Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata

University of Adelaide Genographic Consortium contributers: Christina J. Adler, Alan Cooper, Clio S. I. Der Sarkissian, Wolfgang Haak.Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in ~900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West–South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in Europe.Alessio Boattini, Begoña Martinez-Cruz, Stefania Sarno, Christine Harmant, Antonella Useli, Paula Sanz, Daniele Yang-Yao, Jeremy Manry, Graziella Ciani, Donata Luiselli, Lluis Quintana- Murci, David Comas, Davide Pettener, the Genographic Consortiu

Evolutionary genetics evidence of an essential, non-redundant role of the IFN-γ pathway in protective immunity

International audienceIdentifying how natural selection has affected immunity-related genes can provide insights into the mechanisms that have been crucial for our survival against infection. Rare disorders of either chain of the IFN-γ receptor, but not of IFN-γ itself, have been shown to confer predisposition to mycobacterial disease in patients otherwise normally resistant to most viruses. Here, we defined the levels of naturally-occurring variation in the three specific genes controlling the IFN-γ pathway (IFNG, IFNGR1, IFNGR2) and assessed whether and how natural selection has acted on them. To this end, we resequenced the three genes in 186 individuals from sub-Saharan Africa, Europe and East-Asia. Our results show that IFNG is subject to strong purifying selection against nonsynonymous variants. Conversely, IFNGR1 and IFNGR2 evolve under more relaxed selective constraints, although they are not completely free to accumulate amino-acid variation having a major impact on protein function. In addition, we have identified signatures of population-specific positive selection, including at one intronic variant known to be associated with higher production of IFN-γ. The integration of our population genetic data into a clinical framework demonstrates that the IFN-γ pathway is essential and non-redundant in host defense, probably because of its role in protective immunity against mycobacteria

Functional characterisation of naturally occurring genetic variants in the human TLR1-2-6 gene family

International audienceToll-like receptors are considered an essential component of the innate immune system, initiating inflammatory responses following infection of the host. Humans have 10 functional TLRs, differing in their subcellular distributions and the microbial agonists they sense. The phylogenetically-conserved TLR1-2-6 family is unique in that TLR1 and TLR6 form heterodimers with TLR2 to mediate signalling in response to agonists. Epidemiological genetic studies have identified several TLR variants that appear to influence susceptibility to infectious diseases, but the functional consequences of which remain largely unknown. Here, we assessed the functional impact of the TLR1-2-6 variants with altered amino-acid sequences segregating naturally in the human population. We used an NF-κB reporter assay in TLR-transfected human embryonic kidney 293T cells stimulated with the corresponding TLR agonists. We found that among the 41 naturally occurring variants with amino-acid alterations identified in the TLR1-2-6 family, 14 of them (5 TLR1, 4 TLR2, and 5 TLR6 variants) displayed marked impairment of NF-B activation. Most of these variants are present at very low population frequencies and are population-specific. These observations suggest that rare, non-synonymous TLR mutations are likely to have deleterious effects on immune responses and may therefore contribute to complex susceptibility to infection at the population level

Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

International audienceBuruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a sample of 1524 well characterized patients and controls from rural Benin. Two-stage analyses identify two variants located within LncRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85 × 10-7; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85 × 10-8; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest LncRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer

The Basque paradigm: genetic evidence of a maternal continuity in the Franco-Cantabrian region since pre-neolithic times

Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe.We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H.We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ~4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ~8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland.Doron M. Behar... Wolfgang Haak... Christina Adler... Alan Cooper... Clio Der Sarkissian... et al

Skin-specific antibodies neutralizing mycolactone toxin during the spontaneous healing of Mycobacterium ulcerans infection

International audienceBuruli ulcer, a neglected tropical infectious disease, is caused by Mycobacterium ulcerans. Without treatment, its lesions can progress to chronic skin ulcers, but spontaneous healing is observed in 5% of cases, suggesting the possible establishment of a host strategy counteracting the effects of M. ulcerans. We reveal here a skin-specific local humoral signature of the spontaneous healing process, associated with a rise in antibody-producing cells and specific recognition of mycolactone by the mouse IgG2a immunoglobulin subclass. We demonstrate the production of skin-specific antibodies neutralizing the immunomodulatory activity of the mycolactone toxin, and confirm the role of human host machinery in triggering effective local immune responses by the detection of anti-mycolactone antibodies in patients with Buruli ulcer. Our findings pave the way for substantial advances in both the diagnosis and treatment of Buruli ulcer in accordance with the most recent challenges issued by the World Health Organization

The Basque paradigm: genetic evidence of a maternal continuity in the Franco-Cantabrian region since pre-Neolithic times

Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at 4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at 8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland

Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata

Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in 900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West–South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in EuropeThis study was supported by Strategic Project 2006-09 from the University of Bologna to DP and from MIUR PRIN 2007 and 2009 Grants to DP. The project was also supported by the Spanish Government grant CGL2010-14944/BO