Cytokine Storm Chasers

 

# 8338

 

Readers with good memories will recall that in 2011, in Study: Calming The Cytokine Storm, we looked at research from The Scripps Research Institute  that found a protein located on the surface of endothelial cells, called S1P1, to be largely responsible for flu-associated cytokine storms.

 

Rather than trying to combat the specific virus – which has a nasty habit of evolving resistance to antivirals – Scripps researchers were looking at ways of reducing the body’s sometimes excessive immune response to viral infection known as a Cytokine Storm.

 

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.

 

More recently, we looked at a study by Professor Peter Doherty (see PNAS: Genetic Marker & Cytokine Levels Linked To Severity Of Human H7N9 Infection) that linked a specific genetic marker; IFITM3 CC gene variant (aka C/C Genotype)  to hypercytokinemia (aka a `Cytokine Storm’), and a severe outcome, 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. 

 

Last month, China’s CDC made specific mention of the role of excess cytokine production in H7N9 infection (see NHFPC: H7N9 Avian Flu Guidance Update) where they warn: H7N9 avian influenza virus after infection the human body, can induce cytokine storm, leading to systemic inflammation, may appear ARDS, shock and multiple organ failure.

 

Traditionally, ARDS (Acute Respiratory Distress Syndrome) patients end up on mechanical ventilation in ICUs, and are treated with a variety of pharmacological agents to reduce infection (antibiotics) and lung inflammation (corticosteroids, Nitric Oxide, etc.). 

 

The use of high dose corticosteroids – while fairly common with SARS and and early H5N1 cases – has been discouraged by the WHO and other health agencies due to poor long-term survival rates. 

 

Hence the need for a better tolerated,  more effective, and targeted drug regimen against the cytokine storm.

 

All of which serves as prelude to a new report from the The Scripps Research Institute updating their search for a drug to modulate the body’s immune response, and mapping the cytokine signaling and production process.  Their findings appear this week in the early edition of the journal PNAS.

Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection

John R. Teijaro^a, Kevin B. Walsh^a,¹, Stephanie Rice^a, Hugh Rosen^b,^c,², and Michael B. A. Oldstone^a,²

Significance

Cytokine storm plays an essential and commanding role in the clinical outcome and pathogenesis of influenza virus infection. We previously documented that a small molecule that activates sphingosine-1-phosphate-1 receptor (S1P₁R) signaling is primarily responsible for blunting cytokine storm to protect the infected host from the consequences of influenza infection. In the present study, we map host innate signaling pathways of cytokine storm and chart where along those pathways the drug is effective. We find that the efficacy of S1P₁R agonist in blunting cytokine storm is through global inhibition downstream of myeloid differentiation primary response gene 88 and IFN-β promoter stimulator-1 signaling.

(Continue . . .)

 

Although the bulk of this study is behind a pay wall, we get a pretty detailed overview from the following press release from the Scripps Institute.

 

News Release

Scripps Research Institute Scientists Describe Deadly Immune ‘Storm’ Caused by Emergent Flu Infections

LA JOLLA, CA—February 27, 2014—Scientists at The Scripps Research Institute (TSRI) have mapped key elements of a severe immune overreaction—a “cytokine storm”—that can both sicken and kill patients who are infected with certain strains of flu virus.

Their findings, published in this week’s online Early Edition of the Proceedings of the National Academy of Sciences, also clarify the workings of a potent new class of anti-inflammatory compounds that prevent this immune overreaction in animal models.

“We show that with this type of drug, we can quiet the storm enough to interfere with the virus-induced disease and lung injury, while still allowing the infected host to mount a sufficient immune response to eliminate the virus,” said John R. Teijaro, an assistant professor in TSRI’s Department of Immunology and Microbial Science and first author of the study.

“This study provides insights into mechanisms that are chemically tractable and can modulate these cytokine storms,” said Hugh Rosen, professor in TSRI’s Department of Chemical Physiology and senior author of the study with Michael B. A. Oldstone, professor in TSRI’s Department of Immunology and Microbial Science.

