Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association ($P$-value≤5×10$^{−8}$) in 20 variants located at the $\textit{CFH}$ gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR)=0.62, 95% confidence interval (C.I.)=0.52–0.73; $P$-value=9.62×10$^{−9}$). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR=0.64, 95% C.I.)=0.55–0.76, $\textit{P-value}$=3.25×10$^{−8}$). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of $\textit{CFH}$ with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.This study received support from the Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Instituto Carlos III (Intensificación de la actividad investigadora) (A.V.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2012, PI16/01569), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I+ D+ I and ‘fondos FEDER’ (F.M.T.). More information at: www. esigem.org. The UK cohort was established with support of the Meningitis Research Foundation (UK), who provide ongoing support, and the European Society for Paediatric Infectious Diseases supported the establishment of the international collaboration. This study makes use of data generated by the Wellcome Trust Case-Control Consortium 2. A full list of the investigators who contributed to the generation of the data is available from www. wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 085475. The research leading to these results has received funding from the European Union’s Seventh Framework Programme under EC-GA No. 279185 (EUCLIDS)

Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study

Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p<0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%]), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%]), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis. Interpretation: Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients

Further considerations on rotavirus vaccination and seizure-related hospitalization rates

Jose G&oacute;mez-Rial,1,2 Sonia S&aacute;nchez-Bat&aacute;n,2 Irene Rivero-Calle,1,3 Jacobo Pardo-Seco,1 Jos&eacute; Mar&iacute;a Martin&oacute;n-Mart&iacute;nez,1 Antonio Salas,1,4&ndash;5 Federico Martin&oacute;n-Torres1,31Grupo de Investigaci&oacute;n en Gen&eacute;tica, Vacunas, Infecciones y Pediatr&iacute;a (GENVIP), Instituto de Investigaci&oacute;n Sanitaria (IDIS), Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS); 2Laboratorio de Inmunolog&iacute;a, Servicio de An&aacute;lisis Cl&iacute;nicos, Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS); 3Pediatr&iacute;a Trasnlacional y Enfermedades Infecciossas, Departamento de Pediatr&iacute;a, Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS); 4Unidade de Xen&eacute;tica, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela; 5GenPoB Research Group, Instituto de Investigaci&oacute;n Sanitaria de Santiago (IDIS), Hospital Cl&iacute;nico Universitario de Santiago (SERGAS), Galicia, SpainWe have read with interest the comments from Orrico-S&aacute;nchez et al1 regarding our recent paper on extraintestinal features of rotavirus (RV) infection.2 Their main concerns relate to the section dealing with the potential of RV vaccines to decrease hospitalizations due to seizures, and more specifically, the issues we raised in regards to their non-significant findings that might have been caused by the use of an overfitted statistical model.3 As our article was a general review beyond the relationship between RV and seizures, we did not have room for detailed explanations. We now take the opportunity to address Orrico-S&aacute;nchez et al&#39;s concerns.3This is in response to the Letter to the EditorView the original paper by G&oacute;mez-Rial and colleagues&nbsp

Rotavirus infection beyond the gut

Jos&eacute; G&oacute;mez-Rial,1,2 Sonia S&aacute;nchez-Bat&aacute;n,2 Irene Rivero-Calle,1,3 Jacobo Pardo-Seco,1 Jos&eacute; Mar&iacute;a Martin&oacute;n-Mart&iacute;nez,1 Antonio Salas,1,4,5 Federico Martin&oacute;n-Torres1,3 1Grupo de Investigaci&oacute;n en Gen&eacute;tica, Vacunas, Infecciones y Pediatr&iacute;a (GENVIP), Instituto de Investigaciones Sanitarias (IDIS), Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS), Galicia, Spain; 2Laboratorio de Inmunolog&iacute;a, Servicio de An&aacute;lisis Cl&iacute;nicos, Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS), Galicia, Spain; 3Translational Pediatrics and Infectious Diseases, Department of Pediatrics, Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS), Galicia, Spain; 4Unidade de Xen&eacute;tica, Departamento de Anatom&iacute;a Patol&oacute;xica e Ciencias Forense, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Galicia, Spain; 5GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Cl&iacute;nico Universitario de Santiago de Compostela (SERGAS), Galicia, Spain Abstract: The landscape of rotavirus (RV) infection has changed substantially in recent years. Autoimmune triggering has been added to clinical spectrum of this pathology, which is now known to be much broader than diarrhea. The impact of RV vaccines in these other conditions is becoming a growing field of research. The importance of host genetic background in RV susceptibility has been revealed, therefore increasing our understanding of vaccine effectiveness and giving some clues about the limited efficacy of RV vaccines in low-income settings. Also, interaction of RV with intestinal microbiota seems to play a key role in the process of infection vaccine effect. This article reviews current findings on the extraintestinal impact of RV infection and their widening clinical picture, and the recently described mechanisms of host susceptibility to infection and vaccine effectiveness. RV infection is a systemic disease with clinical and pathophysiological implications beyond the gut. We propose an &ldquo;iceberg&rdquo; model for this pathology with almost hidden clinical implications away from the gastrointestinal tract and eventually triggering the development of autoimmune diseases. Impact of current vaccines is being influenced by host genetics and gut microbiota interactions and these factors must be taken into account in the development of public health programs. Keywords: rotavolution, extraintestinal, seizures, vaccines, autoimmunit

Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease

A mitochondrial genome sequence of a hominin from Sima de los Huesos

Excavations of a complex of caves in the Sierra de Atapuerca in northern Spain have unearthed hominin fossils that range in age from the early Pleistocene to the Holocene1. One of these sites, the ‘Sima de los Huesos’ (‘pit of bones’), has yielded the world’s largest assemblage of Middle Pleistocene hominin fossils2,3, consisting of at least 28 individuals4 dated to over 300,000 years ago5. The skeletal remains share a number of morphological features with fossils classified as Homo heidelbergensis and also display distinct Neanderthal-derived traits6,7,8. Here we determine an almost complete mitochondrial genome sequence of a hominin from Sima de los Huesos and show that it is closely related to the lineage leading to mitochondrial genomes of Denisovans9,10, an eastern Eurasian sister group to Neanderthals. Our results pave the way for DNA research on hominins from the Middle Pleistocene

Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study

BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6–97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3–88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3–97·6) for patients with predicted bacterial infection and 94·7% (87·8–100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1–96·2) for patients with predicted bacterial infection and 69·6% (53·1–86·0) for patients with predicted viral infection. INTERPRETATION: In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. FUNDING: Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre