell and dendritic cell levels. Survivors mostly exhibit rapid and robust responses to Ebola characterized by the production of IgG and IgM targeted at the viral nucleoprotein, the 40kDa viral protein, and the 35kDa viral protein. |
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There is some evidence that Ebola may benefit from antibody-dependent enhancement of infection through binding of complement component C1q to Ebola-specific IgG and IgM/virus complexes. This C1q/Ab/virus complex is then bound by C1q receptor on susceptible cells. The potential of facilitating ADE may be influenced by antibody titer, in that high levels of antibody may be sufficient to neutralize the virus, whereas a subneutralizing antibody titer may contribute to the possibility of C1q being able to bind an antibody-virus complex, facilitating its uptake into vulnerable cells. It is uncertain how significant a role ADE may play in vivo, but it is an important consideration, particularly with regards to vaccine development.
The impact that Ebola has on the adaptive immune system, and the adaptive immune responses that increase the likelihood of survival, are still being elaborated. What is known is that most survivors have a consistent profile of early and robust Ebola-specific IgG and IgM responses, as well as expression of inflammatory cytokines and evidence of a cytotoxic response to infected cells, both of which are moderated by the control and elimination of viral antigen. These adaptive responses, in turn, may be heavily dependent on the rapid and intact functioning of the innate immune system, and it is likely that the production of type I interferon is necessary in order to appropriately activate elements of innate and adaptive immunity.
It is essential to note that the elements of a successful immune response to Ebola are similar to the elements of an anti-Ebola immune response that initiate and aggravate pathology. Pro-inflammatory cytokines must be released at the appropriate stage of infection and not too early; and the antibody response must be fast and robust, or else it might end up facilitating virus entry into cells. The elements of both successful and failed immune responses to Ebola need to be further elaborated in order to fully understand the range of effects the virus has on the immune system, and how those effects influence the immune response as well as pathology. At this point, only the most general information is available on what constitutes a successful immune response; since the likelihood of survival when infected with Ebola is still below 50% even by the most conservative standards, and the pattern of Ebola incidence has not yet been fully elaborated, it is difficult to characterize what in fact determines survival or death.
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This page last updated: 14 April 2004.
