Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians.
Ontology highlight
ABSTRACT:
SUBMITTER: Clemens EB
PROVIDER: S-EPMC5550555 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Indigenous populations, including Indigenous Australians, are highly susceptible to severe influenza disease and the underlying mechanisms are unknown. We studied immune and genetic factors that could predicate severe influenza disease in Indigenous Australians enrolled in the LIFT study: looking into influenza T-cell immunity. To examine CD8(+) T-cell immunity, we characterised human leukocyte antigen (HLA) profiles. HLA typing confirmed previous studies showing predominant usage of HLA-A*02:01, 11:01, 24:02, 34:01 and HLA-B*13:01, 15:21, 40:01/02, 56:01/02 in Indigenous Australians. We identified two new HLA alleles (HLA-A*02:new and HLA-B*56:new). Modelling suggests that variations within HLA-A*02:new (but not HLA-B56:new) could affect peptide binding. There is a relative lack of known influenza epitopes for the majority of these HLAs, with the exception of a universal HLA-A*02:01-M158 epitope and proposed epitopes presented by HLA-A*11:01/HLA-A*24:02. To dissect universal CD8(+) T-cell responses, we analysed the magnitude, function and T-cell receptor (TCR) clonality of HLA-A*02:01-M158(+)CD8(+) T cells. We found comparable IFN-?, TNF and CD107a and TCR?? characteristics in Indigenous and non-Indigenous Australians, suggesting that the ~15% of Indigenous people that express HLA-A*02:01 have universal influenza-specific CD8(+) T-cell immunity. Furthermore, the frequency of an influenza host risk factor, IFITM3-C/C, was comparable between Indigenous Australians and Europeans, suggesting that expression of this allele does not explain increased disease severity at a population level. Our study indicates a need to identify novel influenza-specific CD8(+) T-cell epitopes restricted by HLA-A and HLA-B alleles prevalent in Indigenous populations for the rational design of universal T-cell vaccines.
| S-EPMC4840236 | biostudies-literature
Project description:Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.
| S-EPMC8522271 | biostudies-literature
Project description:Indigenous Australians experience one of the highest rates of pneumococcal disease globally. In the Northern Territory of Australia, a unique government-funded vaccination schedule for Indigenous Australian adults comprising multiple lifetime doses of the pneumococcal polysaccharide vaccine is currently implemented. Despite this programme, rates of pneumococcal disease do not appear to be declining, with concerns raised over the potential for immune hyporesponse associated with the use of this vaccine. We undertook a study to examine the immunogenicity and immune function of a single and repeat pneumococcal polysaccharide vaccination among Indigenous adults compared to non-Indigenous adults. Our results found that immune function, as measured by opsonophagocytic and memory B-cell responses, were similar between the Indigenous groups but lower for some serotypes in comparison with the non-Indigenous group. This is the first study to document the immunogenicity following repeat 23-valent pneumococcal polysaccharide vaccine administration among Indigenous Australian adults, and reinforces the continued need for optimal pneumococcal vaccination programmes among high-risk populations.
| S-EPMC5671990 | biostudies-literature
Project description:Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.
| S-EPMC3034774 | biostudies-other
Project description:OBJECTIVE:To examine the prevalence of atrial fibrillation (AF) and cardiac structural characteristics in Indigenous and non-Indigenous Australians. DESIGN:Retrospective cross-sectional study linking clinical, echocardiography and administrative databases over a 10-year period. SETTING:A tertiary, university teaching hospital in Adelaide, Australia. PARTICIPANTS:Indigenous and non-Indigenous Australians. MAIN OUTCOME MEASURES:AF prevalence and echocardiographic characteristics. RESULTS:Indigenous Australians with AF were significantly younger compared to non-Indigenous Australians (55±13 vs 75±13 years, p<0.001). As a result, racial differences in AF prevalence and left atrial diameter varied according to age. In those under 60 years of age, Indigenous Australians had a significantly greater AF prevalence (2.57 vs1.73%, p<0.001) and left atrial diameters (39±7 vs 37±7 mm, p<0.001) compared to non-Indigenous Australians. In those aged 60 years and above, however, non-Indigenous Australians had significantly greater AF prevalence (9.26 vs 4.61%, p<0.001) and left atrial diameters (39±7 vs 37±7 mm, p<0.001). Left ventricular ejection fractions were less in Indigenous Australians under 60 years of age (49±14 vs 55±11%, p<0.001) and not statistically different in those aged 60 years and above (47±11 vs 52±13, p=0.074) compared to non-Indigenous Australians. Despite their younger age, Indigenous Australians with AF had similar or greater rates of cardiovascular comorbidities than non-Indigenous Australians with AF. CONCLUSIONS:Young Indigenous Australians have a significantly greater prevalence of AF than their non-Indigenous counterparts. In contrast, older non-Indigenous Australians have a greater prevalence of AF compared to their Indigenous counterparts. These observations may be mediated by age-based differences in comorbid cardiovascular conditions, left atrial diameter and left ventricular ejection fraction. Our findings suggest that AF is likely to be contributing to the greater burden of morbidity and mortality experienced by young Indigenous Australians. Further study is required to elucidate whether strategies to prevent and better manage AF in Indigenous Australians may reduce this burden.