Calming the Storm

A cytokine storm is an overproduction of immune cells and their activating compounds (cytokines), which, in a flu infection, is often associated with a surge of activated immune cells into the lungs. The resulting lung inflammation and fluid buildup can lead to respiratory distress and can be contaminated by a secondary bacterial pneumonia—often enhancing the mortality in patients.

This little-understood phenomenon is thought to occur in at least several types of infections and autoimmune conditions, but it appears to be particularly relevant in outbreaks of new flu variants. Cytokine storm is now seen as a likely major cause of mortality in the 1918-20 “Spanish flu”—which killed more than 50 million people worldwide—and the H1N1 “swine flu” and H5N1 “bird flu” of recent years. In these epidemics, the patients most likely to die were relatively young adults with apparently strong immune reactions to the infection—whereas ordinary seasonal flu epidemics disproportionately affect the very young and the elderly.

For the past eight years, Rosen’s and Oldstone’s laboratories have collaborated in analyzing the cytokine storm and finding treatments for it. In 2011, led by Teijaro, who was then a research associate in the Oldstone Lab, the TSRI team identified endothelial cells lining blood vessels in the lungs as the central orchestrators of the cytokine storm and immune cell infiltration during H1N1 flu infection.

In a separate study, the TSRI researchers found that they could quiet this harmful reaction in flu-infected mice and ferrets by using a candidate drug compound to activate immune-damping receptors (S1P1 receptors) on the same endothelial cells. This prevented most of the usual mortality from H1N1 infection—and did so much more effectively than the existing antiviral drug oseltamivir, although the combination of both therapies worked even better. “That was really the first demonstration that inhibiting the cytokine storm is protective,” said Teijaro.

(Continue . . . )

 

This press release goes on to state that the experimental drug – CYM5442 – is now being tested in clinical trials, with uses that extend far beyond just influenza-related ARDS.

 

An optimized version of CYM5442, initially developed by Rosen and fellow TSRI chemist Ed Roberts, has been licensed to the pharmaceutical company Receptos. It is now in Phase 3 clinical trials for treating relapsing-remitting multiple sclerosis and Phase 2 trials for ulcerative colitis. Other S1P1 receptor agonists are in development for inflammatory conditions. A less-specific S1P receptor agonist—which hits S1P1, but also hits S1P3, S1P4 and S1P5, with potential off-target effects—is already approved for treating multiple sclerosis.

 

While it is hard to find anything `good’ to say about the emergence of novel viral threats over the past dozen years (H5N1, SARS, H7N9, etc.), it has prompted a remarkable amount of research – not only into the pathogens themselves - but into the complex and far from completely understood inner workings of our own immune system.

 

Research that has the potential to pay health benefits far beyond simply treating viral infections.

PNAS: Genetic Marker & Cytokine Levels Linked To Severity Of Human H7N9 Infection

# 8102

 

Influenza is a highly variable viral infection that can produce a wide spectrum of illness, ranging from mild or even asymptomatic presentation, to severe and/or life threatening. 

 

While we think of a patient’s age and/or co-morbidities (COPD, Asthma, pregnancy, etc. ) as being predictive of a greater chance of complications, with the 2009 Swine Flu of 2009 (H1N1) and with several strains of avian flu (H5N1, H7N9), we’ve seen young, otherwise healthy adults 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, and which were more likely to recover without incident.

 

Increasingly, scientists have been zeroing in on the Interferon-induced transmembrane protein 3 (IFITM3) protein,  whose levels are controlled by the IFITM3 gene

 

In late 2009, in The Best Defense, we looked at 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.

 

Earlier this year Nature Communications carried a study (Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals) that found that this SNP rs12252-C allele – while relatively rare in Caucasians, is much more common in Han Chinese.  The abstract makes for fascinating reading (excerpts follow):

 

Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.

