H1N1 Influenza strains contain H5N1 genetic material...Are the young and healthy at risk of a massive cytokine storm induced by virus infection?

Human infection with highly pathogenic avian influenza A viruses (HPAIV) such as H5N1 subtypes are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm (Schmolke et al., 2009). Recent reports have linked the genomes of the last three pandemic influenza viruses as having emerged from gene reassortment events and possessing HA genes of avian influenza origin. Thus, these findings provoke the following question: If existing influenza strains (i.e. 2009 H1N1 influenza) undergo gene reassortment similar to H5N1 strains, is it possible that the resulting human adapted form could manifest itself as a deadly pandemic targeting healthy individuals by the onset of a massive cytokine storm?

Review of what the “cytokine storm” is: when the body’s normal immune system overacts to an intruder such as a virus, by overproduction of signaling chemicals (known as cytokines and chemokines) that help mobilize immune cells capable of removing infectious agents from the body. The extremely high levels of cytokines that are produced as a consequence of a healthy immune system are over-exaggerated and fatally damaging to tissues and organs. Death will usually result from multisystem organ failure.

I came across two articles I’d like to reference in regard to this blog. Below is a brief summary of each paper, highlighting the author’s findings which are relevant to this blog topic.

The first paper published in July 2009 in Science (Rebecca J.Garten et al., 2009) involved a large collaborative effort of many authors representing the WHO, CDC, NIH and various health organizations. The objective of this study was to characterize the antigenic and genetic variations of 2009 H1N1 circulating in humans. In their attempts to do this, they analyzed genome sequences isolated from 2009 H1N1 patients with previous strains of influenza including classical swine, human seasonal, American avian, North American and Eurasian swine strains. This paper examines the antigenic capabilities of influenza and how it has evolved overtime resulting in the emergence of pandemic flu strains. The paper provides the lineages and reassortment events that have taken place overtime and which gave rise to three pandemic influenza viruses (1918 H1N1, 1957 H2N2, and 1968 H3N2). The lineage suggests that all three strains originated from nonhuman reservoirs and the HA genes of all, originated from avian influenza virus. Now the most recent 2009 A/H1N1 strain contains a never before seen combination of gene segments which appear to be derived from Eurasian swine and classical swine lineages (Garten et al., 2009).

The second paper, by Schmolke M. et al., 2009 in the Journal of immunology by a group in Germany presents in accordance with numerous reports, the observation that the high fatality rate of avian influenza is a consequence of lethal cytokine storm induced by A/H5N1 virus both in humans and animals (Deng RM. et al., 2008; Claas EC. et al., 1998). The significance of the study is based on the concern of highly pathogenic avian influenza viruses (HPAIV) being directly transmitted to humans as a possible source of a new influenza pandemic. They performed mRNA profiling on human umbilical vein endothelial cells (HUVEC) infected with H5N1 based on the idea that endothelial cells are a major source of cytokines and chemokines, and relevant for systemic viral dissemination. Their results confirm clustering and upregulation of inflammatory/immune response which are accompanied by a massive systemic production of cytokines and chemokines, characteristic of a cytokine storm.

It’s frightening to acknowledge the ongoing threats of the 2009 H1N1 swine flu and the still present Asian avian flu virus (AAV H5N1) and its pandemic potential. In regards to the influenza strain reassortment and antigenic evolution, sequence variation in the gene segments of the H5N1 strain have been shown to contribute to viral virulence. It will be interesting to compare the updated sequencing of gene segment among the 2009 H1N1 strains with previously pandemic strains which could suggest whether it may or may not be likely to elicit such a strong cytokine response associated with highly virulent strains such as H5N1.

Based on the recent publications mentioned above I think it is obvious that 1) the new swine flu influenza A strain appears to be a combination of previous bird, swine and human genetic make-up. In addition, all three show lineage to have originated from avian flu. 2) H5N1 the highly virulent avian flu strain causes lethal cytokine storm in young and healthy individuals. These ideas together implicate that H1N1 viruses have pandemic potential and historically support the possibility that healthy young adults may be more susceptible to severe infection due to a strong immune system capable of eliciting a lethal cytokine storm. If uncontrolled, such a cytokine storm occurring in vital organs can lead to organ failure and death.

What would be the best approach in preventing an influenza pandemic or in addressing the potential damage it could elicit by inducing a cytokine storm in infected individuals? Should health officials stringently monitor strains of the 2009 A(H1N1) virus for any antigenic and genetic changes? In the case of infected patients, should the use of prophylactics such as immune suppressors or antivirals be used to minimize the possibility of the cytokine storm?

References:

Garten RJ et al., 2009. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 325:197-201.

Schmolke M, Viemann D, Roth J, Ludwig S. 2009. Essential impact of NF-κB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol. 183:5180-5189.

Deng RM, Korteweg LC, Gao Z, McNutt MA, Ye J, Zhang I, Gu J. 2008. Distinctly different expression of cytokines and chemokines in the lungs of two H5N1 avian influenza patients. J Pathol. 216:328-336.

Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF. 1998. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 351:472-477.