A research study by scientists at the University of Texas Medical Branch in Galveston sheds light on how Ebola effectively disables the human immune system. Virologist Alex Bukreyev, UTMB professor and senior author of the study, said the research team engineered versions of the Ebola virus in order to understand its effects on immune system. The findings are described in journal PLOS Pathogens.
Previous research shown how Ebola virus inhibits Interferon mediated immune defense system. Interferons are specialized signaling proteins that are made and released in response to an invasion by a virus or other pathogen, which directly inhibit replication of viral particles in cells. These actions were mediated by two protein regions within the Ebola virus’ structure called interferon inhibiting domains, or IIDs, that prevent the host’s interferons from doing their job thus disabling the host’s immune system defenses.
A focus of current research has been how Ebola gets around the host’s cell-mediated immune response, which is another defense mechanism involving some specialized immune cells that either kill virus-infected cells or secrete antibodies that directly neutralize the virus. Researchers assessed role played by interferon inhibiting domains (IID’s) on cell mediated immunity.
The study used genetically altered strains of the Ebola virus that were designed with one or both of the interferon inhibiting domains disabled to study what they do to the host. The altered viruses were placed on specific types of immune cells isolated from human blood, called dendritic cells, T lymphocytes, B lymphocytes and natural killer cells, as these types of cells are key players in marshaling defenses.
“We found that interferon inhibiting domains work not only in ways previously established, which includes interference in cascades of protective biochemical reactions that occur in cells in response to Ebola that limit infection”, Bukreyev said. “The IID’s also counter the activity of immune cells, including T lymphocytes and natural killer cells that kill virus-infected cells as well as B lymphocytes that secrete antibodies.” “It’s a double edged sword – the IIDs not only block interferon signaling, they also prevent infected cells from activating the cell-mediated arm of the immune response,” said Patrick Younan, research scientist and co-lead author of the paper.
Citation: Lubaki, Ndongala Michel, Patrick Younan, Rodrigo I. Santos, Michelle Meyer, Mathieu Iampietro, Richard A. Koup, and Alexander Bukreyev. “The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses.” PLOS Pathogens 12, no. 12 (2016).
Adapted from press release by the University of Texas Medical Branch at Galveston.
The multiple sclerosis (MS) therapy alemtuzumab can trigger severe, unpredictable side effects. This was the finding by a team led by Prof Dr Aiden Haghikia and Prof Dr Ralf Gold from the Department of Neurology of the Ruhr-Universität Bochum at St. Josef’s Hospital. In the journal Lancet Neurology, the scientists report on two patients for whom the infusion of alemtuzumab significantly worsened symptoms. The team also describes a treatment that successfully curbed the harmful side effects.
Alemtuzumab is a therapeutic antibody that docks to the protein CD52 on the surface of certain immunocytes, mainly T and B lymphocytes, leading to the depletion of almost all lymphocytes. It was already known from the approval studies that a quarter of the treated patients display mostly minor side effects, called secondary autoimmune processes: immunocytes turn against cells produced naturally in the body, predominantly in the thyroid gland; but the kidneys and platelets can also be affected.
The two patients described in the Lancet Neurology study received alemtuzumab because they had highly active MS, i.e. despite numerous previous treatments, they suffered from severe illness relapses with inflammation in the central nervous system. Six months after the treatment, these symptoms had worsened significantly. Using MRI, the researchers discovered a kind of new inflammation mode: they found vast areas in the brain with numerous ring enhancing lesion. The patients had not displayed this pattern in their previous medical history.
It is currently unclear whether the observed adverse events represent increased MS activity or an independent secondary autoimmune process.
In both cases, the neurologists were able to curb the side effects, and the observed ring-shaped deposits in the brain receded. Even a year after the treatment, the patients were still in a stable condition. Besides a blood plasma exchange, they treated both with the antibody rituximab that is directed against B lymphocytes. The researchers suspect that precisely these immunocytes were responsible for the observed side effect.
The authors propose that the measures they applied could also benefit other patients who develop similar adverse events under alemtuzumab.
Citation: Haghikia, Aiden, Calliope A. Dendrou, Ruth Schneider, Thomas Grüter, Thomas Postert, Mike Matzke, Heike Stephanik, Lars Fugger, and Ralf Gold. “Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy.” The Lancet Neurology 16, no. 2 (2017): 104-106.
Researchers from New Zealand’s University of Otago have gained fresh insights into how one of the main viruses that cause cervical cancer evades its hosts’ immune systems.
Their findings, which are published in the international journal Scientific Reports, suggest that a protein known as E7, produced by a high-risk type of human papillomavirus (HPV16), may be the key player in suppressing the body’s immune response to the virus.
While most people with an HPV infection will clear the virus from their bodies within two years, 10-20 per cent of those infected will fail to do so and become at much higher risk of developing cervical cancer.
Around 1,550 women are diagnosed with high-grade pre-malignant cervical cancer in New Zealand, and globally around half a million women are diagnosed with cervical cancer each year. In countries without organised screening programmes, cervical cancer is a leading cause of cancer mortality in women.
Study lead author Associate Professor Merilyn Hibma says that exactly how HPV16 suppresses the body’s immune responses has remained a matter of debate.
“Our new findings show that E7, in the absence of other HPV16 proteins, is sufficient enough to cause a range of effects on specialised cells normally involved in priming the body’s T-cells to combat viral infection,” Associate Professor Hibma says.
Further teasing out the mechanisms behind the failure of T-cells to be primed to attack the virus may allow new therapies that enable the body to fight off a persistent HPV infection, she says.
“This knowledge also helps us to understand how cancer cells avoid being detected by the immune system as E7 is also produced by cervical cancer cells. From this we may be able to identify new ways to block cancer suppression of the immune response. This approach is similar to ‘checkpoint inhibitors’ such as Keytruda and Opdiva.”
Press release by University of Otago