Viruses, as intracellular pathogens, rely on specific cells for replication and reproduction. This can also result in multiple viruses infecting the same cell. According to a new study published in Nature Microbiology, multiple viruses can coexist in small compartments in cells, and 10% to 30% of respiratory viral infections are caused by more than one virus.
Although these viruses compete for cellular resources, the new study discovered that competition is not the only way forward. Different virus families may eventually cooperate, fusing into a hybrid virus that continues to replicate.
The heterodimer in the paper consists of influenza A virus (IAV) and respiratory syncytial virus (RSV). "A type of heterodimer that has never been described before," said study corresponding author, virologist Pablo Murcia, "where two different families of viruses combined together, including the genome and outer protein, to become a novel pathogen." In the schematic diagram shown in the study, the heterozygous viruses look somewhat like the feet of a gecko, with RSV as the limb trunk and IAV as the toe.
The team's initial experimental goal was to explore the interaction of viruses upon infection, primarily for understanding the transmission characteristics of the viruses. They selected human lung cells as experimental subjects and added the two aforementioned viruses to them, while the control group added one of the viruses separately.
Temporally, the peak replication of IAV occurred approximately 24-48 hours after infection in the solitary infection group, while RSV was slightly later, reaching peak replication at approximately 72 hours. In the co-infected group, however, the situation seemed to be different, as IAV replication did not change and remained highly replicative for a short period of time. However, RSV appeared to be restricted for unknown reasons, and the viral titer of RSV was significantly lower.
To better understand what was going on in the cells of the co-infected group, the researchers began attempting to localize viral proteins using protein staining methods. First, the researchers noticed that both viral proteins were intact and not abnormal. However, they discovered some filamentous structures from the budding virus, but these intertwined filamentous structures would contain both viral glycoproteins.
With the help of cryo-electron tomography, the researchers showed the details behind this filamentation: IAV and RSV fused together to form a new hybrid virus particle. The new virus shows a different structural domain, dotted with glycoproteins that resemble the original size and shape of IAV and RSV, and some clear pipeline structures in the region where IAV and RSV join.
Although this merging behavior is less friendly to RSV, it allows IAV to have a smoother life. In addition to the unchanged replicative capacity of IAV seen earlier, the infective capacity of IAV becomes stronger. IAV can evade the surveillance of IAV by the immune system in heterozygous viruses by presenting the proteins of RSV, thus increasing the likelihood of infection.
According to the authors' observations, this heterozygous virus is able to enter cells that lack the IAV receptor, which also means that IAV can travel from the respiratory tract all the way down into the lungs, causing more serious infections. "RSV tends to penetrate more deeply into the lungs than IAV, but now IAV can enter together as a heterozygous virus," commented Dr. Stephen Griffin, a virologist at the University of Leeds.