| S-EPMC4212186 | biostudies-literature
Project description:BackgroundCardiovascular diseases contribute substantially to the poor health and reduced life expectancy of Indigenous Australians. Heart failure is a common, disabling, progressive and costly complication of these disorders. The epidemiology of heart failure and the adequacy of relevant health service provision in Indigenous Australians are not well delineated.MethodsA systematic search of the electronic databases PubMed, Embase, Web of Science, Cinahl Plus, Informit and Google Scholar was undertaken in April 2012 for peer-reviewed journal articles relevant to the topic of heart failure in Indigenous Australians. Additionally, a website search was done to identify other pertinent publications, particularly government reports.ResultsThere was a paucity of relevant peer-reviewed research, and government reports dominated the results. Ten journal articles, 1 published conference abstract and 10 reports were eligible for inclusion. Indigenous Australians reportedly have higher morbidity and mortality from heart failure than their non-Indigenous counterparts (age-standardised prevalence ratio 1.7; age-standardised hospital separation ratio ?3; crude per capita hospital expenditure ratio 1.58; age-adjusted mortality ratio >2). Despite the evident disproportionate burden of heart failure in Indigenous Australians, the accuracy of estimation from administrative data is limited by poor indigenous identification, inadequate case ascertainment and exclusion of younger subjects from mortality statistics. A recent journal article specifically documented a high prevalence of heart failure in Central Australian Aboriginal adults (5.3%), noting frequent undiagnosed disease. One study examined barriers to health service provision for Indigenous Australians in the context of heart failure.ConclusionsDespite the shortcomings of available published data, it is clear that Indigenous Australians have an excess burden of heart failure. Emerging data suggest that undiagnosed cases may be common in this population. In order to optimise management and to inform policy, high quality research on heart failure in Indigenous Australians is required to delineate accurate epidemiological indicators and to appraise health service provision.
| S-EPMC3521206 | biostudies-literature
Project description:Conservation and environmental management have been reported as offering opportunities to substantially improve the wellbeing of Indigenous people. Using the holistic wellbeing impact evaluation (W-IE) approach-well suited for use in Indigenous communities-we interviewed 190 Indigenous Australians across four communities. All communities were involved in the Indigenous land and sea management programs (ILSMPs). Our study explored the conceptualisation of 'wellbeing' by participants. In particular, we were interested in the aspects of wellbeing perceived to be affected by ILSMPs. Out of the 26 wellbeing factors explored, 'Health centres'; 'Language'; 'Schools'; and 'Safe community' emerged as being of highest importance to the largest percentage of the respondents. When grouped using principle components analysis (PCA), the 'Community and society' domain emerged as the most important; accounting for 52% of the overall importance of all wellbeing factors. The second most important domain was the 'Country and culture', contributing 31%. Lastly, 'Economic aspects' contributed only 17%. Respondents believed that ILSMPs have played a considerable causal role in improving wellbeing, by positively changing factors most important to them. Specifically, 73% of perceived causal links were related to improvements in the 'Country and Culture' and 23% to 'Community and Society' domain. We thus conclude that land management for Indigenous people is much more than ecological or environmental management with ILSMPs, perceived to cause a wide range of cultural and social benefits. We also propose ways in which the future design of such programs could be improved to further increase benefits.
