Cell: Immunopathogenesis of Lethal H5N1 Avian influenza Virus Clade 2.3.4.4b Infection in Macaques

 
Credit Cell Immunity

#18,843

In 2009 we took a deep (3 blog) dive into a landmark PNAS study - Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al. - which compared the pathogenesis of an older (2004) H5N1 virus, seasonal flu, and with two altered viruses carrying genetic material from the 1918 Spanish Flu in macaques. 

The key finding from this study was that severe morbidity and mortality in macaques infected with H5N1 was linked to a  severe `Cytokine storm'; a strong, early, and sustained innate immune response, marked by elevated pro-inflammatory cytokines and severe lung damage (notably, apoptosis of dendritic cells). 

 

As we've discussed previously, the HPAI H5N1 viruses circulating today are a far cry from the clades and variants that circulated in the early 2000's. They've evolved into new clades and subclades, and have reassorted into numerous genotypes (and subtypes).

The Cambodian clade 2.3.2.1e H5N1 virus appears to produce a nearly 50% CFR (case fatality rate), but the U.S. clade 2.3.4.4b `bovine' B3.13 genotype has a reputation for producing relatively mild symptoms in humans (primarily conjunctivitis, mild fever, cough, and mild flu-like symptoms).

This B3.13 genotype encompasses a wide range of variants, including at least one isolate (huTX37-H5N1) which carried the PB2-E276K mutation (glutamic acid → lysine at position 627), which is associated with increased mammalian adaption and pathogenicity.   

While there are undoubtedly other amino acid changes (e.g. HA-T143A, PB2 D701N, PB2 Q591K, HA Q226L, etc.) that could increase the pathogenicity of HPAI H5N1, the E627K mutation is always at or near the top of the list.

All of which brings us to a new study, published yesterday in Cell Immunity, which revisits the pathogenicity of the new bovine B3.13 genotype (with E627K) in two types of macaques (Cynomolgus and Rhesus). 

This lengthy, and at times technical, report finds that the `mild' bovine B3.13 genotype - when aided and abetted by the PB2-E627K mutation - can be every bit as deadly in macaques as the older H5N1 viruses from Vietnam the mid 2000s.  

It also finds - much like we saw in 2009 - that ` . . . acute inflammation, cytokine storm, and immune dysregulation are hallmarks of H5N1 disease pathogenesis in both cynomolgus and rhesus macaques.'

For now, E627K remains rarely reported in the B3.13 genotype of H5N1, but it has turned up in other genotypes, including the D1.1 genotype variant which caused severe infections in both Canada and the United States. 

Due to its length I've only posted the abstract, and a few excerpts.  Follow the link to read the full report in its entirety.  I'll have a brief postscript after the break. 

Immunopathogenesis of lethal H5N1 avian influenza virus clade 2.3.4.4b infection in macaques
Hanne Andersen1 ∙ Malika Aid2 ∙ Jonathan J. Stone3 ∙ … ∙ Mark G. Lewis1 ∙ Amanda J. Martinot3 ∙ Dan H. Barouch2,6,7 dbarouch@bidmc.harvard.edu
Published online August 18, 2025
DOI: 10.1016/j.immuni.2025.07.020

Highlights

• Cynomolgus macaques developed lethal H5N1 influenza pneumonia
• Rhesus macaques demonstrated dose-dependent H5N1 influenza mortality
• Surviving animals were protected against high-dose re-challenge
• H5N1 influenza was characterized by severe inflammation and immune exhaustion

Summary

The H5N1 avian influenza virus clade 2.3.4.4b outbreak represents a major pandemic threat for humans, with some reported cases of severe and fatal respiratory illness. A key unanswered question is the pathogenesis of severe H5N1 disease following respiratory infection.

In this study, we explored mechanisms of pathogenesis of severe H5N1 disease in cynomolgus and rhesus macaques following infection with the H5N1 isolate A/Texas/37/2024 (huTX37-H5N1). Cynomolgus macaques developed severe pneumonia that was lethal in 100% of macaques by 7 days post-infection. By contrast, rhesus macaques demonstrated dose-dependent mortality, and surviving animals showed protective immunity against high-dose re-challenge.

A multi-omics analysis demonstrated that H5N1 infection was characterized by robust induction of proinflammatory cytokines, innate immune cells, complement, coagulation, apoptosis, and immune exhaustion pathways.

Taken together, our data indicate inflammation and immune dysregulation as key mechanisms of H5N1 pathogenesis in nonhuman primates.

        (SNIP) 

Discussion

In this study, we observed that huTX37-H5N1 infection of cynomolgus and rhesus macaques by the respiratory route resulted in severe and rapidly progressive consolidative necrotizing pneumonia across a broad range of challenge doses. Infection was lethal in 100% (24 of 24) of cynomolgus macaques and in 33% (3 of 9) of rhesus macaques in the titration studies.

Lung consolidation was also more extensive and severe in cynomolgus macaques than in rhesus macaques. Transcriptomic profiling showed enrichment of proinflammatory and immune exhaustion pathways following challenge as well as reduction of NK, T, and B cell activation pathways and increased expression of T cell exhaustion markers, particularly in cynomolgus macaques.

These findings suggest that acute inflammation, cytokine storm, and immune dysregulation may be key contributors to the pathogenesis of H5N1 severe disease.

(SNIP)

In summary, our data demonstrate severe clinical disease with H5N1 clade 2.3.4.4b in cynomolgus and rhesus macaques when inoculated by the respiratory route, particularly in cynomolgus macaques. Although most human cases have been mild, several cases of severe and critical respiratory disease in humans have been reported, suggesting the importance of understanding the pathogenesis of severe H5N1 disease.

Our findings define key features of pathogenesis and immunity to H5N1 clade 2.3.4.4b infection in cynomolgus and rhesus macaques. Future studies could define the role of T cell responses and T cell exhaustion for H5N1 disease pathogenesis. Moreover, these models of H5N1 infection in nonhuman primates should prove useful in evaluating candidate vaccines and therapeutics.

Limitations of the study

This study is limited to the evaluation of one strain of H5N1 influenza in rhesus and cynomolgus macaques, and it is possible that other H5N1 strains may have different characteristics. Moreover, the pathogenicity of H5N1 influenza in macaques may differ from that in humans, potentially because of higher inoculation doses and different challenge routes. In addition, this study involves an H5N1 isolate with the human adaptation mutation PB2-E627K as a model for severe disease. This mutation is currently rare in bovine H5N1 isolates, and thus it is possible that future human infections will have other adaptation mutations.

        (Continue . . . )

Interestingly, while cynomolgus and rhesus macaques are closely related primate species - and are both used in biomedical research - there are some key differences which may  help explain the higher mortality in cynomolgus macaques over rhesus. 

• Cynomolgus macaques tend to be slightly smaller than rhesus macaques, and are generally easier to handle (less aggressive).

• Cynomolgus macaques tend to have smaller lungs - and more abundant avian-like α2,3 receptors in their lower respiratory tract - which may lead to more severe pneumonia 

• Influenza viruses tend to produce higher fever and more acute inflammatory cytokines in cynomolgus versus rhesus monkeys

While neither species likely serve as ideal analogs for human exposure to H5N1, they do provide us with a sobering range of non-human primate responses to infection with this specific H5N1 B3.13 isolate. 

But most of all, this study reaffirms that our currently mild `bovine' genotype may only lack one or two crucial fixed mutations to make it a genuine public health concern. 

Assuming that some other clade/genotype doesn't get there first. 

mBio: The Pathogenicity Of Avian H7N9 In Cynomolgus Macaques

Credit CDC

 

# 8944

 

The open access journal mBio today has published a study today looking at the replication, and pathogenicity of, the avian H7N9 virus in both the upper and lower respiratory tracts of cynomolgus macaques. 

 

Although ferrets and other non-primate animals are often used for influenza transmission  research, when you want to study the pathogenicity of a virus, non-human primates offer the closest analog to humans.

The   Wisconsin National Primate Research Center explains the rationale behind their use:

Why use macaques?

Macaques are genetically very similar to humans. They especially share analogous neurological, reproductive and immunological systems with humans. Rhesus and cynomolgous macaques are not endangered in the wild and adapt well to captive housing. Research with rhesus and cynomolgous monkeys, as well as with other nonhuman primates, tells us a great deal about primate biology. Animal studies can be better controlled and can garner more consistent results than human studies, and are often precursors to human studies.

