![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Previous Article | Next Article 
Clinical and Vaccine Immunology, May 2008, p. 885-887, Vol. 15, No. 5
1071-412X/08/$08.00+0 doi:10.1128/CVI.00035-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Department of Clinical Microbiology, Division of Infectious Diseases, Umeå University, SE-901 85 Umeå, Sweden,1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden,2 Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden3
Received 25 January 2008/ Returned for modification 7 February 2008/ Accepted 11 March 2008
 |
ABSTRACT |
|---|
 Top ABSTRACT TEXTREFERENCES |
|---|
|
TEXT |
|---|
|
TopABSTRACTTEXTREFERENCES |
|---|
In this study, we wished to examine the possible sex differences in cytokine responses to an acute virus infection in humans. We therefore investigated plasma samples from Puumala hantavirus (PUUV)-infected individuals, as this virus causes an acute disease with transient viremia. Samples from the same individuals drawn after recovery were also analyzed to investigate possible normal sex differences in levels of cytokines. Hantaviruses are transmitted from their natural hosts, rodents, to humans via inhalation of virus-contaminated excreta. In humans, the infection causes two severe diseases, hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and hantavirus pulmonary syndrome (HPS) in the Americas, with mortality rates of up to 40% depending on the specific hantavirus strain (13, 16). PUUV causes a mild form of HFRS that is characterized by influenzalike symptoms, followed by renal impairment and, in rare cases, hemorrhage and death (14, 16).
We show that PUUV induces higher levels of interleukin-9 (IL-9), fibroblast growth factor 2 (FGF-2), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and lower levels of IL-8 and gamma interferon (IFN-
)-induced protein 10 (IP-10) in females than in males during the acute phase of infection. Importantly, we show that these differences were specific for the acute phase, as no significant differences in any of the 27 cytokines investigated were observed during the convalescent phase when all infected patients had recovered from HFRS.
Patient samples. Plasma was collected from PUUV-infected patients hospitalized at the Department of Infectious Diseases at Umeå University Hospital in Umeå, Sweden. Plasma samples were obtained by separation of peripheral blood by using BD Vacutainer cell preparation tubes with sodium heparin (Becton Dickinson, Franklin Lakes, NJ). The samples, obtained from 39 patients with typical clinical symptoms of acute HFRS (serologically verified by an immunofluorescence test for PUUV-specific immunoglobulin M and immunoglobulin G), were stored at –70°C until further analysis. Acute-phase samples were drawn at the time of hospitalization, and convalescent-phase samples 64.95 ± 27.39 (mean ± standard deviation [SD]) days later for females and 57.63 ± 16.36 days later for males, respectively.
The project was approved by the Research Ethics Committee of Umeå University, and all patients gave written informed consent.
Multiplex analysis.
The Bio-plex human cytokine 27-plex assay (Bio-Rad, Hercules, CA) for IL-1β, IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF-2, granulocyte colony-stimulating factor (G-CSF), GM-CSF, IFN-, IP-10, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1
(MIP-1), MIP-1β, platelet-derived growth factor BB (PDGF-BB), regulated-on-activation normal T-cell expressed and secreted (RANTES), tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) was performed according to the manufacturer's instructions.
Statistical analysis. The Mann-Whitney U test, a nonparametric test, was used to compare cytokine levels in females and males. Student's t test was used to analyze possible differences in age and sampling time points. P values of <0.05 were considered to be significant.
Statistical analysis was performed with Statistica version 8 software.
Sex-based differences in cytokine responses during hantavirus infection. We first compared the plasma levels of cytokines in females (n = 20; mean days after occurrence of symptoms, 4.90 ± 1.68 days; mean age, 49.08 ± 16.41 years) with the levels in males (n = 19; mean days after occurrence of symptoms, 5.16 ± 1.46 days; mean age, 46.55 ± 14.92 years) during the acute phase. There were no significant differences between females and males for age (P = 0.61; Student's t test) or days after occurrence of symptoms (P = 0.62). Females showed significantly higher plasma levels of IL-9, FGF-2, and GM-CSF and lower levels of IL-8 and IP-10 than males (Table 1).
|
|
The finding of significant sex differences in the cytokine responses during HFRS demonstrates that the general cytokine response during acute virus infections can differ between females and males. Whether sex hormones are involved in shaping the observed differences in cytokine profiles and whether other mechanisms are involved are interesting questions that remain to be studied.
Intriguingly, although as many females as males in the general population have antibodies against PUUV (1), the male-to-female ratio for diagnosed PUUV infections in Europe ranges from 2:1 to 5:1 (12, 16), suggesting that males are more likely than females to develop clinical HFRS upon PUUV infection. It is believed that only approximately one out of every eight human PUUV infections is diagnosed, implying that most infections are asymptomatic or only cause mild disease (1). The initial cytokine response evoked early upon PUUV infection most probably will have profound effects on the subsequent activation of immune cells and on their antiviral function, thereby playing an important role in possible progression to disease.
Interestingly, the production of IL-8 and IP-10 has been shown to be elevated during severe acute respiratory syndrome coronavirus infection and is believed to be involved in the pathogenesis of severe acute respiratory syndrome (2), as well as in that of other virus infections. Infection with the HPS-causing Sin Nombre hantavirus has been shown to increase the production of IP-10 in human lung microvascular endothelial cells per se, and a synergistic effect on IP-10 production has been described for both Sin Nombre hantavirus and the HFRS-causing hantavirus Hantaan when combined with IFN- stimulation of the same cells (15). One could speculate that the observed higher levels of IL-8 and IP-10 in males indicate that males generally respond with a stronger inflammatory response upon virus infection than females.
We did not observe significant sex differences in plasma levels of T helper 1 (Th1) or Th2 or inflammatory cytokines like IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IFN-, or TNF during the acute phase. Thus, it could be speculated that the Th response and at least parts of the inflammatory response are similar in female and male patients during HFRS.
However, all individuals included in this study were admitted to the hospital with confirmed PUUV infection and clear signs of HFRS. Although the observed sex differences may play a role in the severity of the infection, other factors, like the roles that sex differences in occupation and behavior can have on the risk of being exposed to hantavirus, most probably also play important roles for the development of HFRS after PUUV infection.
This study provides the first characterization of sex differences in human cytokine responses during an acute virus infection, without the complicating issue of virus persistence. In conclusion, we show that the cytokine responses in females and males are not similar during an acute virus infection, implying that the subsequent activation and function of immune responses might differ between female and male patients upon infection. This finding may explain parts of the observed sex differences in susceptibility to infectious diseases and in mortality following infection.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Published ahead of print on 19 March 2008.
|
REFERENCES |
|---|
|
TopABSTRACTTEXTREFERENCES |
|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antimicrob. Agents Chemother. | Clin. Microbiol. Rev. | Infect. Immun. |
|---|---|---|
| J. Clin. Microbiol. | J. Virol. | ALL ASM JOURNALS |
