The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state ...of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).
PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.
The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.
Clinical resistance against Bedaquiline, the first new anti-tuberculosis compound with a novel mechanism of action in over 40 years, has already been detected in Mycobacterium tuberculosis. As a new ...drug, however, there is currently insufficient clinical data to facilitate reliable and timely identification of genomic determinants of resistance. Here we investigate the structural basis for M. tuberculosis associated bedaquiline resistance in the drug target, AtpE. Together with the 9 previously identified resistance-associated variants in AtpE, 54 non-resistance-associated mutations were identified through comparisons of bedaquiline susceptibility across 23 different mycobacterial species. Computational analysis of the structural and functional consequences of these variants revealed that resistance associated variants were mainly localized at the drug binding site, disrupting key interactions with bedaquiline leading to reduced binding affinity. This was used to train a supervised predictive algorithm, which accurately identified likely resistance mutations (93.3% accuracy). Application of this model to circulating variants present in the Asia-Pacific region suggests that current circulating variants are likely to be susceptible to bedaquiline. We have made this model freely available through a user-friendly web interface called SUSPECT-BDQ, StrUctural Susceptibility PrEdiCTion for bedaquiline (http://biosig.unimelb.edu.au/suspect_bdq/). This tool could be useful for the rapid characterization of novel clinical variants, to help guide the effective use of bedaquiline, and to minimize the spread of clinical resistance.
A great deal of ink has been spilled reflecting upon the historically contingent nature of race as a category, and as a lived experience. Bringing together the case studies of the interwar sites of ...Harlem, Paris, and London and, in the post-World War Two period of decolonization, the cities of Algiers and Dakar, this article is a contribution to ongoing conversations about how we might develop a critical conceptual apparatus for understanding the relationship between historical examples of black internationalism and the racial assumptions that underpin it by linking it to notions of place.
Methodologies of textual and linguistic analysis have long held sway in Anglo‐American practices of intellectual history. Such approaches tend to decouple the ideas being traced from the human ...subject, or scholar, producing the thought. Taking the lead from the rich theorising work done in feminist, gender, race and cultural histories, this article asks what changes in our understanding of intellectual histories of international thought when we connect the lived and bodily realities of the human subjects producing the ideas to the ideas themselves. In so doing, the article makes a case for the importance of fleshing out what the author calls ‘scholarly habitus’ and suggests the potential utility of oral history as a methodology for reconstructing ‘scholarly habitus’. The article will draw upon an oral history archive comprised of twenty interviews conducted with senior women International Relations scholars from the United States, Canada and the United Kingdom to flesh out this argument. The article argues that oral history, as a medium for autobiographical practice, can reveal aspects of how gender, race and class shaped the scholarly practice and career trajectories of these women, as well as shed light on the historical dynamics of the discipline of International Relations as a whole.
Exposure to
Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish ...larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to
Mycobacterium marinum. A hypersusceptible mutant maps to the
lta4h locus encoding
leukotriene A
4 hydrolase
, which catalyzes the final step in the synthesis of leukotriene B
4 (LTB
4), a potent chemoattractant and proinflammatory eicosanoid.
lta4h mutations confer hypersusceptibility independent of LTB
4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for
LTA4H polymorphisms that have previously been correlated with differential LTB
4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
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► Mutations in zebrafish
lta4h result in hypersusceptibility to mycobacterial infection ► LTA4H activity orchestrates the balance of pro- and anti-inflammatory eicosanoids ► Excess Lipoxin A4 production inhibits TNF induction during infection ► In humans, heterozygosity at the
LTA4H locus protects from tuberculosis and leprosy
Despite devastating mortality among patients with tuberculosis meningitis, little progress has been made in understanding the pathophysiology of this disease since the landmark autopsy studies of ...Rich and McCordick in the 1930s.1 Even with treatment, two-thirds of patients die or are left with severe neurological deficits, including cognitive impairment, epilepsy, and paralysis.2 In The Lancet Infectious Diseases, Arjan van Laarhoven and colleagues3 present an elegant systems biology (or multi-omics) approach designed to elucidate the underlying mechanisms that cause these dire outcomes and ultimately aiming to identify new approaches to therapeutics. Tuberculous meningitis is a paucibacillary disease, with scarcity of organisms in the cerebrospinal fluid (CSF) making it difficult to confirm the diagnosis.4 Harm is done often as a consequence of the host inflammatory response to the invasion of Mycobacterium tuberculosis into the spinal fluid, rather than due to the bacteria themselves.5 However, investigation into the role of the LTA4H pathway has also shown that balance is important, with too weak an inflammatory response being as harmful as too strong a response.6 The complex interplay between different bacterial, host genetic, and environmental factors demands a systems biology approach. van Laarhoven and colleagues3 attempted to use this approach, starting with metabolomics data, combining clinical data, and finally correlating their findings with publicly available data from autopsy samples and genomic data. Proposing that tryptophan metabolism loci could serve as prognostic indicators, the authors then examined genome-wide association data seeking gene variants associated with CSF tryptophan concentrations.
The Two Layer hypothesis is fast becoming the favoured narrative describing East Asian population history. Under this model, hunter-gatherer groups who initially peopled East Asia via a route south ...of the Himalayas were assimilated by agriculturalist migrants who arrived via a northern route across Eurasia. A lack of ancient samples from tropical East Asia limits the resolution of this model. We consider insight afforded by patterns of variation within the human pathogen Mycobacterium tuberculosis (Mtb) by analysing its phylogeographic signatures jointly with the human Y-chromosome. We demonstrate the Y-chromosome lineages enriched in the traditionally hunter-gatherer groups associated with East Asia's first layer of peopling to display deep roots, low long-term effective population size, and diversity patterns consistent with a southern entry route. These characteristics mirror those of the evolutionarily ancient Mtb lineage 1. The remaining East Asian Y-chromosome lineage is almost entirely absent from traditionally hunter-gatherer groups and displays spatial and temporal characteristics which are incompatible with a southern entry route, and which link it to the development of agriculture in modern-day China. These characteristics mirror those of the evolutionarily modern Mtb lineage 2. This model paves the way for novel host-pathogen coevolutionary research hypotheses in East Asia.
Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different ...clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb-stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary, and meningeal TB (n = 4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1,608 and 199 genes that were differentially expressed by >2- and >5-fold, respectively. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to TB.
Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and ...2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.
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