 

Shortly after the outbreak of H7N9 in Eastern mainland China in the spring of 2013 we learned of some of the research studies that were quickly set in motion to better understand this emerging avian flu virus (see ScienceInsider: Laboratory Plans For H7N9 Virus).

 

At that time we knew little about the pathogenicity and transmissibility of the virus in humans, and a top stated priority was to test H7N9 on a variety of lab animals, including ferrets and cynomolgus macaques.

Since then, we’ve seen a steady procession of studies, many of which have suggested that the H7N9 virus – perhaps more than any other avian influenza virus we’ve seen to date – has worrying pandemic potential.

 

• Last year we saw studies suggested H7N9 is unusually well-adapted to mammalian physiology (see mBio: H7N9 Naturally Adapted For Efficient Growth in Human Lung Tissue)  – but thus far this virus has failed to demonstrate the ability to transmit efficiently among humans.
• Last May, in  EID Journal: H7N9 As A Work In Progress, we looked at a study that found the H7N9 avian virus continues to reassort with local H9N2 viruses, making the H7N9 viruses that circulated in wave 2 genetically distinct from those that were seen during the 1st wave.
• While last June, in Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission, we saw even more evidence of the genetic diversity, and continual evolution, of the H7N9 virus in Mainland China.  Researchers found that at least 26 separate genotypes had emerged, mostly during the first wave, through a process they called `genetic tuning’.

 

While this virus is apparently on summer hiatus, few expect it to remain so once temperatures begin to decline this fall and winter.  Last winter’s outbreak came after an exceptionally quiet summer, and was twice the size of the first wave.

 

All of which makes learning as much as we can about the pathogenicity, and pandemic potential, of this virus a high priority. 

 

Influenza Virus A/Anhui/1/2013 (H7N9) Replicates Efficiently in the Upper and Lower Respiratory Tracts of Cynomolgus Macaques

Emmie de Wit^a, Angela L. Rasmussen^b, Friederike Feldmann^c, Trenton Bushmaker^a, Cynthia Martellaro^a, Elaine Haddock^a, Atsushi Okumura^b, Sean C. Proll^b, Jean Chang^b, Don Gardner^c, Michael G. Katze^b,d, Vincent J. Munster^a, Heinz Feldmann^a,e

ABSTRACT

In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection.

Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat.

Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication.

Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277–2285, 2013, doi:10.1056/NEJMoa1305584).

 

Curiously, while more pathogenic to macaques than most strains of the 2009 H1N1 pandemic virus, and seasonal H3N2, the H7N9 virus produced less severe symptoms in these non-human primates than has been common observed in humans. 

 

The authors suggest that the high rate of co-morbidities in the – mostly elderly – cohort of cases in China could explain this difference.  

 

And indeed, the chart below from Dr. Ian Mackay’s VDU Blog shows a pronounced demographic shift towards older, predominantly male, victims in China. Children, and young adults – when they were found to be infected – were more likely to have mild, moderate, or even asymptomatic infections (see Mild Influenza A/H7N9 Infection among Children in Guangdong Province).

 

Compared to infection with the 1918 H1N1 and H5N1 avian flu viruses (see my three part review of the 2009 Baskin Influenza in Primates Study), H7N9 produced far less lung damage and illness in macaques. 

 

You’ll want to read the entire study for details on methods and materials, and a closer look at the results.   In their concluding remarks, the authors summed up their work by saying:

 

Thus, the emerging H7N9 influenza virus is more pathogenic than seasonal influenza A virus and most isolates of the pandemic H1N1 virus but not as pathogenic as the 1918 Spanish influenza virus and HPAI H5N1 virus in cynomolgus macaques.

However, the pathogenicity of the H7N9 virus may decrease if the virus adapts further to solely using α2,6-linked sialic acids as the receptor for entry, as pandemic influenza viruses to date have done (52–55).

Exclusive attachment to α2,6-linked sialic acids would most likely result in a shift to replication mainly in the upper respiratory tract of humans, likely resulting in less severe disease, as has been described for the 2009 pandemic H1N1 virus (56) and upon adaptation of HPAI H5N1 virus to efficient transmission via respiratory droplets or aerosols (57).

 

The switch to an `exclusive attachment to α2,6-linked sialic acids’  is one of the evolutionary changes that is believed would make this virus far more easily transmitted between humans, and is probably required if  H7N9 were to become a viable pandemic virus.

