Scientists at the U.S. Food and Drug Administration (FDA) have developed a method for predicting which influenza A viruses (IAV) are vulnerable to a protein that plays a key role in the immune system’s initial response to their presence in the lung. The avian IAVs studied are four types of influenza virus that have the potential to cause seasonal epidemics and, in some cases, pandemics (global outbreaks).
The FDA scientists based their work on the ability of a protein called pulmonary surfactant protein D (SP-D) to bind to long chains of sugar molecules linked to protein, called high mannose glycans, which extend from the head of a “ball-and-stick” protein called hemagglutinin (HA) on the surface of IAVs. These sites, which hold long mannose chains, are called high mannose glycosites. Viruses coated with SP-D tend to clump together, making it easier for the respiratory system to expel them or for immune cells called phagocytes to ingest and destroy them. Those lacking mannose chains on their HAs escape attack by SP-D and remain in the lungs, where they may infect cells and cause disease.
The FDA finding is important because it suggests a way to distinguish low pathogenicity A type influenza viruses (LPAIV) from high pathogenicity viruses, based on whether SP-D binds to their HA mannose chains. This is especially important when LPAIV acquire new genes that significantly increase their ability to cause disease. This can occur through reassortment—the process of two influenza viruses exchanging some of their genes when they both infect the same cell at the same time, producing a new variant. Such reassortment occurred in 1957 when two different IAVs exchanged certain genes, producing the variant that caused an influenza pandemic.
Therefore, the ability to predict whether an IAV has long mannose chains on their HAs could be useful for determining if they are vulnerable to SP-D and its ability to trigger an early immune system response or represent a potential public health threat.
In order to investigate this possibility, the FDA scientists used mass spectrometry to compare glycosites containing carbohydrate among the various IAV HA proteins and examined the three-dimensional molecular structures of the links between HA and SP-D. This enabled them to determine that a specific position on HA called N165 is occupied by the mannose chains in the HA proteins of seasonal H3N2 and avian H3N8 AIVs, while this site in the HA proteins of all LPAIVs were occupied by other sugars, which are note susceptible to SP-D binding.
The results of the study suggest LPAIVs that have undergone genetic reassortment that increased their pathogenicity might not respond to SP-D. The study also showed that it was possible using the FDA techniques to predict whether specific IAVs were susceptible to SP-D.
Influenza Hemagglutinins H2, H5, H6, and H11 are not Targets of Pulmonary Surfactant Protein D: N-glycan subtypes in host-pathogen interactions
J. Virol. doi:10.1128/JVI.01951-19
Lisa Parsons1, Yanming An2, Li Qi3, Mitchell White4 Roosmarijn van der Woude5, Kevan Hartshorn4 Jeffery K. Taubenberger3, Robert P. de Vries5 and John F. Cipollo2*
- Food and Drug Administration, Center for Biologics Evaluation and Research, Division of Bacterial, Parasitic and Allergenic Products, Silver Spring, Maryland 20993, USA.
- Food and Drug Administration, Center for Drug Evaluation and Research, DBRRII, Silver Spring, Maryland 20993, USA.
- Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 33 North Dr, Bethesda, MD 20892 USA.
- Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
- Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, NL-3508 TB Utrecht, The Netherlands.