Elsevier

Vaccine

Volume 33, Issue 49, 8 December 2015, Pages 6949-6954
Vaccine

Sex differences in H7N9 influenza A virus pathogenesis

https://doi.org/10.1016/j.vaccine.2015.08.044Get rights and content

Abstract

Sex, gender and age have an impact on incidence and severity of several infectious diseases. Here, we analyzed reported human cases of avian H7N9 influenza A virus infections for potential sex-dependent incidence and mortality. We report that females in their reproductive years display an increased tendency to die of H7N9 influenza than males (female-to-male ratio = 1.2). Next, we challenged this potential sex-dependent difference in influenza disease outcome using a mouse infection model. In general, female mice underwent more severe disease than male mice upon infection with various influenza A virus subtypes, such as H7N9, 2009 pH1N1 and H3N2. However, morbidity and mortality were most significantly affected in H7N9 influenza virus infected female mice associated with an increased inflammatory host response. Thus, our mouse infection model described here might assist future investigations on the underlying mechanisms of sex-dependent disease outcome upon zoonotic H7N9 influenza virus infection. Moreover, our findings might help to guide patient management strategies and current vaccine recommendations.

Introduction

Women and men may differ in their susceptibility and response to autoimmune as well as to certain infectious diseases [1], [2]. It was reported before, that males suffer more frequently from infectious diseases such as malaria and tuberculosis than females [1], [2], [3]. These differences in disease manifestation may be affected by sex and/or gender. Gender differences include cultural and behavioral differences among women and men, whereas sex differences comprise biological and physiological differences. Females and males may differ in their immune response to infections which is affected by sex hormones and specific X-chromosome-encoded genes. However, it is not always possible to clearly distinguish between sex, gender and other confounder mediated effects on disease outcome due to the lack of available information.

It was reported that influenza A virus infections are more severe in women than men of reproductive age [3], [4], [5]. This was particularly observed among pandemic influenza virus infections. Recently, an H7N9 influenza virus subtype was transmitted for the first time from infected poultry to humans in China [6], [7]. Since its first detection in April 2013, the virus continues to emerge and has already infected >500 people in multiple recurrent epidemic waves. The risk of death among hospitalized human cases of avian H7N9 influenza was estimated to be 36% in the first [8] and 48% [9] in the second epidemic wave.

In H7N9 infected individuals, a high incidence was observed in men who had frequent contact to live poultry [10]. Nevertheless, it remained unclear whether this is affected by gender or sex.

Due to the continuously emerging nature of H7N9 influenza viruses and the lack of protective immunity among the human population, there is increasing concern that H7N9 influenza viruses may further adapt to humans and cause the next influenza pandemic.

Therefore, in this study, we have analyzed epidemiological data comprising H7N9 infected individuals as of 25th January 2015, in dependence of gender/sex and age. In order to distinguish between potential sex differences, we have infected female and male mice with a human H7N9 influenza virus isolate and analyzed its impact on pathogenesis and the host innate immune response.

Section snippets

Analysis of epidemiological data on H7N9 human infections in China

All laboratory-confirmed human cases of avian H7N9 influenza virus infections and deaths are reported to the Chinese Center for Disease Control and Prevention through a national surveillance system. Here, we analyzed all epidemiological data as available on 25th January 2015 since its first detection in April 2013 on sex, age, survival and death. In total, 535 laboratory-confirmed cases were reported of which 197 died. Female-to-male ratio was calculated for the reported cases (incidence) as

More women undergo a severe H7N9 infection course than men

In order to assess whether there are potential sex/gender differences among H7N9 infected individuals, we have analyzed all reported cumulative cases of H7N9 influenza A virus infections in China as of 25th January 2015 (Fig. 1A). In children between 0 and 14 years of age, no differences in incidence (Fig. 1B) or the death-to-incidence ratio was observed between females and males (Fig. 1C). In contrast, individuals of reproductive age between 15 and 49 years, displayed a higher incidence in

Discussion

Avian H7N9 influenza A viruses continue to emerge causing recurrent outbreaks in humans that are associated with high morbidities and mortalities. Analysis of the first 130 laboratory-confirmed cases revealed that 68% (n = 88) were men and only 28% (n = 37) were women and 4% were children [16]. However, it remained unclear whether these data are biased by confounder effects, such as gender, underlying co-morbidities or by overall low case numbers rather than sex differences.

Here, we analyzed data

Conflicts of interest statement

The authors have no financial relationships relevant to this article.

Acknowledgments

We thank Annette Preuß for excellent technical assistance. The Heinrich Pette Institute, Leibniz Institute for Experimental Virology, is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health.

References (18)

There are more references available in the full text version of this article.

Cited by (36)

  • Sexual dimorphism, aging and immunity

    2021, Vitamins and Hormones
    Citation Excerpt :

    All strains of influenza also show sexual dimorphism and affect more women than men, which results in higher mortality in women (Klein, Passaretti, Anker, Olukoya, & Pekosz, 2010). Lower levels of estrogen and higher androgen suppress immune response to influenza in men limiting pathology (Hoffmann et al., 2015). Studies in patients infected with human immunodeficiency virus (HIV) have shown that HIV infected women carry 40% less viral load than men (Klein & Flanagan, 2016) confirming that women have stronger immunity and can clear viral infections better at young age.

  • Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

    2020, Cell Reports
    Citation Excerpt :

    Immune responses differ between women and men, resulting in sex-specific differences in the manifestations of infectious and autoimmune diseases. A bias between females and males in the incidence and outcome of infectious diseases has been described for viral (HIV, hepatitis C virus [HCV], and influenza), bacterial (tuberculosis), and parasitic (amebiasis and leishmaniasis) infections (Sterling et al., 2001; Meditz et al., 2011; Grebely et al., 2014; Hertz and Schneider, 2019; Bernin and Lotter, 2014; Hoffmann et al., 2015). The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic also exhibits a sex difference with an estimated case mortality rate of 1.7 (male): 1 (female) in Europe (Bunders and Altfeld, 2020; Scully et al., 2020).

  • Characterization of antibody and memory T-cell response in H7N9 survivors: a cross-sectional analysis

    2020, Clinical Microbiology and Infection
    Citation Excerpt :

    Moreover, female patients had stronger HI and MN antibody responses than male patients. It has been shown in animal models that, after infection with the H7N9 virus, female mice had significantly higher morbidity with increased host inflammatory responses [34]. However, a large gap still exists in our understanding about how sex influences immune responses to influenza infection, which needs further studies.

  • The intersection of sex and gender in the treatment of influenza

    2019, Current Opinion in Virology
    Citation Excerpt :

    There is annual, as well as country, variation in the male-female differences suggesting that gender-related factors, including occupational exposure, play a significant role. Furthermore, during the 2013–14 H7N9 avian influenza outbreak, while aged males were more likely than any other sex and age-matched cohort to be hospitalized with severe disease, it was females of reproductive ages (i.e. 18–50 years of age) who were most likely to die from H7N9 infection [22]. Hypothesized mechanisms mediating age-associated male–female differences in IAV notifications and pathogenesis are explored below.

View all citing articles on Scopus
1

Present address: Institute of Biochemistry, University of Kiel, Kiel, Germany.

View full text