 

And while a commensurate decrease in severity would be a welcome result, it is worth noting that a reduction of even a full order of magnitude (30% CFR down to 3%) would still put this virus in the same league as the 1918 Spanish flu.

 

While the tragedy of Ebola has captured the world’s attention this summer, the most serious pandemic threats are those posed by respiratory viruses, such as influenza, SARS, and MERS.

Details & Background On the H5N2 Poultry Outbreak In Hebei Province

Photo Credit CRIENGLISH

 

# 8099

 

 

When it comes to variety, avian influenzas come in more flavors than you’ll find in a Baskin-Robbins store. Which explains  why in the past couple of months our attentions have been divided between H5N1 in Cambodia and Indonesia, H7N9 in Mainland China, an upstart H10N8 (again in China), and now H5N2 in Hebei Province, China.

 

While we worry most about H5N1 and H7N9 – primarily because both have been shown to produce severe illness and even death in humans – all H5 and H7 varieties are of concern, since these subtypes have a history of morphing from low-pathogenic strains to highly pathogenic strains if not controlled.  

 

Which is why all H5 and H7 outbreaks are reportable to the OIE, and quarantine and immediate culling are the preferred course of action.

 

Yesterday China reported an outbreak of H5N2 at a poultry farm in Baoding City, Hebei Province.  Reports today indicate that more than 120,000 birds have been culled, and that 11 people who were in direct contact with the poultry have been placed in isolation (and probably given Tamiflu ®), but none have shown signs of infection.

 

First a report from Sina  News, then I’ll be back with more on the history of H5N2

 

Hebei people infected with H5N2 bird flu yet (Alt Translation Hebei infection of H5N2 avian flu nobody has yet been)

CNA (2013-12-22 18:18)

(CNA Taipei 22 (Xinhua)) Hebei Baoding Nanshiqu officials said today, raising the local chicken farm H5N2 bird flu has been effectively controlled occurred, 11 were in direct contact with the relevant chickens were isolated observation, it was not found infected.

China News Service reported, Baoding Nanshiqu Agriculture Secretary Zhang Guang pointed out that, in addition to the above measures, culling chickens participating Nanshiqu work were monitored twice daily, were not unusual. Meanwhile, the official has the region's comprehensive agricultural and sideline products and fragmented market of live poultry trade to clean up and banned.

Zhang also said that the official and farm stocks of eggs into the marketing ruin handling , disposal of tracing the source of the product sold. Meanwhile, the live poultry within 3-5 km range chicken farm near the outbreak, have been carried out culling.

H5N2 outbreak was discovered south downtown Baoding Zhu Village tiger phoenix chicken farm was built in 1992, is a self-employed business , keeping more than 120,000 laying hens only, no chickens. 4000 chickens on the 17th because the epidemic of death was November 27 to buy from overseas. 1021222

 

It should be noted that we’ve seen both HPAI (Highly pathogenic) and LPAI (Low Pathogenic) H5N2 outbreaks in the past, notably in Taiwan, Canada, the United States, Korea, Japan, and Mexico.

 

The isolation (and usually, antiviral treatment) of those who have been in direct contact with infected birds is standard procedure, and should not be viewed as being particularly alarming.  While not normally thought of as a serious threat to public health (see WHO: Human Risk From H5N2 Is Low), we have seen some limited evidence of H5N2’s ability to infect humans in recent years.

 

Eighteen months ago, in Taiwan: Three Poultry Workers Show H5N2 Antibodies, we looked at a report that three poultry workers and officials working in animal quarantine have tested positive for antibodies for the H5N2, but all remained healthy and asymptomatic (note: refer to article for other possible causes of seropositivity)..  

 

Some earlier H5N2 studies include:

 

J Epidemiol. 2008;18(4):160-6. Epub 2008 Jul 7.

Human H5N2 avian influenza infection in Japan and the factors associated with high H5N2-neutralizing antibody titer.

Ogata T, Yamazaki Y, Okabe N, Nakamura Y, Tashiro M, Nagata N, Itamura S, Yasui Y, Nakashima K, Doi M, Izumi Y, Fujieda T, Yamato S, Kawada Y.

Arch Virol. 2009;154(3):421-7. Epub 2009 Feb 3.

Serological survey of avian H5N2-subtype influenza virus infections in human populations.Yamazaki Y, Doy M, Okabe N, Yasui Y, Nakashima K, Fujieda T, Yamato S, Kawata Y, Ogata T.

