Dissecting the Influenza Pathogenesis Study Pt. 2
# 2796
This is Part II of a multi-part look at the recent 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 part Part I, which appeared on Saturday, we examined the 4 different viruses used in this study, and the methods used by the research team.
Today we'll take a look at the body's innate immune system and then look at some of the results of this study.
Don't worry, for my own sake I intend to keep this pretty simple.
As you've probably noticed, `innate immune response' is a key phrase in the title of this research paper.
Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.
So we know the innate immune response is going to be a big part of this report, but . . .what exactly is it?
And how does it work?
All of us are born with what is called an Innate Immune System that can detect, and launch a generic defense against, a wide variety of invading pathogens.
And if you think about it, 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.
This innate immune system not only fights infections on its own, it also buys us time for our Adaptive Immune System to learn to recognize and fight specific pathogens.
It is this adaptive immune system that produces pathogen-specific antibodies that can remember previous encounters with a virus, and can confer long-term immunity.
We call this trait acquired immunity, and that is what keeps us from suffering through viral infections like the measles or mumps over and over again.
For our innate immunity to work, it must have a way to recognize an infective agent, even from a pathogen it has never seen before.
And that capability comes from PAMPS.
PAMPs (Pathogen-Associated Molecular Patterns) are patterns of molecules associated with many types of pathogens.
In other words, PAMPs are an easily recognizable signature that tells our innate immune system that we have been infected . . . with something.
Our immune systems have cells designed to recognize, and react to these signatures, that include:
- phagocytic cells (neutrophils, monocytes, and macrophages);
- cells that release inflammatory mediators (basophils, mast cells, and eosinophils);
- natural killer cells (NK cells); and
- molecules such as complement proteins, acute phase proteins, and cytokines.
In other words, 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 uncontrolled exuberant immune response has frequently been suggested as being one of the factors leading to the high mortality rate of the 1918 pandemic.
The `other plausible suspect', which has gained a good deal of support over the past year, being secondary bacterial pneumonia.
Of course, neither of these processes need be mutually exclusive.
So, with this bare-bones understanding of the innate immune system, and the role of cytokines, we can begin to look at some of the findings of this study.
The following key points were lifted from the study's abstract:
- Among these viruses, HPAI H5N1 was the most virulent.
- Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions.
- Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays.
- 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.
- While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.
The first two points are self-explanatory.
The third point, about the H5N1 virus targeting type II pneumocytes, could do with a bit of explanation.
Unlike the 1918-like viruses, which largely targeted type I pneumocytes, the H5N1 virus attacked and damaged type II pneumocytes.
Pneumocytes 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.
Since type II pneumocytes are the only repair mechanism available to replace damaged type I pneumocytes, destroying them can have profound effects on the lungs' ability to recover from injury.
One of the other big differences between the pathogenesis of the seasonal, 1918-like, and avian viruses was the production of many types of cytokines, which is represented by this heat map below.
As the press release for this paper stated:
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.
In part III, we'll take a closer look at this heat map, and some more of the findings of this report.
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