The frightening Filoviridae
Ebola hemorrhagic fever is caused by Ebola virus, a filamentous virus that is part of the family Filoviridae. Ebolavirus is of particular concern to global health as a result of killing as many as 90% of its victims. The Hot Zone tells in great detail the discovery and fear driven by Filoviruses, I highly suggest it.* This high mortality can be attributed to its ability to avoid detection by the immune system. Normally the human adaptive and innate immune system are capable of recognizing specific markers, or antigens, from pathogens. These antigens trigger an immune response that can clear the infection. The adaptability and complexity of the immune system is astounding, and can be better understood with the above wikipedia links.** While the immune system plays a large role in infectious disease, the star of the game is Ebolavirus.
Viruses are characterized by their parasitism, and the inability to metabolize and replicate in the absence of a host. Because of this, viruses hijack host cell machinery in order to reproduce. But first, the virus must gain entry into a cell. Viruses have found various ways to enter their host cells. For example, HIV entry is characterized by fusion of the viral envelope to the membrane of the cell, without any endocytosis. In contrast, most viruses utilize a process of endocytosis, where fusion of the virus to the cell membrane triggers a response by the cell to engulf the virus. How Viruses Hijack Endocytic Machinery.
After entering a cell, Ebolavirus uses host proteins, along with a few of its own, to make copies of itself. These new viral copies leave the cell in search of another host to infect. However, after leaving the cell, the viral particles are exposed to the dangers of the human immune system. The mechanism by which Ebolavirus evades the immune system has been dubbed antigenic subversion. The paper by Mohan et al. at Emory University is here, and open access: Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus.
Viruses are subject to natural selection and evolution, similar to all organisms. Many pathogens undergo antigenic variation, where the antigens of the microbe change such that the immune system no longer recognizes it as a pathogen, allowing it to reside in its host undetected. Alternatively, antigenic subversion is a mechanism by which Ebolavirus actively “hides” from the immune system by telling the infected cell to secrete an antigen (secreted GlycoProtein, sGP) that effectively undermines the ability of the immune system to recognize the capsid of the virus. The excreted antigens sequester the antibodies directed toward finding and clearing viral particles coated in GP1,2, the capsid glycoprotein responsible for attachment of the virus to the host cell. Without an appropriate antibody response, clearance of the virus is virtually impossible and free viral particles roam the body destroying cell after cell. This is where it gets heavy.
The translated products that contribute to antigenic subversion are a result of transcriptional editing. The viral polymerase carried by Ebolavirus is prone to slippage, and 20% of the time, the viral RNA polymerase creates a mRNA transcript that allows for the translation of open reading frames as a single protein, the fusion GP1,2 protein. 80% of the time, the polymerase creates a transcript that carries a stop codon before the second open reading frame, creating the secreted sGP protein. (PNAS Sanchez 1996)
Furthermore, antibodies against sGP harbor low reactivity with GP1,2. However, antibodies against GP1,2 react strongly with sGP. Because sGP is simply a truncated version of GP1,2, this suggests that the conformations of sGP create epitopes that differ from those on GP1,2. These conformational changes alter the immune response, leading to the production of antibodies that can strongly opsonize sGP, but weakly bind GP1,2.
Many pathogens employ a decoy mechanism, where they create an antigen that absorbs the effects of the antagonizing antibodies. However, this differs in that the “decoy” antigen is not only sequestering antibodies, but also altering the immune response to create ineffective and poorly protective antibodies against sGP when the immune system would be better off producing anti-GP1,2 antibodies.
A 3 minute discussion about the entry of Ebolavirus:
*A crappily formatted, but readable, PDF version of the book is here.
**I tried to keep it concise, but introduction to viruses is no brief task. I should do a pathogen 101, in addition to an immune system 101. I would like to delve into specific molecular mechanisms, but it’s easier to think about than it is to write about. Next time.