 

While these reports are suggestive of prior H5N2 human infection – particularly among poultry workers – we haven’t seen any good evidence that it has produced significant or serious human illness. 

 

The caveat being, that up until the emergence of H7N9 in March of this year, H7 avian flu viruses had been generally regarded as posing a minor threat to human health, and until this past week, we’d never seen a human infection with the H10N8 virus.

 

With influenza viruses, the only constant is change.  What may be relatively benign today, may become virulent or increase its host range tomorrow.

 

Which makes the rapid and intense response to bird flu outbreaks  – such as we are seeing  with H5N2 in China right now – the prudent course of action.

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,...

(Continue . . . )

 

 

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

BMC: Exploring The `Age Shift’ Of Pandemic Mortality

 

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.

 

# 6778

 

Seasonal influenza can strike people of any age, but exacts its greatest toll on the elderly – those over the age of 65 – whose weaker immune systems (and comorbid conditions) often render them less able to fight off the infection.

 

Exact numbers remain elusive, 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.

 

Admittedly, younger fatalities are more likely to be investigated, and documented, than those that occur among the elderly, but still . . . this is a significant shift.

 

And it corresponds closely to the results of the Years Of Life Lost Study mentioned above, which found the mean age of death from the novel H1N1 virus to be half that of seasonal flu, or 37.4 years.

 

In terms of years of life lost (YLL), the average pandemic flu death has a many fold greater impact than the average seasonal flu fatality.   

 

This same pattern was repeated (to greater and lesser degrees) during the 1918, 1957, and 1968 pandemics  . . .  along with the 1977 return of the H1N1 virus after an absence of 20 years.

 

All of which has led to a good deal of speculation.

 

What drives this age shift?  Why were apparently healthy, younger flu victims, with robust immune systems more likely to die from pandemic flu?

 

Although not universally accepted, one popular theory has centered around the production of a `cytokine storm’, which is believed to be the product of a robust immune system typically found in younger, healthier individuals.

 

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 site of infection, that if it races out of control, can literally kill the patient.

 

The patient’s 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.

 

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 theory has held that older populations are more likely to have been exposed to a similar influenza strain in the past and are more likely to carry some level of immunity to the emerging pandemic strain.

 

This was clearly the case in 1977, when the H1N1 virus – supplanted by the H2N2 virus in 1957 – made an unexpected comeback.  Those born after the virus last circulated in the mid 1950s – were the hardest hit age group.

 

Again with the 2009 H1N1 pandemic virus, those born before the early 1950s appeared to have higher levels of immunity, resulting in fewer severe outcomes among older individuals.

 

All of which serves as prelude to a research article, published yesterday in BMC Medicine, that looks at the age shift during pandemic outbreaks.

 

The age distribution of mortality due to influenza: pandemic and peri-pandemic

Tom Reichert, Gerardo Chowell and Jonathan A McCullers

Background

Pandemic influenza is said to 'shift mortality' to younger age groups; but also to spare a subpopulation of the elderly population. Does one of these effects dominate? Might this have important ramifications?

Methods

We estimated age-specific excess mortality rates for all-years for which data were available in the 20th century for Australia, Canada, France, Japan, the UK, and the USA for people older than 44 years of age. We modeled variation with age, and standardized estimates to allow direct comparison across age groups and countries. Attack rate data for four pandemics were assembled.

Results

For nearly all seasons, an exponential model characterized mortality data extremely well; For seasons of emergence and a variable number of seasons following, however, a subpopulation above a threshold age invariably enjoyed reduced mortality. 'Immune escape', a stepwise increase in mortality among the oldest elderly, was observed a number of seasons after both the A(H2N2) and A(H3N2) pandemics. The number of seasons from emergence to escape varied by country. For the latter pandemic, mortality rates in four countries increased for younger age groups but only in the season following that of emergence. Adaptation to both emergent viruses was apparent as a progressive decrease in mortality rates, which, with two exceptions, was seen only in younger age groups. Pandemic attack rate variation with age was estimated to be similar across four pandemics with very different mortality impact.

