How Does Influenza Jump between Species?

Feb. 23, 2018

One of the pernicious characteristics of influenza A virus is its ability to infect multiple types of animal species. This means that even if a long-lasting universal influenza vaccine were generated, the virus would continue to transmit between species such as ducks, chickens, pigs, horses, and bats. Understanding how the virus adapts between different species, which may have different internal temperatures or cell receptors, could help researchers predict the steps that would be necessary for an influenza strain to jump into human populations. Several new Journal of Virology reports look at the activity of influenza virus inside different animal hosts, and how viral genetics may influence the virus’ adaptation within a new host.

JVirology: Influenza A virus reassortment is limited by anatomical compartmentalization following coinfection via distinct routes

JVirology: Mammalian adaptation of an avian influenza a virus involves stepwise changes in NS1

JVirology: Unexpected functional divergence of bat influenza virus NS1 proteins

There are several characteristics of the influenza virus that give it a species specificity, including the binding preference of its hemagglutinin glycoprotein and the optimal temperature for viral RNA-dependent RNA polymerase (RdRp) activity. The poor fidelity of the RdRp when making copies of the viral genome is one source of new mutations that may allow better growth in a new type of host, but another mechanism can lead to big changes within the influenza virus: genetic reassortment.

When two viruses infect the same animal, different pieces of the RNA that compose the influenza genome may be mixed and matched as progeny viruses are assembled, in a process called reassortment (and described well here). Reassortment of different influenza genome pieces can quickly generate new viral strains that can jump into a naïve population, as was the case with the 2009 H1N1 influenza pandemic. While genetic reassortment is certainly a danger that requires continued surveillance, a new Journal of Virology report demonstrates that coinfection with two strains in a ferret model results in anatomical compartmentalization, limiting virus-virus interaction.

2018.2.23 JVI 1Schematic of intranasal versus intratracheal inoculation, where the subsequent infection occurs, and where tissue was sampled. Source.

First author Mathilde Richard and senior scientist Anice Lowen compared ferrets that were either inoculated with two unique viral strains through the same intranasal route to those that received one strain intranasally and another strain intratracheally. The intranasal inoculation promoted an upper respiratory tract infection, while the intratracheal inoculation promoted a lower respiratory tract infection (see figure, right). When animals were infected by two different routes, there was little reassortment seen between the two viral strains. This is important, because different animal viruses tend to primarily infect either upper or lowerrespiratory tracts, and suggests that a natural physical separation of the two infection types can minimize the risk of some viral strains interacting with each other.

Once a virus has jumped into a new species, mutations that promote viral reproduction and immune avoidance will continue to be selected for, refining that viral strain’s selection for its new host. This was demonstrated in a second Journal of Virology report that focused on an equine influenza virus (EIV) that had jumped from birds to horses in the 1960s. The NS1 protein within the circulating EIV strain has accumulated several mutations that help the virus to avoid detection and elimination by the horse immune system.

2018.2.23 JVI 2Phylogenetic tree showing the early, intermediate, and late NS1 protein sequences. Source.

First author Caroline Chauce and senior scientist Pablo Murcia looked at NS1 proteins from 13 EIV strains past and present. Sequencing analysis showed that the strains had acquired sequential mutations within the NS1 gene compared to the initial EIV, and that the mutant forms were quickly selected for within the EIV population (see figure, right). NS1 proteins are interferon antagonists that normally act to block interferon induction. The NS1 mutations described in this study didn’t affect interferon itself, but blocked the cell’s ability to induce interferon-stimulated genes, which are required for cell antiviral activity. These mutations, that allow the virus to grow even in the presence of interferon, have refined the ability of EIV to replicate in horses after making the initial species jump.

While the avian influenza virus jump into horses was detected decades ago, scientists have only recently discovered influenza A virus in bats, which are known to be reservoirs for other zoonotic diseases. A third Journal of Virology paper investigates the function of the bat influenza NS1 function. In most organisms, the NS1 gene is both an interferon antagonist and a cell signaling modulator, activating phosphotidyl inositol 3-kinase (PI3K) signaling to influence cell metabolism. The NS1 from bat influenza viruses uniquely lack this latter function, an adaptation that first author Hannah Turkington and senior scientist Benjamin Hale hypothesize is selected for because of unique bat energy strategies. 

In influenza viruses that infect other species, the ability to activate PI3K signaling is important for efficient replication. Why have bat influenza viruses lost this ability? It may be that PI3K signaling had no evolutionary advantage and was therefore lost in this population. In fact, the metabolic pathways of bats are regulated by signal cascade pathways that are wired differently than those of most mammals, and some of these signaling differences may affect the bat anti-viral responses. The scientific team attempted to test the effect of bat NS1 that activates PI3K signaling, but though the engineered protein could interact with signaling cascade members, it didn’t activate signaling, leaving this question unanswered. Understanding how–and why–influenza virus has adapted differently in this species may help scientists predict whether bat influenza poses a risk to people or other animal species.

Understanding how influenza A viruses jump between different species is one of the most important questions to protecting global health. Even if we could one day protect humans with a universal influenza vaccine, the disease could still devastate domesticated and wild animal populations, play a role in trade restrictions, and affect food availability. Studies like these are necessary to find the characteristics of viruses that may make the species jump, and important prediction to protect animal and human health. 

Author: Julie Wolf

Julie Wolf
Dr. Julie Wolf is in science communications at Indie Bio, and was a former ASM employee. Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.