Immunopathology of highly virulent pathogens insights from ebola virus

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Recent Activity. Search life-sciences literature Over 39 million articles, preprints and more Search Advanced search. This website requires cookies, and the limited processing of your personal data in order to function. Learn More. This genus of negative single-stranded RNA viruses consists of five known species that are part of the Filoviridae family.

This 25th known EBOV outbreak is unprecedented in its magnitude, duration, and societal impact. Given the likelihood of future EBOV outbreaks, significant efforts are being devoted to develop vaccines that block EBOV transmission and novel therapeutic interventions to treat infected individuals 2 , 3. Progress in these pursuits requires better understanding of what key elements of the immune response correlate with virus replication control and protection from disease.

Their data provide critical insight into aspects of the host response in humans to EBOV that have not previously been examined using contemporary immunologic methods, and provide the foundation for future studies, elucidating immune responses mediating effective virus control. The high mortality rate of EBOV infections indicates that the immune system often fails to control viral replication. In fact, it has been suggested that a key pathogenic mechanism of EBOV is its ability to cause global immunosuppression Fig.

Studies of the interaction of EBOV with cells in culture have shown that at least three Ebola virus-encoded proteins viral protein 24, viral protein 35, and glycoprotein act on cell-intrinsic resistance pathways, resulting in inhibition of type I IFN production, impairing the action of IFN on infected cells, and counteracting the effects of tetherin, a host factor that prevents virion release 5.

Moreover, in vitro studies have indicated that Ebola virus impairs dendritic cell responses, including cytokine production, maturation, and ability to induce T-cell proliferation. The acute reduction in circulating T-cell counts seen during in vivo Ebola virus infection, which parallels the high levels of bystander lymphocyte apoptosis described in culture, has also been proposed to contribute to impaired adaptive immune responses reviewed in refs.

Schematic of viral replication and immune activation for two models accounting for the failure of the immune system to control EBOV in lethal infections. Model 1 proposes that EBOV leads to substantial immune suppression that prevents an effective immune response from being raised. Model 2 suggests that the timing and kinetics of viral replication and of the immune response is key to infection outcome, with a late or abortive immune response leading to death.

New data from McElroy et al. Because of the unpredictability of EBOV outbreaks, their often rural location, the priority to provide medical care, and the need for biosafety-level 4 biohazard containment of specimens obtained, detailed studies of human immune responses to EBOV infections have been very limited.

From this work, the picture that emerges is one of a potent inflammatory response rather than global immune suppression reviewed in ref. In the case of lethal infections, the pace of emergence of host immune responses may be outstripped by very rapid viral replication, precipitating infection-associated tissue damage, including vascular leakage, dysregulated coagulation, and multiorgan failure Fig.

Similarly, contrary to what in vitro work might suggest, some human studies have detected a type I IFN response, which studies in mice have emphasized as important in curtailing Ebola virus disease 9 — Lower antibody levels and greater viremia have been associated with fatal infections and an early inflammatory response may be characteristic of less severe infection, consistent with mouse data 12 , Notably, only one study has thus far examined T-cell responses during Ebola virus infection and found significantly lower levels of activation in patients that died The new data from McElroy et al.

Peak frequencies of activated T cells and plasmablasts were comparable to other acute viral infections studied 15 , 16 , rather than the delayed responses seen in some persistent infections, like hepatitis C Use of tetramers to track specific T cells during the course of infection will help discern the extent to which the high level of T-cell response is antigen-driven and fully functional.

Given the high level of PD-1 expression on T cells, a receptor known to inhibit function in settings of very high or chronic antigen loads, it is possible that these emerging T cells may exhibit some functional impairment Importantly, interrogation of the specificity, breadth, and functional capacity of antibodies from responding plasmablasts will also help illuminate the role humoral responses play in viral clearance [and if, as described for ZMapp, multiple simultaneous antibody engagements of EBOV glycoprotein are essential 3 ].

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Immune barriers of Ebola virus infection. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. Clinical features and pathobiology of Ebolavirus infection. Joining Europe PMC. Tools Tools overview. ORCID article claiming. Journal list.

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