Conclusions

In all influenza pandemics of the 20th century, emergent viruses resembled those that had circulated previously within the lifespan of then-living people. Such individuals were relatively immune to the emergent strain, but this immunity waned with mutation of the emergent virus. An immune subpopulation complicates and may invalidate vaccine trials. Pandemic influenza does not 'shift' mortality to younger age groups; rather, the mortality level is reset by the virulence of the emerging virus and is moderated by immunity of past experience. In this study, we found that after immune escape, older age groups showed no further mortality reduction, despite their being the principal target of conventional influenza vaccines. Vaccines incorporating variants of pandemic viruses seem to provide little benefit to those previously immune. If attack rates truly are similar across pandemics, it must be the case that immunity to the pandemic virus does not prevent infection, but only mitigates the consequences.

The complete article is available as a provisional PDF.

 

The entire article is worthy of your attention, and the authors delve into a good many areas, including future pandemic mitigation planning, and vaccine strategies. 

 

But essentially the authors propose that all recent influenza pandemics (over the past century) have involved `recycled’ flu strains to which some portion of the population had previously been exposed to.

 

They conclude:

Pandemics do not ‘shift’ mortality to younger ages

From this study, it is evident that pandemics do not ‘shift’ mortality to younger ages. Rather, the
entire mortality level is simply reset to the virulence level of the emergent virus. This reset is accompanied by immunoprotection in older age groups, which is determined by their level of previous experience with viruses similar to that emerging. 

 

In other words, were older populations not carrying some vestiges of immunity from previously flu encounters, these researchers suggest they would suffer the same levels (or higher) of mortality and morbidity as do younger populations.

 

The authors also point out that initial levels of immunity to emerging (or more properly, re-emerging) influenza viruses in older populations tends to wane in subsequent seasons, leading to what they call Immune Escape: `a stepwise increase in mortality among the oldest elderly’.

 

Does this blow the whole cytokine storm theory out of the water?

 

Not necessarily, although it does call into question just how much of an impact it has on the perceived `age shift’ in pandemic flu cases.

 

These two theories need not be mutually exclusive, however, and so I wouldn’t rule out the possibility that both may play a part in driving pandemic mortality demographics.

Study: Initial Flu Dose Dictates Immune Response

 

H3N2 influenza virions –CDC PHIL

 

# 6408

 

There’s a popular belief that once you’ve had a particular strain of the flu, your body’s immune system will protect you against it in the future. And under the right circumstances, that’s true.

 

But human physiology and its immune response is rarely as simple, and straightforward, as that.

 

Our immune systems vary considerably from one person to the next, and within a single individual, can change  radically over time. We’ve also discovered that some flu viruses leave a stronger `imprint’ on our immune system, than others.

 

Both of these factors can influence how strong . . . and how long lasting . . . any acquired immunity to a flu virus might be.

 

Which is one of the reasons why the CDC reminds us to get a flu shot every year, since the immunity from last year’s vaccine (or a bout with the flu) may have diminished over time – even if the same flu strains remain in circulation.

 

Now a study, published today in Journal of Leukocyte Biology, looks at another variable in influenza infection that appears to influence the type, and strength, of the immune response (at least in mice).

 

The initial viral dose.  The study is called:

 

Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract

Isabelle Marois, Alexandre Cloutier, Émilie Garneau and Martin V. Richter

Abstract

Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection.

(Continue . . . )

 

In this experiment, researchers infected two groups of mice – one with a low dose and one with a high dose –of influenza A (H3N2), and then gauged various aspects of their immune response. Later, they exposed these mice to a different strain of flu to see what, if any, immune response was `left over’ from the initial infection.

 

As I’ve cautioned before, mouse models are often very useful in laboratory research, but what happens with mice doesn’t always correspond to what happens with human physiology. 

 

Still, they came up with some intriguing results. They found that the larger the initial infectious dose, the greater, broader, and longer-lived was the immune response.

 

The full study is behind a pay wall, but we’ve got a press release (slightly reparagraphed for readability) from the Federation of American Societies for Experimental Biology that provides the broad strokes to this research.

 

Flu immunity is affected by how many viruses actually cause the infection

New research published in the Journal of Leukocyte Biology suggests that the immune response differs depending on the amount of virus received during infection

Bethesda, MD—Not only does the type of flu virus affect a patient's outcome, but a new research report appearing in the Journal of Leukocyte Biology suggests that the number of viruses involved in the initial infection may be important too.

