Highly Pathogenic H5N1 Influenza A Virus Spreads Efficiently in Human Primary Monocyte-Derived Macrophages and Dendritic Cells.

Veera Westenius,Ilkka Julkunen,Pamela Österlund,Sanna M Mäkelä

doi:10.3389/fimmu.2018.01664

Veera Westenius, Ilkka Julkunen + Show 2 more

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https://doi.org/10.3389/fimmu.2018.01664

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Abstract

Influenza A viruses cause recurrent epidemics and occasional global pandemics. Wild birds are the natural reservoir of influenza A virus from where the virus can be transmitted to poultry or to mammals including humans. Mortality among humans in the highly pathogenic avian influenza H5N1 virus infection is even 60%. Despite intense research, there are still open questions in the pathogenicity of the H5N1 virus in humans. To characterize the H5N1 virus infection in human monocyte-derived macrophages (Mɸs) and dendritic cells (DCs), we used human isolates of highly pathogenic H5N1/2004 and H5N1/1997 and low pathogenic H7N9/2013 avian influenza viruses in comparison with a seasonal H3N2/1989 virus. We noticed that the H5N1 viruses have an overwhelming ability to replicate and spread in primary human immune cell cultures, and even the addition of trypsin did not equalize the infectivity of H7N9 or H3N2 viruses to the level seen with H5N1 virus. H5N1 virus stocks contained more often propagation-competent viruses than the H7N9 or H3N2 viruses. The data also showed that human DCs and Mɸs maintain 1,000- and 10,000-fold increase in the production of infectious H5N1 virus, respectively. Both analyzed highly pathogenic H5N1 viruses showed multi-cycle infection in primary human DCs and Mɸs, whereas the H3N2 and H7N9 viruses were incapable of spreading in immune cells. Interestingly, H5N1 virus was able to spread extremely efficiently despite the strong induction of antiviral interferon gene expression, which may in part explain the high pathogenicity of H5N1 virus infection in humans.

Highlights

Influenza A viruses are one of the most important viral pathogens annually infecting even 5–10% of the human population and causing an estimated 250,000–500,000 deaths worldwide
In the single-cycle infection (6 h), the infectivity curves with different doses of H5N1, H7N9, or H3N2 viruses both in Mɸs (Figure 1A) and monocyte-derived DCs (moDCs) (Figure 1C) corresponded well to the determined focus forming units per milliliter (FFU/ml) values
In moDCs and Mɸs where both α-2,3- and α-2,6-linked sialic acids are expressed [14, 15], the infectivity titer of H5N1 stock was the highest when compared with H3N2 or H7N9 viruses

Summary

Introduction

Influenza A viruses are one of the most important viral pathogens annually infecting even 5–10% of the human population and causing an estimated 250,000–500,000 deaths worldwide. Influenza A viruses cause global pandemics of which the most devastating one was the pandemic caused by Spanish flu in 1918 leading up to 50 million deaths [1]. The segmented genome of influenza A viruses confers evolutionary advantages and influenza A viruses have a great ability to evolve by two different mechanisms, antigenic drift and shift. All pandemics in the twentieth century have been of avian origin [2, 3]. Avian influenza A viruses circulate continuously in birds and occasionally they have caused infections in humans. The highly pathogenic avian influenza (HPAI) H5N1 viruses

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