Human cytomegalovirus (HCMV)—a name that sounds like it was derived straight from a 1970s low-budget sci-fi movie. And while this microbial pathogen does quite invoke the same fear as say Ebola, HCMV is extremely pervasive and can be 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. Moreover, HCMV is the number one infectious cause of congenital birth defects in the world, including developmental disabilities and deafness. Yet counterintuitively, how can a protein be a major contributor to the development of birth defects, and also hold the potential to provide symptom relief from autoimmune diseases like lupus?
Now, investigators at the University of Maryland (UMD) believe they may have found the answer. In a new study, published recently in Nature Communications through an article titled “Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor,” scientists uncover the mechanisms that may lead to multi-faceted prevention and treatment approaches.
“HCMV stays asleep inside our cells,” explained senior study investigator Xiaoping Zhu, PhD, professor and chair in veterinary medicine at UMD. “Then one day, you get stressed, you have too much going on, and your immunity decreases allowing the virus to spring up again.” This is the case with all strains of the herpes virus-like HCMV, chickenpox, and herpes simplex. HCMV can present similar symptoms to the flu virus. However, unlike the flu, it persists in your body and your immune system must work harder than normal to combat the virus and keep it at bay.
HCMV can also be passed through the placenta to the fetus, 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,” Zhu noted. “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 50–80% of the population globally, depending on where you live.”
This makes the study of HCMV and the mechanisms that contribute to its persistence and transmission a high priority for the medical community. 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 previous work from Zhu and colleagues discusses a newly discovered function of the same protein that impairs antibody immunity.
Antibody immunity normally prevents viruses from entering and infecting cells, while simultaneously labeling infected cells to be destroyed by the white blood cells. But in the current study, the investigators found that US11 attacks a specific receptor that not only naturally bolsters host immunity, it 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.
“We showed that US11 inhibits the assembly of FcRn with β2m and retains FcRn in the endoplasmic reticulum (ER), consequently blocking FcRn trafficking to the endosome,” the authors wrote. “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.”
“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,” Zhu added. “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 researchers described another potential treatment benefit of 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,” explained Zhu. “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 UMD through Zhu and Xiaoyang Liu, a postdoctoral fellow at UMD, 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,” Zhu concluded. “Similar knowledge can be used to promote animal and human health, and diseases pass directly from animals to humans and vice versa.”
