Bats, Viruses, And Their Immune Response

Common pipistrelle (Pipistrellus pipistrellus) – Credit Wikipedia

 

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For virologists and chiroptologists, an enduring mystery has been how bats are able to carry – without apparent ill effect – viruses that are normally deadly to most other mammals.

 

Long known for carrying rabies, over the past two decades we’ve discovered that bats can also harbor viruses such as Ebola, Marburg, Nipah, Hendra, and a variety of coronaviruses (including SARS). 

 

This week, in an article that appears in the Journal Science, we learn that some of the evolutionary changes that enable the bat to be the only mammal that can fly, may also help them to carry deadly viruses.

 

First a link to the Abstract (the whole paper is behind a pay wall), then excerpts from a Reuter’s news article that help flesh out the findings.

 

Published Online December 20 2012
< Science Express Index

Science DOI: 10.1126/science.1230835

• Report

Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity

Guojie Zhang, Christopher Cowled, Zhengli Shi, Zhiyong Huang, Kimberly A. Bishop-Lilly, Xiaodong Fang, James W. Wynne, Zhiqiang Xiong, Michelle L. Baker, Wei Zhao, Mary Tachedjian, Yabing Zhu, Peng Zhou, Xuanting Jiang, Justin Ng, Lan Yang, Lijun Wu, Jin Xiao, Yue Feng, Yuanxin Chen, Xiaoqing Sun, Yong Zhang, Glenn A. Marsh, Gary Crameri, Christopher C. Broder, Kenneth G. Frey, Lin-Fa Wang, Jun Wang

Abstract

Bats are the only mammals capable of sustained flight and are notorious reservoir hosts for some of the world’s most highly pathogenic viruses, including Nipah, Hendra, Ebola, and severe acute respiratory syndrome (SARS). To identify genetic changes associated with the development of bat-specific traits, we performed whole-genome sequencing and comparative analyses of two distantly related bat species, fruit bat Pteropus alecto and insectivorous Myotis davidii.

 

We discovered an unexpected concentration of positively selected genes in the DNA damage checkpoint and nuclear factor–κB pathways that may be related to the origin of flight, as well as expansion and contraction of important gene families. Comparison of bat genomes with other mammalian species has provided new insights into bat biology and evolution.

 

 

Admittedly, there is not much specificity in this abstract. 

 

Luckily, Tan Ee Lyn - Asia Health correspondent for Reuters – has an interview with the lead author -Professor Lin-Fa Wang, who reveals that some genetic changes necessary for flight may also help to moderate dangerous out-of-control immune responses known as Cytokine Storms.

Cytokines are a category of signaling molecules – proteins – that are released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

Although poorly understood, the theory behind a `cytokine storm’ is this signaling process spirals out of control, resulting in an overwhelming immune response that can potentially kill the host.

 

According to Professor Lin-Fa Wang, this built-in suppression of the inflammatory (cytokine) response may be behind the bat’s unusual longevity (20 to 40 years), and their ability to `handle’ infection by normally deadly viruses.

 

 

Long-lived bats offer clues on diseases, aging

December 21, 2012 12:52 PM

HONG KONG: The bat, a reservoir for viruses like Ebola, SARS and Nipah, has for decades stumped scientists trying to figure out how it is immune to many deadly bugs but a recent study into its genes may finally shed some light, scientists said on Friday.Studying the DNA of two distant bat species,...

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In another article, this time in The Asian Scientist, the author talks about practical applications of this research, and is quoted as saying, “Our findings highlight the potential of using bats as a model system to study infection control, tumor biology, and the mechanisms of aging,”

 

 

Bats’ Immunity Against Deadly Viruses Linked To Their Ability To Fly

AsianScientist (Dec. 21, 2012) – An international team led by an infectious disease expert, Professor Lin-Fa Wang, at the Duke-NUS Graduate Medical School (Duke-NUS) in Singapore has found that the evolution of flight in bats may have contributed to the development of a highly effective immune system, allowing bats to harbor some of the world’s deadliest viruses such as Ebola and SARS.

(Continue . . . )

 

Both news articles are worth reading in their entirety.

 

For more on cytokine storms, and how they may affect pandemic influenza mortality, you may wish to revisit some of these earlier blogs.

 

Study: Calming The Cytokine Storm

Cytokine Storm Warnings

The Baskin Influenza Pathogenesis Study

Pt. 1   Pt. 2   Pt. 3

»» Read More

Study: Calming The Cytokine Storm

 

 

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Some fascinating research coming out of The Scripps Research Institute today that looks at what may turn out to be a new way of treating serious illness due to influenza.  

