Dissecting the Influenza Pathogenesis Study Pt. 1



# 2793


Last night we got our first look at a study that compared the pathogenesis (disease progression) of non-human primates (macaques) infected with the H5N1 virus, seasonal flu, and with two altered viruses carrying genetic material from the 1918 Spanish Flu.

The study, 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.  appears in the latest issue of PNAS (The Proceedings of the National Academy of Science).

While there is much here to consider (and we'll get to that), the upshot is that:

The avian virus was found to significantly outpace not only run-of-the-mill influenza but even the highly virulent 1918 ressortants, in terms of its relentless pathogenicity.


I'm not going to try to critique this research, as I'm obviously unqualified to do so.   Someone with more letters after their name than EMT-II (Ret.) will have to take that on.



But what I'd like to do is explain, in layman's language, what the authors are reporting, and some of the implications of what they've learned.


And here I run into a bit of a dilemma.


Just about every facet of this study requires a bit of `background', to make it understandable.  At least if we're going to do more than give it a cursory look.


Even the title, which refers to the `innate immune response' requires a bit of explanation.   And the deeper you plunge into this paper, the more `detours' - areas that require a good deal of explanation -  you find.  


I have to ask myself. 


How many of my readers understand the difference between Type I and Type II Pneumocytes?  (I hope the number is low, since I had to look it up)


I suddenly realized that, in order to make all of this understandable to the widest number of readers, I'd have to write a multi-part post.   Not really a problem, of course.  After nearly 2800 blogs, what's a multi-part post?


So, while I fully expect we can get `there' from `here', I'll warn my readers in advance it may require a serpentine route.   As to how many installments it will take to get `there' - well, we'll know when we've arrived.

Given the long, and awkward title of the research paper, once I link to it in at the top of each post, I'm simply going to refer to it as The Baskin Study


So, without further ado,  I present Part I of my series Dissecting the Influenza Pathogenesis Study.


MEET THE PLAYERS


To perform a systematic comparison of several highly pathogenic influenza viruses, we inoculated cynomolgus macaques (8 animals per group) with either influenza A/Vietnam/1203/2004 (referred to as H5N1), 1918HA/NA:A/Texas/36/91 (1918HANA), 1918HA/NA/NS:A/Texas/36/91 (1918HANANS), or the parental H1N1 A/Texas/36/91 (Texas) virus. - The Baskin Study


The hodgepodge of letters and numbers above identify 4 very different influenza viruses, which researchers used to infect macaques in order to study their different disease processes.

To understand what these numbers and letters mean, we need to digress briefly. 


Influenza viruses come in 3 broad types; A, B, and C.  

  • Influenza `C' viruses are relatively rare, generally produce milder symptoms in humans, and are not considered to have epidemic or pandemic potential. 

  • `B' viruses, which are far more common, may produce serious illness and spark regional epidemics, but aren't viewed as `pandemic strains'.

  • It is only the `A' influenza strain - which is characterized by two surface glycoproteins known as hemagglutinin (HA) and neuraminidase (NA) - that mutates rapidly and can cause an influenza pandemic.


Influenza `A' viruses are identified by their HA and NA proteins.  There are 16 known HA subtypes and 9 known NA subtypes.  While many combinations are possible, currently only a few are in circulation.


Among humans, the H1N1, H1N2, and H3N2 viruses currently circulate globally.    H5s, H7s, and H9s are commonly found in birds.


The H1N1 viruses today are all descendants of the 1918 Spanish Flu.   The H3N2 viruses are descendants of the 1968 pandemic. 


The H1N2 virus, which was first detected in 2002, appears to be a hybrid, consisting of the hemagglutinin (HA) from the H1N1 virus and the neuraminidase (NA) from the H3N2 virus.


Influenza `A'  viruses are actually complex entities comprised of 10 genes on 8 separate RNA molecules (called: PB2, PB1, PA, HA, NP, NA, M, and NS)



image


This study compared 4 influenza viruses.

  • One wholly avian virus (H5N1), a clade 1 H5N1 virus collected from Vietnam in 2004.

  • One seasonal influenza virus (Texas) H1N1 A/Texas/36/91, which circulated widely in the mid and early 1990's.

  • One genetically modified seasonal H1N1 virus (1918HANA) with the HA and NA from the 1918 virus spliced to it.

  • And one genetically modified seasonal H1N1 virus (1918HANANS) with the HA, NA, and NS1 from the 1918 virus spliced to it.


The (HA) and neuraminidase (NA) surface proteins are known conveyors of virulence, and while the resultant reassortant viruses might not have been an exact match to the 1918 pandemic virus, they do represent a reasonable facsimile.
 
The NS1, grafted onto the 2nd 1918-like virus, is known to inhibit the host interferon response.   
 
Interferon is a natural protein produced by the cells of the immune system when they sense a viral or bacterial invader.  Interferons belong to the larger class of glycoproteins known as cytokines. 
 
 
The stage is now set. 
 
Thirty-four macaques were used in this study, four groups of 8 - with 2 `mock infected' to serve as a reference for host response without viral challenge.  
 
Each group of 8 were macaques were infected with a different strain of the virus via tracheal, nasal, conjunctival, and tonsillar routes.
 
On days 1, 2, 4, and 7 postinfection (PI), 2 animals per group were euthanized.  One macaque died from excessive pulmonary damage between day 6 and 7.
 
On day 7, the two `mock infected' animals were euthanized.  
 
Necropsies were performed on each animal and tissue and serum samples were subjected to numerous tests. 
 
In the next installment Dissecting the Influenza Pathogenesis Study Pt. 2 , we'll look at some of the results.


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