| S-EPMC6981778 | biostudies-literature
Project description:Among previously healthy children with severe influenza, the mechanisms leading to increased pathology are not understood. We hypothesized that children with severe influenza would have high levels of circulating cytokines. To examine this, we recruited patients with severe influenza and examined plasma cytokine levels as well as the ability of peripheral blood cells to respond to stimuli. Ten patients with severe influenza were enrolled during the 2005-2007 influenza seasons. We evaluated plasma cytokine levels, circulating NK cells, and responses to TLR ligands during the illness. We compared these patients with five patients with moderate influenza, six patients with respiratory syncytial virus (RSV), and 24 noninfected controls. Patients with influenza showed depressed responses to TLR ligands when compared with RSV patients and healthy controls (P<0.05). These normalized when retested during a convalescent phase. Plasma levels of IL-6, IL-12, and IFN- were elevated in influenza patients compared with controls (P<0.05). A compromised ability to produce TNF- was reproduced by in vitro infection, and the magnitude of the effect correlated with the multiplicity of infection and induction of IFN regulatory factor 4 expression. Aberrant, systemic, innate responses to TLR ligands during influenza infection may be a consequence of specific viral attributes such as a high inoculum or rapid replication and may underlie the known susceptibility of influenza-infected patients to secondary bacterial infections.
| S-EPMC2698588 | biostudies-literature
Project description:BackgroundChronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations. Despite the identification of numerous genetic loci associated with kidney disease through GWAS, the Indigenous population such as Tiwi remains severely underrepresented and the increased prevalence of CKD in this population may be due to unique disease-causing alleles/genes.MethodsWe used albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) to estimate the prevalence of kidney disease in the Tiwi population (N = 492) in comparison to the UK Biobank (UKBB) (N = 134,724) database. We then performed an exploratory factor analysis to identify correlations among 10 CKD-related phenotypes and identify new multi-phenotype factors. We subsequently conducted a genome-wide association study (GWAS) on all single and multiple phenotype factors using mixed linear regression models, adjusted for age, sex, population stratification, and genetic relatedness between individuals.ResultsBased on ACR, 20.3% of the population was at severely increased risk of CKD progression and showed elevated levels of ACR compared to the UKBB population independent of HbA1c. A GWAS of ACR revealed novel association loci in the genes MEG3 (chr14:100812018:T:A), RAB36 (rs11704318), and TIAM2 (rs9689640). Additionally, multiple phenotypes GWAS of ACR, eGFR, urine albumin, and serum creatinine identified a novel variant that mapped to the gene MEIS2 (chr15:37218869:A:G). Most of the identified variants were found to be either absent or rare in the UKBB population.ConclusionsOur study highlights the Tiwi population's predisposition towards elevated ACR, and the collection of novel genetic variants associated with kidney function. These associations may prove valuable in the early diagnosis and treatment of renal disease in this underrepresented population. Additionally, further research is needed to comprehensively validate the functions of the identified variants/genes.
| S-EPMC10860247 | biostudies-literature
Project description:ObjectivesTo quantify the independent roles of geography and Indigenous status in explaining disparities in Potentially Preventable Hospital (PPH) admissions between Indigenous and non-Indigenous Australians.Design, setting and participantsAnalysis of linked hospital admission data for New South Wales (NSW), Australia, for the period July 1 2003 to June 30 2008.Main outcome measuresAge-standardised admission rates, and rate ratios adjusted for age, sex and Statistical Local Area (SLA) of residence using multilevel models.ResultsPPH diagnoses accounted for 987,604 admissions in NSW over the study period, of which 3.7% were for Indigenous people. The age-standardised PPH admission rate was 76.5 and 27.3 per 1,000 for Indigenous and non-Indigenous people respectively. PPH admission rates in Indigenous people were 2.16 times higher than in non-Indigenous people of the same age group and sex who lived in the same SLA. The largest disparities in PPH admission rates were seen for diabetes complications, chronic obstructive pulmonary disease and rheumatic heart disease. Both rates of PPH admission in Indigenous people, and the disparity in rates between Indigenous than non-Indigenous people, varied significantly by SLA, with greater disparities seen in regional and remote areas than in major cities.ConclusionsHigher rates of PPH admission among Indigenous people are not simply a function of their greater likelihood of living in rural and remote areas. The very considerable geographic variation in the disparity in rates of PPH admission between Indigenous and non-Indigenous people indicates that there is potential to reduce unwarranted variation by characterising outlying areas which contribute the most to this disparity.
| S-EPMC4032338 | biostudies-literature