Dysregulated T-Helper Type 1 (Th1):Th2 Cytokine Profile and Poor Immune Response in Pregnant Ferrets Infected With 2009 Pandemic Influenza A(H1N1) Virus (original) (raw)
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Journal of Clinical Virology, 2015
Background: During pregnancy, immunological and hormonal alterations place women at increased risk for influenza-related severe illnesses including hospitalization and death. Although A(H1N1) pdm09 infection resulted in increased disease severity in pregnant women, the precise mechanisms responsible for this risk have yet to be established. Objectives: The present study was aimed to investigate the role of host chemokines and cytokine profiles in A(H1N1) pdm09 infection regarding disease severity in pregnant women. Study design: This retrospective survey examined 41 pregnant women with confirmed A(H1N1) pdm09 infection. Of them, 12 died (D), 29 survived (S), and 17 remained uninfected and served as controls (C). Antiviral response was evaluated for IFN- expression and gene expression profiles of cytokines (TNF-␣, IL-6, IL-12, TGF-) and chemokines (IL-8, RANTES, MCP-1, IP-10), and the viral Matrix (M1) gene was quantified and normalized using the housekeeping gene product -actin mRNA. Results: Higher IL-8 and TNF-␣ mRNA expression were found in D and S compared with C, while IL-6 showed higher expression in D. Interestingly, these results were associated with a decrease in the antiinflammatory response of TGF- mRNA and IFN-. These alterations would lead to an imbalance in the immune response of those patients. Conclusions: Pregnancy-related reductions in IFN- and TGF- expression levels and elevated levels of pro-inflammatory cytokines could explain the increased severity of infection and death of pregnant women. These findings may help improve the understanding of the high susceptibility and disease severity to influenza virus infection during pregnancy.
PLoS ONE, 2014
The first pandemic of the 21 st century occurred in 2009 and was caused by the H1N1pdm influenza A virus. Severe cases of H1N1pdm infection in adults are characterized by sustained immune activation, whereas pregnant women are prone to more severe forms of influenza, with increased morbi-mortality. During the H1N1pdm09 pandemic, few studies assessed the immune status of infected pregnant women. The objective of this study was to evaluate the behavior of several immune markers in 13 H1N1pdm2009 virus-infected pregnant (PH1N1) women, in comparison to pregnant women with an influenza-like illness (ILI), healthy pregnant women (HP) and healthy non-pregnant women (HW). The blood leukocyte phenotypes and the serological cytokine and chemokine concentrations of the blood leukocytes, as measured by flow cytometry, showed that the CD69+ cell counts in the T and B-lymphocytes were significantly higher in the PH1N1 group. We found that pro-inflammatory (TNF-a, IL-1b, IL-6) and anti-inflammatory (IL-10) cytokines and some chemokines (CXCL8, CXCL10), which are typically at lower levels during pregnancy, were substantially increased in the women in the ILI group. Our findings suggest that CD69 overexpression in blood lymphocytes and elevated levels of serum cytokines might be potential markers for the discrimination of H1N1 disease from other influenza-like illnesses in pregnant women.
PloS one, 2017
Maternal influenza infection during pregnancy is associated with increased risk of morbidity and mortality. However, the link between the anti-influenza immune responses and health-related risks during infection is not well understood. We have analyzed memory T and NK cell mediated immunity (CMI) responses in pandemic influenza A(H1N1)pdm09 (pdm09) virus infected non-vaccinated pregnant women participating in the Norwegian Influenza Pregnancy Cohort (NorFlu). The cohort includes information on immunization, self-reported health and disease status, and biological samples (plasma and PBMC). Infected cases (N = 75) were defined by having a serum hemagglutination inhibition (HI) titer > = 20 to influenza pdm09 virus at the time of delivery, while controls (N = 75) were randomly selected among non-infected pregnant women (HI titer <10). In ELISpot assays cases had higher frequencies of IFNγ+ CD8+ T cells responding to pdm09 virus or conserved CD8 T cell-restricted influenza A virus...
Frontiers in Immunology, 2018
In 2009, the H1N1 swine flu pandemic highlighted the vulnerability of pregnant women to influenza viral infection. Pregnant women infected with influenza A virus were at increased risk of hospitalization and severe acute respiratory distress syndrome (ARDS), which is associated with high mortality, while their newborns had an increased risk of pre-term birth or low birth weight. Pregnant women have a unique immunological profile modulated by the sex hormones required to maintain pregnancy, namely progesterone and estrogens. The role of these hormones in coordinating maternal immunotolerance in uterine tissue and cellular subsets has been well researched; however, these hormones have wide-ranging effects outside the uterus in modulating the immune response to disease. In this review, we compile research findings in the clinic and in animal models that elaborate on the unique features of H1N1 influenza A viral pathogenesis during pregnancy, the crosstalk between innate immune signaling and hormonal regulation during pregnancy, and the role of pregnancy hormones in modulating cellular responses to influenza A viral infection at mid-gestation. We highlight the ways in which lung architecture and function is stressed by pregnancy, increasing baseline inflammation prior to infection. We demonstrate that infection disrupts progesterone production and upregulates inflammatory mediators, such as cyclooxygenase-2 (COX-2) and prostaglandins, resulting in pre-term labor and spontaneous abortions. Lastly, we profile the ways in which pregnancy alters innate and adaptive cellular immune responses to H1N1 influenza viral infection, and the ways in which these protect fetal development at the expense of effective long-term immune memory. Thus, we highlight advancements in the field of reproductive immunology in response to viral infection and illustrate how that knowledge might be used to develop more effective post-infection therapies and vaccination strategies.
Cell host & microbe, 2017
Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the underlying mechanisms are limited. Here, we present models of H1N1 infection in syngenic and allogenic pregnant mice; infection in the latter mirrors the severe course of 2009 pandemic influenza in pregnant women. We found that the anti-viral immune response in the pregnant host was significantly restricted as compared to the non-pregnant host. This included a reduced type I interferon response as well as impaired migration of CD8(+) T cells into the lung. The multi-faceted failure to mount an anti-viral response in allogenic pregnant mice resulted in a less stringent selective environment that promoted the emergence of 2009 H1N1 virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity. These insights underscore the importance of influenza vaccination compliance in pregnant women and may open novel therapeutic avenues.
Frontiers in Immunology, 2020
While the majority of influenza-infected individuals show no or mild symptomatology, pregnant women are at higher risk of complications and infection-associated mortality. Although enhanced lung pathology and dysregulated hormones are thought to underlie adverse pregnancy outcomes following influenza infection, how pregnancy confounds long-term maternal anti-influenza immunity remains to be elucidated. Previously, we linked seasonal influenza infection to clinical observations of adverse pregnancy outcomes, enhanced lung and placental histopathology, and reduced control of viral replication in lungs of infected pregnant mothers. Here, we expand on this work and demonstrate that lower infectious doses of the pandemic A/California/07/2009 influenza virus generated adverse gestational outcomes similar to higher doses of seasonal viruses. Mice infected during pregnancy demonstrated lower hemagglutination inhibition and neutralizing antibody titers than non-pregnant animals until 63 days post infection. These differences in humoral immunity suggest that pregnancy impacts antibody maturation mechanisms without alterations to B cell frequency or antibody secretion. This is further supported by transcriptional analysis of plasmablasts, which demonstrate downregulated B cell metabolism and post-translational modification systems only among pregnant animals. In sum, these findings corroborate a link between adverse pregnancy outcomes and severe pathology observed during pandemic influenza infection. Furthermore, our data propose that pregnancy directly confounds humoral responses following influenza infection which resolves post-partem. Additional studies are required to specify the involvement of plasmablast metabolism with early humoral immunity abnormalities to best guide vaccination strategies and improve our understanding of the immunological consequences of pregnancy.
PLoS pathogens, 2017
Increased susceptibility to influenza virus infection during pregnancy has been attributed to immunological changes occurring before and during gestation in order to "tolerate" the developing fetus. These systemic changes are most often characterized by a suppression of cell-mediated immunity and elevation of humoral immune responses referred to as the Th1-Th2 shift. However, the underlying mechanisms which increase pregnant mothers' risk following influenza virus infection have not been fully elucidated. We used pregnant BALB/c mice during mid- to late gestation to determine the impact of a sub-lethal infection with A/Brisbane/59/07 H1N1 seasonal influenza virus on completion of gestation. Maternal and fetal health status was closely monitored and compared to infected non-pregnant mice. Severity of infection during pregnancy was correlated with premature rupture of amniotic membranes (PROM), fetal survival and body weight at birth, lung viral load and degree of system...
Postpandemic Influenza A/H1N1pdm09 is still Causing Severe Perinatal Complications
Mediterranean journal of hematology and infectious diseases, 2015
Although influenza A/H1N1pdm09 is not causing a pandemic anymore, we recently observed two critically ill pregnant women infected by this virus. We present these cases to illustrate the possible severe complications of an - at that moment - seasonal influenza in pregnancy. We discuss the epidemiological differences between the pandemic and post pandemic phase and try to explain the high virulence of influenza A/H1N1pdm09 -infections in pregnancy by discussing insights in immunology during pregnancy. We conclude that although influenza A/H1N1pdm09 is in the post pandemic phase, infection by this influenza virus still needs to be considered in pregnant women with progressive respiratory dysfunction.
American Journal of Obstetrics and Gynecology, 2011
T he emergence of 2009 pandemic influenza A (H1N1) virus (2009 H1N1) resulted in the first influenza pandemic in over 40 years. The Centers for Disease Control and Prevention (CDC) estimated that about 61 million people were infected, 274,000 were hospitalized, and about 12,740 died due to 2009 H1N1 in the United States. 1 About 90% of all hospitalizations and 87% of all deaths during the 2009 H1N1 pandemic were among people Ͻ65 years in contrast with experience from seasonal influenza when about 40% of all hospitalizations and 10% of deaths were found in this age group. 1 It is well recognized that pregnancy represents a risk factor for influenza complications and death during both pandemic and seasonal influenza. 2-6 Thus, with illness being widespread among the younger segments of the population We sought to describe characteristics of hospitalized reproductive-aged (15-44 years) women with seasonal (2005/2006 through 2008/2009) and 2009 pandemic influenza A (H1N1) virus infection. We used population-based data from the Emerging Infections Program in 10 US states, and compared characteristics of pregnant (n ϭ 150) and nonpregnant (n ϭ 489) seasonal, and pregnant (n ϭ 489) and nonpregnant (n ϭ 1088) pandemic influenza cases using 2 and Fisher's exact tests. Pregnant women represented 23.5% and 31.0% of all reproductive-aged women hospitalized for seasonal and pandemic influenza, respectively. Significantly more nonpregnant than pregnant women with seasonal (71.2% vs 36.0%) and pandemic (69.7% vs 31.9%) influenza had an underlying medical condition other than pregnancy. Antiviral treatment was significantly more common with pandemic than seasonal influenza for both pregnant (86.5% vs 24.0%) and nonpregnant (82.0% vs 55.2%) women. Pregnant women comprised a significant proportion of influenza-hospitalized reproductive-aged women, underscoring the importance of influenza vaccination during pregnancy.