Friday, March 27, 2015

A Genetic Predisposition To Severe Flu Infection


Photo Credit – CDC PHIL



# 9874


Influenza can produce a wide spectrum of illness, ranging from mild or even asymptomatic presentation to severe and/or life threatening disease.  


Often we talk about `high risk’ patients – where their age and/or co-morbidities (COPD, Asthma, pregnancy, etc. ) can sometimes lead to a greater chance of complications, but there may be other factors at work as well. 


As we saw in the 2009 H1N1 pandemic, with seasonal flu, and with several strains of avian flu (H5N1, H7N9), young, otherwise healthy adults can be quickly overwhelmed by their infections.


For a number of years researchers have been looking for a hematological or genetic marker that would help predict which patients would be most likely to experience severe influenza.


In 2008, in the Journal of Infectious Diseases, we saw a study that suggested there might be a heritable susceptibility to death from the influenza virus:

Evidence for a heritable predisposition to death due to influenza.

Albright FS, Orlando P, Pavia AT, Jackson GG, Cannon Albright LA.  


While interesting, this study didn’t provide us with a smoking gene.


In 2009 (see The Best Defense) we inched a bit closer, with research from Harvard Medical School and the Howard Hughes Medical Institute, that identified the IFITM3 protein as capable of inhibiting the replication of influenza, and other viruses, such as West Nile and Dengue. 


We revisited the IFITM3 story again in early 2012, in Luck Of The Draw, when we looked at research from the Wellcome Trust Sanger Institute, that found that people who carried a particular variant of the IFITM3 gene - (SNP rs12252-C) - were more likely to be hospitalized with severe influenza


In 2013, a study by Professor Peter Doherty (see PNAS: Genetic Marker & Cytokine Levels Linked To Severity Of Human H7N9 Infection) linked IFITM3 CC gene variant (aka C/C Genotype)  to hypercytokinemia (aka a `Cytokine Storm’), and severe outcomes in H7N9 infections.


This genetic marker– while comparatively rare in Caucasians - is far more common in Han Chinese, and may (partially) account for some of the particularly high mortality rates we’ve seen with novel influenza’s in Asia. 


Fast forward to yesterday, and we get a study published in Science Express that identifies yet another (rare) genetic marker -  a mutation of the IRF7 gene -  linked to a lack of interferon production which can lead to a more severe influenza infection. 


Published Online March 26 2015

Science DOI: 10.1126/science.aaa1578

Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency

Michael J. Ciancanelli1, Sarah X. L. Huang2,3,*, Priya Luthra4,*, Hannah Garner5,*, Yuval Itan1, Stefano Volpi6,7, Fabien G. Lafaille1, Céline Trouillet5, Mirco Schmolke4, Randy A. Albrecht4,8, Elisabeth Israelsson9, Hye Kyung Lim1, Melina Casadio1, Tamar Hermesh1, Lazaro Lorenzo10,11, Lawrence W. Leung4, Vincent Pedergnana10,11, Bertrand Boisson1, Satoshi Okada1,12, Capucine Picard1,10,11,13, Benedicte Ringuier14, Françoise Troussier15, Damien Chaussabel9,16,†, Laurent Abel1,10,11,†, Isabelle Pellier17,†, Luigi D. Notarangelo6,†, Adolfo García-Sastre4,8,18,†, Christopher F. Basler4,†, Frédéric Geissmann5,†, Shen-Ying Zhang1,10,11,†, Hans-Willem Snoeck2,3,†, Jean-Laurent Casanova1,10,11,19,20,‡ 


Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient’s leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient’s dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.

Some excerpts from the Rockefeller University press release follow:


Genetic mutation helps explain why, in rare cases, flu can kill

March 26, 2015 | Science News


The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.


Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.

What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”

(Continue . . . )


In a separate press release from HHMI, in view of the likelihood that others care this or similar genetic factors, Dr. Casanova recommends that clinicians may want to consider including interferon alpha in the treatment of severe unexplained flu.


[ March 26, 2015 ]

Rare Genetic Mutations May Make Influenza Life-Threatening for Some


HHMI researchers identify a rare genetic mutation that tamps down immune response to influenza.


  • Why did the flu develop into a life-threatening infection in a two-year-old girl?
  • HHMI researchers tried to identify the cause of the girl's severe response to influenza infection.
  • They found that the girl carries a genetic mutation that affects production of natural antiviral molecules.

(Continue . . . )

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