Thursday, December 07, 2017

Nature: Pandemic H1N1 Flu Viruses Suppress Dendritic Immune Reponse


Although it is hardly light reading, there's a fascinating study published this week in Nature Communications that sheds new light on why some pandemic viruses are so much more virulent than seasonal flu.
Before we get to that study, some (extremely) basic background is probably in order. I'll have to keep it simple, because I'm far from being an expert on the subject.
If you are already familiar with DAMPs, PAMPs, and the function of dendritic cells in the immune system, feel free to skip ahead.  Apologies in advance to any real scientists who stick around to read my humble attempt at explaining the basics of the immune system.

The human immune system is extremely complex, multifaceted, and far from completely understood. But in the simplest of terms, we have two basic types of immune defense systems: 

First, 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 as we'd be quickly overrun by opportunistic infections.
For our innate immunity to work, it must have a way to recognize an infective agent, even one it has never seen before. Toll-like receptors (TLRs) are a type of protein that are able to recognize molecules that are broadly shared by infectious agents called PAMPs (Pathogen-Associated Molecular Patterns). 
In other words, PAMPs are an easily recognizable molecular 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 order to buy enough time for the second part of our immune system - our Adaptive Immune System - to learn to recognize and fight specific pathogens.
The adaptive immune system produces pathogen-specific antibodies after exposure to a virus that can provide us with varying degrees of acquired immunity. This acquired immunity explains why we rarely get the same virus twice, and why vaccines work.
While PAMPs are easily recognizable traits of many pathogens, when certain types of cells die (necroptosis) - they release intracellular components called DAMPs (danger associated molecular patterns), which can also alert the immune system of an infection and help rally the troops.

Dendritic cells are a special type of immune cell, most commonly found in tissues that are exposed to the outside environment (skin, lungs, digestive tract), that boosts immune responses by showing antigens on its surface to other cells of the immune system.

Reduced to terms that even I can understand, dendritic cells help `teach' the adaptive immune system how to recognize a virus, are key in the creation of pathogen-specific antibodies, and are involved in signaling other parts of the immune system.
They also tend to die within hours of being infected by seasonal influenza viruses, and when they do, they release DAMPs. 
Eighteen months ago, a study appeared in the Journal of Immunology, that described the suppression of dendritic cell death with pandemic influenza virus infection, which they suggested contributed to the pathogenicity of these viruses. 

Suppression of dendritic cell necroptosis by pandemic influenza virus 
Boris M. Hartmann, Randy A Albrecht, Nada Marjanovic and Stuart C Sealfon
J Immunol May 1, 2016, 196 (1 Supplement) 78.11;

Necroptosis leads to the release of intracellular components which serve as danger associated molecular patterns (DAMP), making this a highly immunogenic cell death mechanism. Consistent with this view, we find that the suppression of virus-induced necroptosis by the pandemic IAV reduces T cell activation.
These studies show that pandemic viruses are unique in suppressing a key immunological danger signal. The suppression of the generation of DAMPs from infected immune cells may contribute to the pathogenicity of pandemic H1N1 IAV viruses.
         (Continue . . . )

These same authors are back this week with a new study, which identifies the HA genomic segment that serves as the mediator of cell death inhibition, thereby increasing the virulence of pandemic H1N1 infection.

Pandemic H1N1 influenza A viruses suppress immunogenic RIPK3-driven dendritic cell death
Boris M. Hartmann,Randy A. Albrecht, Elena Zaslavsky,German Nudelman, Hanna Pincas, Nada Marjanovic, Michael Schotsaert, Carles Martínez-Romero, Rafael Fenutria, Justin P. Ingram, Irene Ramos, Ana Fernandez-Sesma, Siddharth Balachandran, Adolfo García-Sastre & Stuart C. Sealfon


The risk of emerging pandemic influenza A viruses (IAVs) that approach the devastating 1918 strain motivates finding strain-specific host–pathogen mechanisms. During infection, dendritic cells (DC) mature into antigen-presenting cells that activate T cells, linking innate to adaptive immunity.

DC infection with seasonal IAVs, but not with the 1918 and 2009 pandemic strains, induces global RNA degradation. Here, we show that DC infection with seasonal IAV causes immunogenic RIPK3-mediated cell death. Pandemic IAV suppresses this immunogenic DC cell death.

Only DC infected with seasonal IAV, but not with pandemic IAV, enhance maturation of uninfected DC and T cell proliferation. In vivo, circulating T cell levels are reduced after pandemic, but not seasonal, IAV infection. Using recombinant viruses, we identify the HA genomic segment as the mediator of cell death inhibition. These results show how pandemic influenza viruses subvert the immune response.

(Continue . . . )

Simply put, regular seasonal influenza kills dendritic cells, which serve in multiple capacities on the front lines of our immune system, while pandemic H1N1 does not.  By continuing to live, dendritic cells fail to release DAMPs, and so a weaker immune response is mounted.

Highlights of this research shows that:
  • Seasonal but not pandemic IAVs induce human dendritic cell death
  • Pandemic IAV inhibits RIPK3-mediated cell death
  • RIPK3-mediated cell death activates T cell proliferation
  • Viral genomic segment HA mediates necroptosis inhibition
  • And that Pandemic IAV reduces T cell proliferation in humans

This is just a simplistic, and heavily truncated, summary of their findings. Those with a reasonably good grasp of the science and an hour or five to spare will certainly want to follow the link and read this study in its entirety.

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