 

All of which serves as prelude to a study that appeared yesterday in PNAS, that finds this IFITM3 CC gene variant (aka C/C Genotype) is linked to hypercytokinemia (aka a `Cytokine Storm’), and a severe outcome, in H7N9 infections. 

 

Briefly, 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  `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.

 

The lead author is Laureate Professor Peter C. Doherty (who shared the 1996 Nobel Prize for medicine for his work in immunology), who divides his time between St Jude Children’s Research Hospital in Memphis and the Department of Microbiology and Immunology at the University of Melbourne.

 

 

Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection

Zhongfang Wang, Anli Zhang, Yanmin Wan, Xinian Liu, Chao Qiu, Xiuhong Xi, Yanqin Ren, Jing Wang, Yuan Dong, Meijuan Bao, Liangzhu Li, Mingzhe Zhou, Songhua Yuan, Jun Sun, Zhaoqin Zhu, Liang Chen, Qingsheng Li, Zhiyong Zhang, Xiaoyan Zhang, Shuihua Lu, Peter C. Doherty, Katherine Kedzierska, and Jianqing Xu

PNAS 2013 ; published ahead of print December 23, 2013, doi:10.1073/pnas.1321748111

Significance

A unique avian-origin H7N9 influenza virus caused 134 human infections with 44 deaths. The host factors contributing to moderate vs. severe disease are not clear. Here, we show that H7N9 severity was associated with a higher level of cytokines/chemokines. We demonstrate that the cytokines in the infected lung were 100- to 1,000-fold higher than those in the plasma. Furthermore, we found that the IFN-induced transmembrane protein-3 (IFITM3) C/C genotype was associated with severe clinical outcome, as reflected by reduced time in seeking medical aid; more rapid progression to acute respiratory distress syndrome; and higher viral load, cytokine/chemokine levels, and mortality rate. Overall, our data suggest that the IFITM3 genotype is a primary driver of the observed differences in clinical outcome after H7N9 infection.

 

The entire study is available to download, and is well worth doing so.

 

It is important to note that while the variant C/C genotype was over represented among seriously ill patients (compared to its prevalence in the local population), and the C/C genotype was also linked to more rapid disease progression than with the others, that severe disease was also seen with the T/C and the T/T WT genotypes.

 

So it doesn’t mean that if you have one of the other genotypes, you are guaranteed an easy time of it.  But your odds of a bad outcome apparently go up with the C/C genotype.

 

The authors suggest that rs12252 sequencing along with the monitoring of plasma cytokines could help predict which patients would be most at risk of developing a severe, or even life-threatening, infection.

The authors also suggest that given the high frequency of the C/C genotype in China, it may be worth considering preferentially targeting that cohort for (routine,or presumably pandemic) influenza immunization. They caution, however, that `a thorough assessment of the relative risk of vaccination, as well as its protective efficacy in the C/C group, needs to be determined first.’

 

These findings may mean that anti-inflammatory drugs, or other therapies that can reign in a runaway immune response (see Study: Calming The Cytokine Storm), may prove effective in treating severe influenza.

 

And returning briefly to the Nature Communications study on the incidence of the CC genotype in Han Chinese, mentioned above, the authors compare the incidence of this genetic variant between Asian and Caucasian populations and write:

 

It is intriguing that the CC genotype⁴ is rare in Northern Europeans and common in Asian populations. As many other viral infections are restricted by IFITM3 in vitro, including severe acute respiratory syndrome (SARS) coronavirus, Dengue virus and West Nile virus^{1, 7} the high population allele frequencies may have been influenced by complex virus exposures.

