Human cytomegalovirus (HCMV) may not be a household name as far as viruses go, but according to the senior author, half of the population walking around campus is likely to be a carrier. Once contracted, it lays dormant in your body for the rest of your life and can flare up whenever your immune system is severely compromised, giving you flu-like symptoms.
This becomes a severe problem for people who already have weakened immune systems, for example the very young, old, pregnant women, organ transplant recipients, or HIV/AIDS patients. More concerning, however, is that HCMV is the number one infectious cause of congenital birth defects in the world, including developmental disabilities and deafness. But how can a protein be a major contributor in the development of birth defects, and also hold the potential to provide symptom relief from autoimmune diseases like lupus?
In a new paper published in Nature Communications, researchers are helping to answer this question and uncover the mechanisms that will lead to multi-faceted prevention and treatment.
HCMV can also be passed through the placenta to a pregnant mother's unborn child, not only affecting the child's immune system, but also potentially causing birth defects. "When the mother gets infected, the virus spreads from mother to baby and can cause mental disabilities, vision loss, and deafness. People are aware of this concern with Zika virus for instance, but Zika doesn't stay in your system for life like HCMV, and it isn't present in 50 to 80 percent of the population globally depending on where you live," says the senior author.
The immune system has two arms of immunity, at the cellular and antibody levels, to specifically destroy bugs. The mechanisms of the US11 protein that allow HCMV to evade white blood cells that kill viruses on the cellular level are well known, but in this latest publication discuss a newly discovered function of the same protein that impairs antibody immunity.
Antibody immunity normally prevents viruses from entering and infecting uninfected cells and labels the infected cells to be destroyed by the white blood cells. But US11 attacks a specific receptor that not only naturally bolsters your immunity, but also directs protective antibodies from the mother to be transferred to the fetus. With this receptor impaired, HCMV may reduce transmission of these critical antibodies, resulting in vulnerability to all sorts of birth defects, and at the very least compromising the child's immunity throughout their life.
Mechanistically authors show that US11 inhibits the assembly of Fc receptor (FcRn) with β2m and retains FcRn in the endoplasmic reticulum (ER), consequently blocking FcRn trafficking to the endosome. Furthermore, US11 recruits the ubiquitin enzymes Derlin-1, TMEM129 and UbE2J2 to engage FcRn, consequently initiating the dislocation of FcRn from the ER to the cytosol and facilitating its degradation. Importantly, US11 inhibits IgG-FcRn binding, resulting in a reduction of IgG transcytosis across intestinal or placental epithelial cells and IgG degradation in endothelial cells. Hence, these results identify the mechanism by which HCMV infection exploits an ER-associated degradation pathway through US11 to disable FcRn functions.
"This is the first time that we discovered that this virus, or any pathogen, has this strategy to destroy this receptor function and reduce antibody functionality," says the senior author. "Antibodies are also used to treat diseases like AIDS, cancer, and make vaccines, and this mechanism makes that less effective. By understanding this function, we can hopefully figure out methods to block that mechanism in the future."
Beyond prevention for birth defects and immune system dysfunction, the senior author sees another potential treatment benefit for this mechanism for patients struggling with autoimmune diseases. "Humans have many autoimmune diseases, and in these cases like with lupus, it is actually our immune response that causes the disease, which is regulated by antibodies. In these patients, we are concerned with how to reduce autoimmune antibodies, because their overproduction causes damage on our own tissues and cells, swelling in the joints, and substantial pain. Since this protein US11 can facilitate antibody degradation and suppress antibody function, it could be used in humans to treat autoimmune disease and target these disease-causing antibodies to indirectly benefit patients with immune diseases."
This therapeutic prospect is being patented by the authors, who stress the importance of directly translating basic research like this into applied outcomes and treatment options, not just for humans, but for animals that are infected with similar viruses as well. "Human and animal health research is interconnected," says the senior author. "Similar knowledge can be used to promote animal and human health, and diseases pass directly from animals to humans and vice versa."
How human cytomegalovirus (HCMV) protein evades antibody immunity
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