Maternal Influenza A Virus Infection Restricts Fetal and Placental Growth and Adversely Affects the Fetal Thymic Transcriptome.

Maternal influenza A viral infections in humans are associated with low birth weight, increased risk of pre-term birth, stillbirth and congenital defects. To examine the effect of maternal influenza virus infection on placental and fetal growth, pregnant C57BL/6 mice were inoculated intranasally with influenza A virus A/CA/07/2009 pandemic H1N1 or phosphate-buffered saline (PBS) at E3.5, E7.5 or E12.5, and the placentae and fetuses collected and weighed at E18.5. Fetal thymuses were pooled from each litter. Placentae were examined histologically, stained by immunohistochemistry (IHC) for CD34 (hematopoietic progenitor cell antigen) and vascular channels quantified. RNA from E7.5 and E12.5 placentae and E7.5 fetal thymuses was subjected to RNA sequencing and pathway analysis. Placental weights were decreased in litters inoculated with influenza at E3.5 and E7.5. Placentae from E7.5 and E12.5 inoculated litters exhibited decreased labyrinth development and the transmembrane protein 150A gene was upregulated in E7.5 placentae. Fetal weights were decreased in litters inoculated at E7.5 and E12.5 compared to controls. RNA sequencing of E7.5 thymuses indicated that 957 genes were downregulated ≥2-fold including Mal, which is associated with Toll-like receptor signaling and T cell differentiation. There were 28 upregulated genes. It is concluded that maternal influenza A virus infection impairs fetal thymic gene expression as well as restricting placental and fetal growth.

Mortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Although the burden of influenza is often discussed in the context of historical pandemics and the threat of future pandemics, every year a substantial burden of lower respiratory tract infections (LRTIs) and other respiratory conditions (like chronic obstructive pulmonary disease) are attributable to seasonal influenza. The Global Burden of Disease Study (GBD) 2017 is a systematic scientific effort to quantify the health loss associated with a comprehensive set of diseases and disabilities. In this Article, we focus on LRTIs that can be attributed to influenza. METHODS: We modelled the LRTI incidence, hospitalisations, and mortality attributable to influenza for every country and selected subnational locations by age and year from 1990 to 2017 as part of GBD 2017. We used a counterfactual approach that first estimated the LRTI incidence, hospitalisations, and mortality and then attributed a fraction of those outcomes to influenza. FINDINGS: Influenza LRTI was responsible for an estimated 145 000 (95% uncertainty interval [UI] 99 000-200 000) deaths among all ages in 2017. The influenza LRTI mortality rate was highest among adults older than 70 years (16·4 deaths per 100 000 [95% UI 11·6-21·9]), and the highest rate among all ages was in eastern Europe (5·2 per 100 000 population [95% UI 3·5-7·2]). We estimated that influenza LRTIs accounted for 9 459 000 (95% UI 3 709 000-22 935 000) hospitalisations due to LRTIs and 81 536 000 hospital days (24 330 000-259 851 000). We estimated that 11·5% (95% UI 10·0-12·9) of LRTI episodes were attributable to influenza, corresponding to 54 481 000 (38 465 000-73 864 000) episodes and 8 172 000 severe episodes (5 000 000-13 296 000). INTERPRETATION: This comprehensive assessment of the burden of influenza LRTIs shows the substantial annual effect of influenza on global health. Although preparedness planning will be important for potential pandemics, health loss due to seasonal influenza LRTIs should not be overlooked, and vaccine use should be considered. Efforts to improve influenza prevention measures are needed. FUNDING: Bill & Melinda Gates Foundation.

Viral infections during pregnancy.

Viral infections during pregnancy have long been considered benign conditions with a few notable exceptions, such as herpes virus. The recent Ebola outbreak and other viral epidemics and pandemics show how pregnant women suffer worse outcomes (such as preterm labor and adverse fetal outcomes) than the general population and non-pregnant women. New knowledge about the ways the maternal-fetal interface and placenta interact with the maternal immune system may explain these findings. Once thought to be 'immunosuppressed', the pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus. When this protection is breached, as in a viral infection, this security is weakened and infection with other microorganisms can then propagate and lead to outcomes, such as preterm labor. In this manuscript, we review the major viral infections relevant to pregnancy and offer potential mechanisms for the associated adverse pregnancy outcomes.

Air pollution, temperature and pediatric influenza in Brisbane, Australia.

Previous studies have demonstrated the importance of weather variables in influencing the incidence of influenza. However, the role of air pollution is often ignored in identifying the environmental drivers of influenza. This research aims to examine the impacts of air pollutants and temperature on the incidence of pediatric influenza in Brisbane, Australia. Lab-confirmed daily data on influenza counts among children aged 0-14years in Brisbane from 2001 January 1st to 2008 December 31st were retrieved from Queensland Health. Daily data on maximum and minimum temperatures for the same period were supplied by the Australian Bureau of Meteorology. Winter was chosen as the main study season due to it having the highest pediatric influenza incidence. Four Poisson log-linear regression models, with daily pediatric seasonal influenza counts as the outcome, were used to examine the impacts of air pollutants (i.e., ozone (O3), particulate matter≤10µm (PM10) and nitrogen dioxide (NO2)) and temperature (using a moving average of ten days for these variables) on pediatric influenza. The results show that mean temperature (Relative risk (RR): 0.86; 95% Confidence Interval (CI): 0.82-0.89) was negatively associated with pediatric seasonal influenza in Brisbane, and high concentrations of O3 (RR: 1.28; 95% CI: 1.25-1.31) and PM10 (RR: 1.11; 95% CI: 1.10-1.13) were associated with more pediatric influenza cases. There was a significant interaction effect (RR: 0.94; 95% CI: 0.93-0.95) between PM10 and mean temperature on pediatric influenza. Adding the interaction term between mean temperature and PM10 substantially improved the model fit. This study provides evidence that PM10 needs to be taken into account when evaluating the temperature-influenza relationship. O3 was also an important predictor, independent of temperature.

Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice.

Epidemiological reports describe a strong association between prenatal human influenza viral infection and later development of schizophrenia. Postmodern human brain studies, however, indicate a lack of gliosis in schizophrenic brains presumably secondary to absence of glial cells during the second trimester viral infection in utero. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of glial fibrillary acidic protein (GFAP, an important marker of gliosis, neuron migration, and reactive injury) in developing brains of postnatal days 0, 14 and 35 mice. Determination of cellular GFAP immunoreactivity (IR) expressed as cell density in cortex and hippocampus of control and experimental brains showed increases in GFAP-positive density in exposed cortical (P = 0.03 day 14 vs control) and hippocampal cells (P = 0.035 day 14, P = 0.034 day 35). Similarly, ependymal cell layer GFAP-IR cell counts showed increases with increasing brain age from day 0, to days 14 and 35 in infected groups (P = 0.037, day 14) vs controls. The GFAP-positive cells in prenatally exposed brains showed 'hypertrophy' and more stellate morphology. These results implicate a significant role of prenatal human influenza viral infection on subsequent gliosis, which persists throughout brain development in mice from birth to adolescence.

Differential expression of synaptosome-associated protein 25 kDa [SNAP-25] in hippocampi of neonatal mice following exposure to human influenza virus in utero.

We investigated the role of maternal exposure to human influenza virus [HI] in C57BL/6 mice on day 9 of pregnancy on the hippocampal expression of SNAP-25 in postnatal day 0 neonates, and compared them to sham-infected pups. The expression of SNAP-25 in infected neonates varied along the septotemporal axis of hippocampus and in various anatomic layers. Quantitative densitometric analysis of specific immunogold silver-enhanced SNAP-25 immunoreactivity [IR] showed increases of 40-347% over control in all septal-dorsal hippocampal layers except for the subplate layer. In mid septo-temporal hippocampus, SNAP-25 IR increased by 10-114% over control in all layers, except for the hippocampal plate, but the extent of this increase was smaller than in the dorsal-septal area. Finally,in temporal-ventral levels, SNAP-25 expression was reduced in all infected layers by 21-33% below control except for mild increases of 8.8 and 10% in subplate and hippocampal plate layers. Additionally, the infected SNAP-25 maximal density bin shifted to lower values dorsally and to higher values medially, with ventral maximal bins remaining unchanged when compared to controls. The differential expression of SNAP-25 in the hippocampi of infected neonates indicates a variable degree of vulnerability across the septo-temporal axis of hippocampus. It is surmised that while viral infection may induce excitotoxicity in the ventral hippocampus, it may cause reactive synapto-genesis in the medial and dorsal sectors of the developing brains of postnatal day 0 neonates.

Prenatal exposure to influenza and schizophrenia in Surinamese and Dutch Antillean immigrants to The Netherlands.

There is evidence of an increased incidence of schizophrenia in Afro-Caribbean immigrants to the UK and in Surinamese- and Dutch Antillean immigrants to The Netherlands. We tested the hypothesis that second-trimester exposure to the 1957 A2 influenza pandemic, which swept through the Caribbean in the same period as it affected Western Europe, contributes to this phenomenon. The dates of birth of immigrants, discharged from a Dutch psychiatric institute with a diagnosis of schizophrenia, were examined for any effect of the pandemic. Individuals who were in their second-trimester of fetal life at the peak of the pandemic were at no greater risk of developing schizophrenia than controls.

Prenatal exposure to influenza and increased cerebrospinal fluid spaces in schizophrenia.

Several epidemiological studies have suggested that maternal exposure to influenza during midgestation is a risk factor for schizophrenia. In exploring the possible pathogenic mechanism, we examined the relationship between computed tomography structural brain measures in 83 schizophrenia patients and 113 controls and also their risk of maternal exposure to influenza. Four brain measures of the cerebrospinal fluid (CSF) spaces (lateral ventricle, maximum third ventricle, sulcal fluid, and sylvian fissure) were investigated in relation to the risk exposure level. In schizophrenia patients, these measures, in particular sylvian fissures, were found to increase with higher levels of risk exposure to influenza during the susceptible period (i.e., midgestation); no such effect was found in controls. These results indicate that risk for midgestational influenza exposure is associated with generalized enlargement of the CSF spaces, especially in the region of the temporal lobe. The findings suggest that certain morphological abnormalities of the brain frequently reported in schizophrenia patients may be partly attributable to antenatal exposure to influenza.