<SNIP>

In conclusion, our data clearly extend the earlier observation in a European cohort that the IFTM3-rs12252CC genotype is significantly associated with influenza severity. The association is primarily with severity of disease rather than susceptibility to infection, although larger studies are required to prove this specific association. IFITM3 may have an important role in virus replication and dissemination following the initial infection. The much higher level of the CC genotype in the Han Chinese population compared with Caucasians may place the Chinese at a higher risk for developing severe illness upon influenza infection. It is not known whether those who are more severely infected with influenza virus are more likely to spread the infection. If this is the case, the high frequency of the C allele in Asian populations may influence the epidemiology of influenza.

 

Which may mean that the high morbidity and mortality rates we’ve seen with the H7N9 virus in China might be moderated somewhat, should the virus spread to populations where this genetic variant is less common.

 

Or not, as we are still in early days in understanding  how pandemic viruses behave across a diverse population.

 

A final thought, in 2006 we saw a Lancet study called Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918—20 pandemic: a quantitative analysis that found as much as a 30-fold difference in population mortality as the Spanish Flu traversed the globe.  While good records were not always kept, anecdotal reports suggest that China and India were hit many times harder than Northern Europe, or North America.

 

While a large number of variables (economic, climatic, population density, access to healthcare, diet) might well account for this, a genetic propensity towards more severe infection might have been a factor as well.

 

Questions that we’ll hopefully have much better answers for after the next severe pandemic has passed, and has been thoroughly analyzed. 

The Cytokine Storm Revisited

Credit CDC

 

 

# 7577

 

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 overwhelm 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 detected during the 2009 pandemic that was thought to be due to this overreaction of the immune system.

 

Last night Robert Roos, Editor of CIDRAP NEWS, wrote about a study that appeared this week in the American Journal of Pathology that looked at the lungs from 50 fatal cases of H1N1 during the 2009 pandemic, and their finding of "remarkably" high levels of cytokines in the lung tissue.

 

Robert does a terrific job explaining this research, so I’ll invite you to read his article at the link below. When you return, I’ll have some more background on the cytokine response.

 

Study shows cytokine storm in fatal 2009 H1N1 cases

Aug 16, 2013

Researchers who studied lung tissue samples from 50 people who died of pandemic H1N1 (pH1N1) influenza infections in 2009 say they found clear evidence that the intense immune response known as a cytokine storm played a role in their demise.

 

The scientists found that the peak levels of virus in the victims' lungs correlated with "remarkably" high levels of certain cytokines in the same tissues, according to their report, which was released ahead of print this week in the American Journal of Pathology.

(Continue . . . )

 

The abstract to the study is available at:

Cytokine and Chemokine Profiles in Lung Tissues from Fatal Cases of 2009 Pandemic Influenza A (H1N1

Role of the Host Immune Response in Pathogenesis

Rongbao Gao, Julu Bhatnagar, Dianna Blau, Patricia Greer, Dominique C. Rollin, Amy M. Denison, Marlene Deleon-Carnes, Wun-Ju Shieh, Suryaprakash Sambhara, Terrence M. Tumpey, Mitesh Patel, Lindy Liu, Christopher Paddock, Clifton Drew, Yuelong Shu, Jacqueline M. Katz, Sherif R. Zaki

 

 

While influenza can strike people of any age, it generally exacts its greatest toll on the elderly – those over the age of 65 - whose weaker immune systems (and comorbidities) can render them less able to fight off an infection.

 

Exact numbers are unknown, since influenza is only rarely cited as the primary cause of death. If a cause of death (beyond`natural causes’) is given, comorbidities like COPD, heart disease, asthma are far more likely to listed on a death certificate.

 

Still, estimates are that 90% of seasonal flu mortality occurs in those over the age of 65 (cite CDC Pink book).

 

In 2010, (see Study: Years Of Life Lost Due To 2009 Pandemic), researchers estimated the median age of death due to seasonal influenza-related illness in the United States to be 76.

 

In contrast, pandemic influenza strains, at least during the first few years after their introduction, often produce a dramatic `age shift’ downward in mortality. 

