When influenza viruses that infect birds and humans meet in the same cell, they can shuffle their genomes and produce new strains that might have pandemic potential. Think of this process, called reassortment, as viruses having sex.
In the last several years, public health officials have been monitoring two varieties of bird flu viruses with alarming properties: H7N9 and H5N8. Scientists at Emory have been probing the factors that limit reassortment between these strains and a well-known strain (H3N2) that has been dominating the last few flu seasons in the United States.
Helen Branswell has an article in STAT this week, explaining that H5N8 actually emerged from reassortment involving much-feared-but-not-damaging-to-humans-so-far H5N1:
Several years ago, these viruses effectively splintered, with some dumping their N1 neuraminidase — a gene that produces a key protein found on the surface of flu viruses — and replacing it with another. The process is called reassortment, and, in this case, it resulted in the emergence of a lot of new pairings over a fairly short period of time.
The most common and most dangerous viruses to emerge — for birds at least — have been H5N6 and H5N8 viruses. Both are highly pathogenic, meaning they kill domestic poultry.
“The H5N1 virus has not gone away. It’s just changed into different versions of itself,” explained influenza expert Malik Peiris, a professor of virology at the University of Hong Kong.
From the Emory study, the good news is that “packaging signals” on the H5 and H7 viral RNA genomes are often incompatible with the H3N2 viruses. That means it could be difficult for segments of the genome from the bird viruses to get wrapped up with the human viruses. But mix and match still occurred at a low level, particularly with H5N8. Read more
Zika virus can infect and replicate in immune cells from the placenta, without killing them, scientists have discovered. The finding may explain how the virus can pass through the placenta of a pregnant woman, on its way to infect developing brain cells in her fetus.
Infected placental macrophages. Zika antigens visible in red. From Quicke et al (2016).
The results were published in Cell Host & Microbe.
“Our results substantiate the limited evidence from pathology case reports,” says senior author Mehul Suthar, PhD, assistant professor of pediatrics at Emory University School of Medicine. “It was known that the virus was getting into the placenta. But little was known about where the virus was replicating and in what cell type.”
Scientists led by Suthar and Emory pediatric infectious disease specialist Rana Chakraborty, MD, found that Zika virus could infect placental macrophages, called Hofbauer cells, in cell culture. The virus could also infect another type of placental cell, called cytotrophoblasts, but only after a couple days delay and not as readily. Other researchers recently reported that syncytiotrophoblasts, a more differentiated type of placental cell than cytotrophoblasts, are resistant to Zika infection.
The cells for the experiments were derived from full-term placentae, obtained from healthy volunteers who delivered by Cesarean section. The level of viral replication varied markedly from donor to donor, which hints that some women’s placentae may be more susceptible to viral infection than others. Read more
One can take two very different angles when approaching Bill Kaiserâ€™s and Ed Mocarskiâ€™s work on RIP kinases and the mechanisms of cell death. These are: the evolutionary where-does-apoptosis-come-from angle, and the anti-inflammatory drug discovery angle.
A pair of papers published this week, one in PNAS and one in Journal of Immunology, cover both of these angles. (Also, back to back papers in Cell this week, originating from Australia and Tennessee, touch on the same topic.)
First, the evolutionary angle.
Cellular suicide can be a â€œscorched earthâ€ defense mechanism against viruses. Kaiser and Mocarski have been amassing evidence that some forms of cellular suicide arose as a result of an arms race of competition with viruses. The PNAS paper is part of this line of evidence. It shows that the cell-death circuits controlled by three different genes (RIP1, RIP3 and caspase 8) apparently can be lifted cleanly out of an animal. Mice lacking all three genes not only can be born, but have well-functioning immune systems.
Apoptosis is thought to be a form of cellular suicide important for the development of all multicellular organisms. Thatâ€™s why, to cell and developmental biologists, it seemed rather shocking that researchers can mutate a group of genes that drive apoptosis and other forms of cellular suicide and have adult animals emerge.
Next, the drug discovery angle.
The J. Immunol paper makes that angle clear enough. Most of the authors on this paper are from GlaxoSmithKlineâ€™s â€œPattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area.â€ Here, they show that a mutation in RIP1 inactivating the kinase enzyme protects mice against severe skin and multiorgan inflammation. They conclude their abstract with: “Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.”
Note: TNF-driven inflammatory diseases include rheumatoid arthritis, inflammatory bowel diseases and psoriasis, representing a multibillion dollar market.
Emory influenza researchers Richard Compans, Anice Lowen and John Steel are co-signers of a statement announcing the end of a self-imposed moratorium on H5N1 avian flu research.
Last year, an international group of researchers called for the moratorium after public concern over studies of H5N1 transmissibility in ferrets, a model for spread of infection between humans. The group of researchers has now recommended ending the moratorium, citing safeguards and safety review procedures put in place by the National Institutes of Health and authorities in other countries. From the letter published today in Science and Nature:
In January 2012, influenza virus researchers from around the world announced a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. We declared a pause to this important research to provide time to explain the public-health benefits cheap oakley of this work, to describe the measures in place to minimize possible risks, and to enable organizations and governments around the world to review their policies (for example on biosafety, biosecurity, oversight, and communication) regarding these experiments.
…Thus, acknowledging that the aims of the voluntary moratorium have been met in some countries and are close to being met in others, we declare an end to the voluntary moratorium on avian flu transmission studies.
Dan Vergano has a more extensive story in USA Today.
Compans is professor of microbiology and immunology at Emory University School of Medicine and scientific director of Emory’s Influenza Pathogenesis and Immunology Research Center. Lowen and Steel are assistant professors of microbiology and immunology at Emory and IPIRC investigators.