Flu Virus binding to Receptor Cells – Credit CDC
A little over a week ago, in EID Journal: Emergence of D225G Variant A/H1N1, 2013–14 Flu Season, Florida, we re-visited one of the mutations linked to greater virulence in the (formerly pandemic, now seasonal) A/H1N1pdm09 virus.
This relatively rare amino acid substitution at position 225 (222 using H1 Numbering) from aspartic acid (D) to glycine (G) allows the virus to bind to receptors found deeper in the lungs, and is linked to the development of more severe pneumonia.
A 2013 study in Influenza Other Respir Viruses called A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection linked this, and the D225N mutation to more severe respiratory symptoms.
While probably the best known, and most studied, of the virulence enhancing mutations in the pH1N1 virus, D225G/N is certainly not the only one. And in truth, there are likely other mutations – or combinations of amino acid substitutions – that would increase the virus’s transmissibility, replication, antiviral resistance, or pathogenicity that we don’t even know about.
With the D225G/N mutation, it is believed that while it increases virulence, it reduces transmissibility. But that may simply mean that the right combination of concurrent changes hasn’t emerged to increase both . . . yet.
Last November, in When Influenza Goes Rogue, we looked at the long history of extreme variability between flu seasons, and the emergence of mutated, or `drifted’ viruses. And by now everyone knows that this year we are experiencing exactly that scenario with an antigenically drifted H3N2 virus.
The point being that flu viruses – even seasonal flu viruses that have been around for a long time – can occasionally throw us a curve.
This winter we’ve seen India reporting a large number of pH1N1 cases – which they call `swine flu’ – supposedly with an unusually high mortality rate. We’ve seen these sorts of reports from India in the past, and so it has been difficult to determine if anything is really different about this year’s flu strain (see India swine flu toll inches towards 1500).
Although the numbers seem high (and likely represent only the smallest tip of much larger iceberg), in a nation of over a billion people – millions would be expected to contract the flu in an average year - and of those, thousands would likely die.
A couple of weeks ago, in India’s H1N1 Outbreak, we looked at some of these reports along the Indian Government’s denials that anything untoward was occurring . India’s National Institute of Virology (NIV) and their National Centre for Disease Control (NCDC) both reported No mutation of H1N1.
Today, however, we’ve a report that suggests (based on very limited data) that perhaps something has changed with the H1N1 virus, and that it may be affecting its transmissibility, and severity, in India.
First, this press release, and then a link to the study.
A flu outbreak in India that has claimed over 1200 lives may not be identical to the 2009 North American strain, as recently reported in India. A comparative analysis conducted by scientists at the Massachusetts Institute of Technology (MIT) shows that the flu virus in India seems to have acquired mutations that could spread more readily and therefore requires deeper studies. As flu season in India winds down, the researchers call on officials to increase surveillance of this and future flu outbreaks and rethink vaccination strategies to account for potential new viruses.
The MIT analysis, which compared viral proteins important for virulence and transmissibility in the 2009 and 2014 flu epidemics, was conducted by professor Ram Sasisekharan, PhD, at the Koch Institute for Integrative Cancer Research, and his research scientist colleague Kannan Tharakaraman, PhD. It appears in the March 11 issue of the journal Cell Host & Microbe.
"It has been extensively reported in India that a virus similar to A/California/07/2009 is responsible for the current outbreak," Sasisekharan says. "Examination of the Indian H1N1 flu viruses that circulated in 2014 shows amino acid mutations that make them distinct (in terms of receptor binding, virulence, and antigenic drift) from the A/California/07/2009 virus."
"It is widely believed that the current H1N1 flu vaccine is still effective for the most part," he adds. "Effectiveness of the current H1N1 flu vaccine is debatable, and there have been calls for updating the vaccine. The Indian H1N1 viruses that circulated in 2014 are different compared to the 2009 vaccine strain A/California/07/2009."
This commentary (see below), which calls for greater testing and genetic sequencing on the Indian Subcontinent, notes that - despite the vastness of the Indian subcontinent, only two sequences have been deposited during 2014–2015 from India, suggesting poor surveillance and potentially limiting the response to a deadly outbreak.
Based on an analysis of Indian-origin strain A/India/6427/2014, they reported finding:
Although there are limited Indian-origin influenza sequences available in the public database to make any causal inference on the perceived increased fatalities in India, examination of the 2014 Indian H1N1 HA sequences shows traits with potential cause for concern. Amino acid changes in specific positions in the receptor binding site (RBS) of 2009pdmH1N1 have been shown to impact glycan RBS specificity and have been linked to increased virulence and disease severity.
Among these changes, the Indian-origin strain A/India/6427/2014 contains amino acid changes T200A and D225N compared to the 2009pdmH1N1 pandemic strain. The T200A amino acid change has been shown to improve human glycan receptor-binding of 2009pdmH1N1 HA (Xu et al., 2012b). The D225N mutation has been linked to increased virulence and disease severity in patients infected by the 2009 pdm virus (Ruggiero et al., 2013).
A third mutation, K166Q, was also detected and has been linked to increased severity of pH1N1 in middle-aged adults during the 2013-14 flu season (see CIDRAP Study: Middle-aged adults susceptible to recent flu virus mutation).
The lack of any recent sequencing of H1N1 viruses from India is particularly frustrating in light of recent news reports. The authors write: It is unknown if the strain A/India/6427/2014 is still in circulation; however, the apparent severity of the current outbreak seems to suggest that it could be.
The entire report/commentary – which emphasizes the need for more robust and timely influenza surveillanece and sequencing data - may be accessed at:
The 2014-15 H1N1 outbreak in India has reportedly led to 800 fatalities. The reported influenza hemagglutinin sequences from India indicate that these viruses contain amino acid changes linked to enhanced virulence and are potentially antigenically distinct from the current vaccine containing 2009 (Cal0709) H1N1 viral hemagglutinin.