 

The CDC’s estimate of average and median age of death due to the 2009 Pandemic virus reads:

 

Based on two CDC investigations of confirmed 2009 H1N1-related deaths that occurred during the spring and fall of 2009, the average age of people in the U.S. who died from 2009 H1N1 from April to July of 2009 was 40. The median age of death for this time period was 43. From September to October of 2009, the average age of people in the U.S. who died from 2009 H1N1 was 41, and the median age was 45.

 

An even more pronounced `age shift’ was observed during the 1918 Spanish Flu, which exacted its heaviest toll among those aged 25 to 34 – an age group that would normally be expected to weather the illness better than any other.

 

The infamous `W shaped curve’ of the 1918 pandemic clearly shows that the death rates among those in their teens, 20s, and 30s was much higher than was normally seen in previous influenza years. Those over the age of 65, however, saw a reduction in mortality during the pandemic.

 

Similarly, the H5N1 avian flu virus has shown a disturbing predilection for younger victims, as illustrated by the following chart showing the ages of H5N1 cases in China over the past decade (see WHO Perspective Human infections with avian influenza A(H7N9) virus in China: preliminary assessments of the age and sex distribution).

.

 

Although not universally embraced, the Cytokine Storm theory has been adopted by many researchers as the most likely reason why the young, and healthy – those with presumably the most robust immune systems – would suffer disproportionately with some pandemic flu strains.

 

Somewhat surprisingly, we haven’t seen this age shift during the first wave of H7N9 avian flu cases in China this spring.  We’ll have to see if this trend continues if, and when, the virus re-emerges.

 

 

 

As you can imagine, many researchers and doctors are looking for effective ways to safely dampen runaway immune responses as a possible treatment for pandemic influenza.

 

This is particularly important as most of the world would have little hope of seeing a vaccine for a pandemic flu during the first year or two of its arrival.

 

Dr. David Fedson – former Professor of Medicine at the University of Virginia School of Medicine and formerly Director of Medical Affairs, Aventis Pasteur MSD - has long championed the idea that we should be looking at statins for pandemic flu, which he believes may help modulate the immune response.

 

If they can be proved effective, statins have the advantage of being cheap, easy to manufacture and distribute, and have relatively few side effects.

 

The problem is, while some studies on statins and pneumonia have yielded promising results, not all of the research is in agreement. Complicating matters, since many statins are now generic, there is little financial incentive for drug companies to fund expensive research.

 

You can read about the potential for statin therapy in the blogs below.

 

Study: Statins, Influenza, & Mortality

Another Study On Statins And Pneumonia

Dr. David Fedson: The Case For Using Statins In A Pandemic

Statins Revisited

 

There are other approaches under investigation as well. 

 

In 2011, in Study: Calming The Cytokine Storm, we looked at research from The Scripps Research Institute  that found a protein located on the surface of endothelial cells, called S1P1, to be largely responsible for flu-associated cytokine storms.

 

While a specific drug to target this protein is likely a long way off, their discovery provides new avenues for research into dampening the cytokine response.

 

This latest study in the American Journal of Pathology provides some of the strongest evidence we’ve seen on the impact of cytokine production in the pathogenesis of influenza.

 

Results that will likely spur additional interest in finding ways to moderate the cytokine storm.

 

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 from 2009.

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt.3

Nature: Biological Features Of H7N9

Credit CDC

 

 

# 7444

 

 

A study, published today in the Journal Nature, provides new insights into the H7N9 avian flu virus which emerged on the Chinese mainland earlier this spring, and suggests that should it return this winter, it could prove a far more formidable foe than than has H5N1 to date.

 

Chinese researchers, looking both at the virus in the laboratory, and at patient responses to infection, have concluded that this virus `poses a potentially high risk to humans.’.

 

Among their findings:

 

• Unlike the H5N1 virus – which binds preferentially to avian receptor cells (a2,3-linked sialic acid) -  H7N9 binds to both the avian and human (a2,6-linked sialic acid) receptor cells.