 

Scientists from Canada found that when mice were infected by relatively high concentrations of the flu virus, they not only developed immunity against the virus that infected them, but this also promoted the generation of a type of immune cell in the lungs poised to rapidly react against infections with other strains of the flu, as well.

 

Mice that were infected with a relatively low concentration of the virus developed weaker immunity against the strain that infected them, did not build up this crucial population of immune cells in the lungs, and showed only delayed immunity toward other flu strains.

 

This discovery could pave the way for new prophylactic strategies to fight flu infections and provides a novel basis for vaccine design.

 

"Hopefully, the findings of our study will help to develop better vaccine preparations that will be more effective in inducing protective cellular immunity to fight against infectious pathogens such as bacteria, viruses and fungi," said Martin V. Richter, Ph.D., the lead researcher involved in the work from the Department of Medicine at the Université de Sherbrooke and Centre de Recherche Clinique Étienne-Le Bel in Québec, Canada.

 

(Continue . . . )

 

 

While both are complex and multifaceted, our immune systems can be divided into two types of protection.

 

We have natural immunity – so called `innate immunity’ – that can detect, and launch a generic defense against a wide variety of invading pathogens

 

Were it not for this built-in immunity, none of us would survive past the first few hours or days of life; we'd be quickly overrun by opportunistic infections.

 

Innate immune system buys us time for our Adaptive Immune System to learn to recognize and fight specific pathogens.

 

The adaptive immune system produces pathogen-specific antibodies that can remember previous encounters with a virus, and provides us with varying degrees of acquired immunity.

 

For more information on some of the complexities of our immune system, you may wish to revisit some of these earlier blog posts.

 

 

Study: Vitamin D And The Innate Immune System

GM-CSF: An Innate Ability To Fight Flu

Cytokine Storm Warnings

PAMP and Circumstance

 

And for a fascinating look at 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 pathogenesis study from 2009.

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

A Little Background On H11 Avian Influenzas

 

 

 

 

# 5204

 

 

Overnight news of an avian H11N1 virus, detected in an Eurasian Spoonbill in India, crossed the wires.  While not exactly startling news, it is interesting.

 

First a little background (feel free to skip ahead if this is familiar territory), then more on this finding. 

 

Fair warning: I’ll have to keep this simple, so I can understand it.  Real experts may wish to avert their eyes . . .

 

 

Influenza A viruses have 8 gene segments (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2) and are broadly categorized by their HA (hemagglutinin) and NA (neuraminidase) genes.

 

Scientists have identified 15 16 different serotypes of Hemagglutinin (HA) and 9 serotypes of Neuraminidase (NA), which could theoretically yield 144 different HA/NA combinations.

Just over 100 have actually been isolated in nature.

 

But the flu universe is actually far more diverse than that might lead to you believe, since influenza’s 8 gene segments are largely interchangeable parts.

 

If you were to take two different influenza A viruses (say H3N2 and H5N1) and reshuffle them using reverse genetics, you can come up with 254 possible reassortments.

 

 

 

In fact, this has been done in the laboratory, as I detailed nearly a year ago in PNAS: H3N2 And H5N1 Reassortment.

 

Admittedly, many of these combinations might never occur naturally, but they do illustrate the potential that influenza has for generating reassortments.

 

And none of this begins to  consider the thousands of potential single amino acid substitutions that can further `customize’ a viral strain.

 

This mixing and matching of influenza viruses goes on constantly in nature, and while most of these combinations don’t turn out to be `biologically fit’, and are therefore evolutionary dead ends – more than a few prove competitive and capable of spreading.

 

Which brings us to today’s report in the Times of India.

 

H11N1 strain isolated in one Eurasian Spoonbill: Report

Neha Madaan, TNN, Jan 4, 2011, 06.57am IST

 

 

While H11 avian viruses have been detected in aquatic birds in other parts of the world, this is the first time it has been found in India.  And this particular H11N1 is – according to this report – a new reassortment, distinct from other H11N1’s detected elsewhere around the world.

 

Proof once again that nature’s laboratory is open, and operating, 24/7.

 

H11 viruses have been known to infect humans, although how often this happens is completely unknown.   Like many avian viruses, H11 is thought to produce only mild symptoms, and is therefore likely to go undetected. 

 

A fascinating bit of research, published in 2006 in the CDC’s EID Journal , looked for avian influenza antibodies in duck hunters and wildlife professionals.

