Vaunted virulence: Keys to 1918’s fatal infections

Could current bird flu be as deadly?

The virulence of the 1918 pandemic strain was so extraordinary that there are accounts of people who felt well in the morning but were dead by nightfall. Mice infected with the recently recreated strain did not drop quite as dramatically, surviving three to five days before the viral infection overwhelmed their bodies. But considering that human strains of influenza don’t typically even faze mice, the results suggest the resurrected virus has lost none of its vaunted virulence.

"The huge specter of 1918 is that it killed so many people," says Jeffery K. Taubenberger, MD, PhD, the Armed Forces Institute of Pathology researcher who genetically reconstructed the 1918 pandemic flu strain. "There is pretty good evidence now, at least in mice models, that the 1918 surface protein gene — the hemagglutinin — certainly is contributing to virulence."

Researchers also have identified three polymerase genes — proteins in the 1918 virus — that allow it to rapidly replicate its RNA. "Those are also important in virulence, probably by allowing the virus to replicate extremely well, very efficiently to high copy numbers," he says.

While the currently circulating avian influenza H5N1 virus is lethal in mice in five to seven days after infection, the bird flu — unlike the 1918 virus — does not transmit between humans. Researchers are hopeful that should that ever become the case, lessons learned about the virulence of the 1918 virus will lessen the human toll.

In the ongoing research, the infecting 1918 strain replicated deep within mice lungs, prompting an immune system hyperreaction — the so-called "cytokine storm." Cytokines are proteins in the immune system that send out messages as part of the body’s response to an invading pathogen. A cytokine storm is a term used to describe an extremely powerful cytokine reaction — an overreaction, if you will — that may do more harm than good.

"We are seeing a lot of inflammation and a lot of cytokines," says Terrence Tumpey, PhD, the senior microbiologist at the Centers for Disease Control and Prevention who recreated the 1918 virus strain and infected the research mice. "People talk about the cytokine storm in various tissues. We feel that too much of it is a bad thing in the delicate tissues of the lungs. When you see all these cells that migrate into the deeper airways and the cytokines that build up, then maybe they might be involved in blocking airways."

That could possibly explain one of the enigmas of the 1918 pandemic: its devastating mortality in young and healthy people who usually survive disease epidemics. Provoking a hyperimmune response — something that would be even stronger in people with healthy immune systems — may be the key to the 1918 strain’s legendary virulence.

Could it happen again? A recently published study found that similar cytokine storms have occurred in the lungs of some of the people fatally infected with H5N1 avian flu, which again seems to be targeting a young, healthy population.1

Another clue to the virulence of the 1918 strain is its ability to replicate deep within the lungs. Tumpey found the virus was able to replicate in mice lungs in the absence of the trypsin, an enzyme typically associated with flu virus replication. In the human lung, for example, trypsin may be present in some lung cells and absent in others. Typically, a human flu virus invading a cell needs trypsin to continue replicating. "It is unique for a particular virus to be able to replicate in the absence of trypsin," Tumpey says. "Normally, when we isolate human influenza it won’t grow in our tissue cultures without adding trypsin to it. We think that the 1918 virus had this selective advantage."

Deeper lung involvement of a replicating virus can result in many things, and none of them are good. While stirring up a cytokine storm, the viral infection also may be doing sufficient damage to set up the lungs for a bacterial pneumonia coinfection. Bacterial coinfections are thought to be key reason the 1918 pandemic had such a staggering mortality rate, particularly since the virus was circulating in the pre-antibiotic era.


  1. Chan MCW, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 2005; 6:135.