 

Rather than trying to combat the virus – which has a nasty habit of evolving resistance to antivirals - they are looking at ways of reducing the body’s sometimes excessive immune response known as a Cytokine Storm.

 

Right now their research has been conducted on mice, and it is helping to unlock the long standing mystery of how and where cytokines are produced. 

 

Cytokines are a category of signaling molecules that are used extensively in cellular communication. They are often released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

This cascade of immune cells rushing to the infection, if it races out of control, can literally kill the patient. Their lungs can fill with fluid (which makes a terrific medium for a bacterial co-infection), and cells in the lungs (Type 1 & Type II Pneumocytes) can sustain severe damage.

 

Previously, in Swine Flu Sequelae and Cytokine Storm Warnings, we looked at some of the severe lung damage during the 2009 pandemic that was thought to be due to this overreaction of the immune system.

 

All of which serves as prelude to a study published today in the Journal Cell with the somewhat daunting title of:

 

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

 

Cell, Volume 146, Issue 6, 980-991, 16 September 2011  10.1016/j.cell.2011.08.015

Authors

John R. Teijaro, Kevin B. Walsh, Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona Scott, Esther Martinborough, Robert Peach, Michael B.A. Oldstone, Hugh Rosen

 

No worries. 

 

We have two explanations available to us, one pretty basic, and a second with more meat to it.

First, the basics from a Cell Press Release.

 

Avoiding fatal responses to flu infection

Most of the time, being ill with the flu is little more than a nuisance. Other times, it can spark an exaggerated immune response and turn deadly. Researchers reporting in the September 16th issue of the journal Cell, a Cell Press publication, have now traced the origins of this severe immune response -- called a cytokine storm -- to its source.

 

Cytokines are the chemical signals that drive inflammation, and cytokine storms are thought to be the cause of many of the deaths attributed to the 1918 worldwide influenza pandemic and to the more recent outbreaks of swine and bird flu infection. The new study provides encouraging news by offering the foundations for a completely new kind of flu therapy.

 

"We are showing for the first time that you can actually separate the deleterious events from those needed to control the virus," said Hugh Rosen, senior author of this study, from The Scripps Research Institute.

 

"It had been thought for a long time that all injury from influenza was due to the virus itself, consequently, and rationally, the focus was on developing antiviral drugs," said study co-author Michael Oldstone, also of Scripps.

 

The new results suggest that drugs aimed at the dangerous immune response may offer a life-saving new line of defense, by protecting infected hosts from themselves. Another bonus is that such an approach doesn't put the same pressure on viruses to adapt and develop drug resistance.

 

The cytokines associated with flu infection were thought to come from virus-infected cells found primarily in the lungs and nasal passages. The authors find that the cytokines are instead released from the endothelial cells that line blood vessels. A protein found on the surface of endothelial cells, called Sphingosine-1-phosphate receptor (S1P1), is essential for flu-associated cytokine storms.

 

In mice treated with a molecule that targets S1P1, cytokine production and the early signs of inflammation are suppressed. As a result, the animals are much more likely to survive infection with H1N1 swine flu virus. Notably, several companies are already testing S1P1-targeted drugs in clinical trials, the researchers say.

(Continue . . . )

 

A more in-depth explanation can be found in The Scripps Research Institute’s press room.

 

 

Scripps Research Team Discovers Treatable Mechanism Responsible for Often Deadly Response to Flu

LA JOLLA, CA – September 15, 2011 – Researchers at The Scripps Research Institute have found a novel mechanism by which certain viruses such as influenza trigger a type of immune reaction that can severely sicken or kill those infected.

 

This severe immune reaction—called a “cytokine storm”—floods the tiny air sacs of the lungs with fluid and infection-fighting cells, blocking off airways and damaging body tissues and organs. Cytokine storms are believed to have played a major role in the staggering mortality of the 1918-1919 worldwide influenza pandemic, as well as in the more recent swine flu and bird flu outbreaks.

(Continue . . . )

 

And lastly, in concert with the publication of this study, two of the primary researchers - Professors Michael BA Oldstone and Hugh Rosen – discuss their findings in the following video.

 

 

 

Like I say, it’s fascinating stuff. 

 

And while it won’t produce an FDA approved flu drug anytime in the near future, research like this helps show us how the immune system works, and that in turn opens up new avenues of exploration for tomorrow's drugs.

»» Read More

Cytokine Storm Warnings

 

 

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Many scientists subscribe to the theory that novel viruses (like the 1918 pandemic, H5N1, and now novel H1N1) can unleash what is known as a `cytokine storm’ in some patients with a robust immune system.

 

Last February, in part 2 of my 3-part look at the Baskin Influenza Pathogenesis study  I wrote this description of how we think a cytokine storm comes about.