 

Avian Influenza among Waterfowl Hunters and Wildlife Professionals

James S. Gill,* Richard Webby,† Mary J.R. Gilchrist,* and Gregory C. Gray‡
*University of Iowa Hygienic Laboratory, Iowa City, Iowa, USA; †St Jude Children's Research Hospital, Memphis, Tennessee, USA; and ‡University of Iowa College of Public Health, Iowa City, Iowa, USA

ABSTRACT

We report serologic evidence of avian influenza infection in 1 duck hunter and 2 wildlife professionals with extensive histories of wild waterfowl and game bird exposure. Two laboratory methods showed evidence of past infection with influenza A/H11N9, a less common virus strain in wild ducks, in these 3 persons.

 

 

While antibodies to the relatively rare H11N9 virus were detected in these 3 individuals, antibodies for the far more common H4 and H6 avian viruses (known to circulate in American ducks) were not.

 

Which leads one to ask, why not?

 

One theory is that humans are less likely to develop long-lasting antibodies when exposed to avian-type influenza viruses.  

 

In 1991, Beare and Webster published a study where 40 volunteers were inoculated with three avian influenza strains (H4N8, H6N1, and H10N7).  

 

While 11 subjects had mild clinical symptoms, none developed a detectable antibody response.

 

 

Replication of avian influenza viruses in humans.

Beare AS, Webster RG.

Clinical Research Centre, Harvard Hospital, Salisbury, Wiltshire, U.K.

Abstract

Volunteers inoculated with avian influenza viruses belonging to subtypes currently circulating in humans (H1N1 and H3N2) were largely refractory to infection. However 11 out of 40 volunteers inoculated with the avian subtypes, H4N8, H6N1, and H10N7, shed virus and had mild clinical symptoms: they did not produce a detectable antibody response.

 

This was presumably because virus multiplication was limited and insufficient to stimulate a detectable primary immune response. Avian influenza viruses comprise hemagglutinin (HA) subtypes 1-14 and it is possible that HA genes not so far seen in humans could enter the human influenza virus gene pool through reassortment between avian and circulating human viruses.

 

 

This is a theme revisited in a more recent study, the PNAS paper entitled Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al., which analyses the pathogenesis of the H5N1 virus compared to seasonal flu, and 1918-like viruses.

 

In that study, the authors found:

 

The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection.

 

In the simplest language, dendritic cells help `teach' the adaptive immune system how to recognize a virus, and are key in the creation of pathogen-specific antibodies.

 

Theoretically, a loss of dendritic cells at the site of infection (lungs) could negatively impact the body's ability to generate post-infection immunity. 

 

Even when clinical symptoms are severe.

 

You can read more about the Baskin Study in my 3-part series (Part 1, Part 2, Part 3).

 

Other possibilities as to why H11 viruses were detected in these subjects, but not the more common avian strains, include:

 

• H11 viruses may be more able to infect humans
• H11 viruses may induce a relatively strong immune response
• Available serologic tests are more sensitive to H11 than to other strains

 

The authors of the 2006 Iowa study conclude by saying:

 

The relative lack of antibody response in our study population, who had substantial exposures to waterfowl with influenza A infections, and in inoculated volunteers from Beare and Webster (12) suggests that avian influenza infections in humans exposed to wild waterfowl may occur more commonly than we are able to detect with current methods.

 

Although the sample size of our study was relatively small, our results suggest that handling wild waterfowl, especially ducks, is a risk factor for direct transmission of avian influenza virus to humans.

 

 

Every year billions of people around the world experience flu-like symptoms that can stem from any of hundreds of different viruses.

 

Of those, only the tiniest fraction are tested to see what pathogen caused the illness.

 

In recent months we’ve seen the emergence of a small number of trH3N2 swine influenza infections.   Like avian influenzas, swine-origin influenzas probably jump to humans more often than we realize. 

 

Luckily, these viruses generally produce mild symptoms, and are not well enough adapted to humans to replicate, or spread, efficiently.  Every once in a great while, though, a biologically `fit’ virus makes the jump.

 

Which is why increased surveillance in humans and in livestock - around the world - is desperately needed. Early detection of an emerging virus might allow for containment.

 

But even if that isn’t possible, the sooner we know about a new virus, the sooner we can begin to produce a vaccine.