Dr. Kielian and her colleagues have named these virus-induced structures intercellular long extensions, or ILEs. “This mode of viral transmission may not only shield some copies of the virus from the host’s immune response, but it may also explain why symptoms of chikungunya infection can persist for many months or years,” added First Author Peiqi Yin, PhD, a postdoctoral fellow in Dr. Kielian’s lab.
In addition to fever, chikungunya infections often lead to chronic and debilitating arthritis. The virus is spread to humans by the bite of infected mosquitoes, which become infected by feeding on people who already have the virus. Over the past 15 years, chikungunya virus has become an important and increasingly widespread human pathogen. Multiple outbreaks have caused millions of human infections in numerous areas, including the Americas, Africa, Asia, Europe and the Caribbean. The National Institute of Allergy and Infectious Diseases lists chikungunya virus as a Category B Pathogen, the second-highest priority for organisms posing threats to national security and public health.
Confirming a Cell Structure’s Role
Dr. Kielian and colleagues discovered the presence of ILEs in chikungunya-infected cells several years ago, but it wasn’t clear whether the structures facilitated cell-to-cell viral transmission. The study described in the Nature Microbiology paper was designed to answer that question.
The first part of the study involved the use of cultured mouse cells. The researchers exposed the cells to chikungunya virus that expressed a fluorescent reporter protein, allowing them to observe that infectious virus particles were indeed being transmitted from cell to cell via ILEs. Cell-to-cell transmission occurred even in the presence of high quantities of neutralizing antibodies that were added to the culture medium.
To confirm this mode of cell-to-cell transmission in living animals, the researchers studied chikungunya infection in mice. Mice that were first inoculated with neutralizing antibodies and were then directly injected with chikungunya virus did not become infected. However, antibody-treated mice that were then injected with virus-infected cells (rather than just the virus) did develop chikungunya infections that were resistant to the neutralizing antibodies.
“Together, these studies show that ILEs shield chikungunya virus from neutralizing antibodies and promote intercellular virus transmission, both in vitro and in vivo,” said Dr. Yin. The mouse studies were conducted by Thomas E. Morrison, PhD, and his group at the University of Colorado School of Medicine in Aurora.
Short-Circuiting the Connections
In a final set of studies, the researchers determined that certain antiviral antibodies were able to block ILEs from forming and to prevent cell-to-cell transmission. “If we can generate the production of such antibodies in human patients, or develop other methods to stop ILE formation, that could be especially helpful in combating the chronic symptoms of chikungunya infection,” said Dr. Kielian. “We’re currently studying different ways to do this.”
The study is titled “Chikungunya Virus Cell-to-Cell Transmission Is Mediated by Intercellular Extensions In Vitro and In Vivo.” Other Einstein authors were Jonathan R. Lai, PhD, MD/PhD student Karen Tong and Judy J. Wan, PhD. Other contributors include Bennett J. Davenport, PhD, and PhD student Brian C. Ware at the University of Colorado School of Medicine, Aurora, CO; Arthur S. Kim, PhD, and Michael S. Diamond, MD, PhD, at Washington University School of Medicine, Saint Louis, MO; Thérèse Couderc, PhD, at Institut Pasteur, Université de Paris, Paris, France; and Marc Lecuit, MD, PhD, at Institut Pasteur, Université de Paris, and Hôpital Necker-Enfants malades - AP-HP, Institut Imagine, Paris, France.
The research was supported by grants from the National Institutes of Health (R01GM057454, R01AI141436, R01AI125462 and R01AI143673) and by an NCI Cancer Center Support Grant (P30CA013330).
Competing interests: Dr. Lai is a paid consultant for Celdara Medical, LLC. Dr. Diamond is a consultant for InBios, Vir Biotechnology, Senda Biosciences, Ocugen, Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, Generate Biomedicines and Emergent BioSolutions. The other authors declare no competing interests.