 

Our innate immune system throws just about everything but the kitchen sink at an unrecognized infection.

 

In response our bodies spike a fever while natural killer cells and phagocytes rush to fight the infection.  Our bodies produce protein and cytokine rich fluids at the site of the infection and cells throughout our body release inflammatory mediators.

 

Generally all of these things are good things, as they help fight the invading pathogen, although they are what make us so miserable when we have an infection.

 

Unfortunately, it is possible to have too much of a good thing.

 

On very rare occasions the body's innate immune system can overreact, go into overdrive, and overwhelm and damage the body's own organs - sometimes resulting in death.

 

This process is commonly called a `Cytokine Storm', although it is actually a poorly understood phenomenon, and not without controversy.

  

Cytokines, broadly speaking, are a category of signaling molecules that are used extensively in cellular communication.

 

They are often released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

This  `Cytokine Storm' has been described as a positive feedback loop, where immune cells - encountering a pathogen - secrete  signaling cytokines which call more immune cells to the site of infection - which in turn secrete more cytokines - which call even more immune cells to join in the fight . . .

 

This cascade of immune cells rushing to the infection can, in rare instances, literally kill the patient. Their lungs can fill with fluid (which makes a terrific medium for a bacterial co-infection), and cells in the lungs (Type 1 & Type II Pneumocytes) can sustain severe damage.

 

Today, we’ve a press release in advance of the publication of a study to appear next month in American Thoracic Society's American Journal of Respiratory and Critical Care Medicine, that looks at the autopsy results of 21 pandemic flu victims.

 

Researchers found three separate types of severe lung damage, and point to signs of a cytokine storm response in some of these cases.

This from the American Thoracic Society.

   

Contact: Keely Savoie
ksavoie@thoracic.org
212-311-58620
American Thoracic Society

 

Researchers find new patterns in H1N1 deaths

Brazilian researchers have performed the first-ever autopsy study to examine the precise causes of death in victims of the H1N1 swine flu.

 

"The lack of information on the pathophysiology of this novel disease is a limitation that prevents better clinical management and hinders the development of a therapeutic strategy," said lead author, Thais Mauad, M.D., Ph.D., associate professor of the Department of Pathology at São Paulo University, in Brazil.

 

The results of their study will be published in the January 1 issue of the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

 

The researchers examined 21 patients who had died in São Paulo with confirmed H1N1 infection in July and August, 2009. Most were between the ages of 30 and 59. They found that three-quarters (76 percent) of the patients had underlying medical conditions such as heart disease or cancer, but there was no clear complicating medical condition in the remaining quarter. All presented a progressive and rapidly fatal form of the disease.

 

While previous data has shown that most patients with a non-fatal infection have fever, cough and achiness (myalgia), Dr. Mauad noted that "most patients with a fatal form of the disease presented with difficulty breathing (dyspnea), with fever and myalgia being less frequently present."

 

All patients died of severe acute lung injury, but there were three distinct patterns of the damage to their lungs, indicating that the infection killed in distinct ways. "All patients have a picture of acute lung injury," said Dr. Mauad. "In some patients this is the predominant pattern; in others, acute lung injury is associated with necrotizing bronchiolitis (NB); and in others there is a hemorrhagic pattern."

 

"Patients with NB are more likely to have a bacterial co-infection. Patients with heart disease and cancer are more likely to have a hemorrhagic condition in their lungs. It is important to bear in mind that patients with underlying medical conditions must be adequately monitored, since they are at greater risk of developing a severe H1N1 infection," said Dr. Mauad. In these patients, H1N1 infection may present as a potential fatal disease, requiring early and prompt intensive care management, including protective ventilation strategies and adequate hemodynamic management. "We found that 38 percent of these patients had a bacterial infection (bronchopneumonia). This has important consequences because these patients need to receive antibiotic therapy, in addition to antiviral therapy."

 

The researchers also found evidence of an influenza-associated "cytokine storm," an aberrant immune response in the lungs of certain individuals, which was almost certainly involved in the pathogenesis in these fatal cases of the H1N1 infection. "[This] suggests that an overly vigorous host inflammatory response triggered by the viral infection may spill over to and damage lung tissue, thereby causing acute lung injury and fatal respiratory failure," noted John Heffner, M.D., past president of the ATS.

(Continue . . . )

 

More pieces of the puzzle that will, in time, hopefully give us a better understanding how this novel virus, and perhaps other pandemic strains, affect their hosts.

 

For a better understanding of the pathogenesis of influenza, the innate immune system, and the role of cytokines I would invite you to read my 3-part look at the Baskin study.

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

»» Read More