• This dual receptor cell binding ability likely enhances the virus’s ability to transmit from birds to humans.

• The virus appears to replicate well in the lower human respiratory tract - but less well in the trachea – which may have helped to limit its ability to spread from human-to-human.

• Once infected, the virus often produces severe illness in humans, and patients tested showed increased serum levels of chemokines and cytokines, suggesting the possibility of infection inducing a `cytokine storm’.

• There appears to be little  or no community immunity to H7 viruses.

 

 

First, a link to the letter in Nature (the abstract is available, but the whole letter is behind a pay wall). Given the barebones nature of the abstract, I’ll return with a little more background on some of their findings.

 

Biological features of novel avian influenza A (H7N9) virus

Jiangfang Zhou1*,DayanWang1*,RongbaoGao1*, Baihui Zhao2*, Jingdong Song1,XianQi3 ,Yanjun Zhang4, Yonglin Shi 5, LeiYang1, Wenfei Zhu1, Tian Bai 1,KunQin1, Yu Lan1, Shumei Zou1, JunfengGuo1, JieDong1 , LiboDong1 ,Ye Zhang1, HejiangWei 1, Xiaodan Li 1, Jian Lu1 , Liqi Liu1 , Xiang Zhao1, Xiyan Li 1, Weijuan Huang1, LeyingWen1 ,HongBo1 , Li Xin1, Yongkun Chen1 , Cuilin Xu1, Yuquan Pei 6,YueYang6 , Xiaodong Zhang6, ShiwenWang1,  Zijian Feng7 , JunHan7 ,Weizhong Yang7, George F. Gao7 , GuizhenWu1 ,Dexin Li 1, Yu Wang7 & Yuelong Shu1

 

 

Highlighting a few points raised by this study.

 

The authors note that H7N9:`. . .can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli . . ‘.

 

Pneumocytes (aka pneumonocytes) are a collective term for the two types of cells lining the alveoli (the air sacs) in the lung; Type I and Type II pneumocytes.

 

• Type I pneumocytes are responsible for the gas exchange (02 and C02) between the lungs and the blood stream.  Type I pneumocytes are easily damaged and cannot reproduce themselves.

• Type II pneumocytes are responsible for the production of surfactant, which reduces the surface tension of pulmonary fluids and contributes to the elasticity of the lungs.  

• Type II pneumocytes are able to replicate in the alveoli and can create new Type I pneumocytes.

 

A loss of type II pneumocytes can severely degrade the lungs ability to fight off an infection, and to repair damaged tissue. Earlier studies have demonstrated tropism for, and destruction of, type II pneumocytes by the avian H5N1 virus.

 

While still only partially understood, the idea behind a `cytokine storm’ is that the host’s immune system goes into overdrive, producing excessive levels of cytokines that can provoke damaging inflammation in the lungs.

 

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.

 

You can find more on this theory in these earlier posts:

 

Study: Calming The Cytokine Storm

Cytokine Storm Warnings

The Baskin Influenza Pathogenesis Study

Pt. 1               Pt. 2             Pt. 3

 

Another finding (across all age groups tested) was a lack of pre-existing immunity to the H7N9 virus, and that the current seasonal vaccine conveyed absolutely no protection.

 

As we’ve discussed earlier, while work is underway on creating seed strains for an H7N9 vaccine, getting one through the testing and manufacturing process and into the arms of hundreds of millions of people, is unlikely to happen in the near term (see JAMA: Challenges Of Producing An Effective & Timely H7N9 Vaccine).

 

For now, the saving grace with this virus is its apparent inability to spread efficiently from human-to-human. But should that change, the world could find itself facing a particularly nasty pandemic threat.

Bats, Viruses, And Their Immune Response

Common pipistrelle (Pipistrellus pipistrellus) – Credit Wikipedia

 

# 6797

 

 

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.

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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

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.

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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.

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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.

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.

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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