PNAS: IFITM3 Protects The Heart During Influenza Virus Infection

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Over the past few years research has shown an apparent link between current (or recent) influenza infection and cardiovascular complications, including heart attack.

• A few weeks ago, in PLoS One: Transient Depression of Myocardial Function After Influenza Virus Infection, we looked at a study that found transient myocardial function changes among a small group of influenza patients studied.

• In 2018's NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection, we saw a study that found a `significant association ' between recent (lab confirmed) influenza infection and Myocardial Infarction.

• And in May 2017, in Int. Med. J.: Triggering Of Acute M.I. By Respiratory Infection we looked at research from the University of Sydney that found the risk of a heart attack is increased 17-fold in the week following a respiratory infection such as influenza or pneumonia.

While a serious complication, for most healthy adults, flu related heart problems are very rare. Each year, however, hundreds of thousands (out of tens of millions) of flu cases are hospitalized in the United States.  

For most people, flu produces only a mild-to-moderate self-limiting illness. And for a lucky cohort, flu often presents with few if any clinical symptoms (see Study: Natural T Cell–mediated Protection against Seasonal and Pandemic Influenza).

But for many others - even those without comorbidities - flu can be a life threatening illness. All of which has some scientists on the hunt for genetic predispositions that might exacerbate - or mitigate - the severity of influenza infection.

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, that 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. 

And in 2015, in A Genetic Predisposition To Severe Flu Infection, we looked at a study published in Science Express that identified 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.

And just over two years ago, in New IFITM3 Genetic Marker May Help Identify High Risk Flu Patients, researchers from St. Jude Children's Research Hospital  found patients who carried a particular inherited variation in the  IFITM3 gene were `more than twice as likely to develop severe, life-threatening flu symptoms as those who carried the protective version of the gene'.

While there's certainly more than one genetic factor at work, variations in the IFITM3 gene currently leads the pack.

All of which brings us to a new study - published this week in PNAS - that combines both lines of research; the impact of IFITM3 gene mutations and heart damage due to influenza infection.

By using genetically altered mice (without the IFITM3 gene) researchers at Ohio State University have demonstrated that influenza infection can cause cardiac abnormalities. From an Ohio State University press release, the lead researcher Dr. Jacob Yount said:

“By knocking out this gene in mice, and infecting them with various strains of flu, we were able to show that this gene’s absence increases the chances of heart abnormalities – decreased heart rate and irregular heartbeat – and death,” Yount said. “There’s been no known link between this gene and flu-related heart complications until now.”

First a link and the abstract from the PNAS study, then I'll return with a bit more:

IFITM3 protects the heart during influenza virus infection

Adam D. Kenney, Temet M. McMichael, Alexander Imas, Nicholas M. Chesarino, Lizhi Zhang, Lisa E. Dorn, Qian Wu, Omar Alfaour, Foued Amari, Min Chen, Ashley Zani, Mahesh Chemudupati, Federica Accornero, Vincenzo Coppola, Murugesan V. S. Rajaram, and Jacob S. Yount

PNAS September 10, 2019 116 (37) 18607-18612; first published August 26, 2019 https://doi.org/10.1073/pnas.1900784116

Significance

We discovered that IFITM3 prevents efficient dissemination and replication of influenza virus in heart tissue, thereby limiting cardiac fibrosis and electrical dysfunction during infection. Since IFITM3 polymorphisms are among the only human genetic factors that have been reproducibly associated with hospitalization and mortality during influenza virus infection, our findings are relevant to the serious threat of influenza virus infection to human health. Furthermore, IFITM3 KO mice provide one of the first models for studying cardiac complications of influenza.

Abstract

Influenza virus can disseminate from the lungs to the heart in severe infections and can induce cardiac pathology, but this has been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear.

We show that IFITM3 deficiency in a new knockout (KO) mouse model increases weight loss and mortality following influenza virus infections. We investigated this enhanced pathogenesis with the A/PR/8/34 (H1N1) (PR8) influenza virus strain, which is lethal in KO mice even at low doses, and observed increased replication of virus in the lungs, spleens, and hearts of KO mice compared with wild-type (WT) mice.

Infected IFITM3 KO mice developed aberrant cardiac electrical activity, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals, whereas WT mice exhibited a mild decrease in heart rate without irregular RR intervals. Cardiac electrical dysfunction in PR8-infected KO mice was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Infection with a sublethal dose of a less virulent influenza virus strain (A/WSN/33 [H1N1]) resulted in a milder cardiac electrical dysfunction in KO mice that subsided as the mice recovered.

Our findings reveal an essential role for IFITM3 in limiting influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model for studying mild and severe influenza virus-induced cardiac dysfunction.

(Continue . . . )

A genetic test that could help triage flu patients who are most likely to develop severe illness - including cardiac complications - would undoubtedly save many  lives during regular flu seasons, and even more during a pandemic.

But in addition to the previously discussed IFITM3 (rs12252) and mutations of the IRF7 gene, in 2016 Chinese researchers (see Nature: Mulitple Gene Mutations Identified In Patients With A/H7N9) reported finding 21 genes that showed a high rate of mutation among infected patients when compared to the general population.

All of which suggests we are a long way from knowing all of the genetic risk factors for severe influenza. 

And for those who see progress as a double-edged sword, there's a fascinating commentary in the AMA's Medical Ethics journal from last summer, which explores a potential darker side to genetic testing for flu susceptibility.

Should Genetic Testing for Variants Associated with Influenza Infection Be Mandatory for Health Care Employees?

Michelle Huckaby Lewis, MD, JD