Alternative patterns of sex chromosome differentiation in Aedes aegypti (L).

BACKGROUND: Some populations of West African Aedes aegypti, the dengue and zika vector, are reproductively incompatible; our earlier study showed that divergence and rearrangements of genes on chromosome 1, which bears the sex locus (M), may be involved. We also previously described a proposed cryptic subspecies SenAae (PK10, Senegal) that had many more high inter-sex FST genes on chromosome 1 than did Ae.aegypti aegypti (Aaa, Pai Lom, Thailand). The current work more thoroughly explores the significance of those findings. RESULTS: Intersex standardized variance (FST) of single nucleotide polymorphisms (SNPs) was characterized from genomic exome capture libraries of both sexes in representative natural populations of Aaa and SenAae. Our goal was to identify SNPs that varied in frequency between males and females, and most were expected to occur on chromosome 1. Use of the assembled AaegL4 reference alleviated the previous problem of unmapped genes. Because the M locus gene nix was not captured and not present in AaegL4, the male-determining locus, per se, was not explored. Sex-associated genes were those with FST values ≥ 0.100 and/or with increased expected heterozygosity (H exp , one-sided T-test, p < 0.05) in males. There were 85 genes common to both collections with high inter-sex FST values; all genes but one were located on chromosome 1. Aaa showed the expected cluster of high inter-sex FST genes proximal to the M locus, whereas SenAae had inter-sex FST genes along the length of chromosome 1. In addition, the Aaa M-locus proximal region showed increased H exp levels in males, whereas SenAae did not. In SenAae, chromosomal rearrangements and subsequent suppressed recombination may have accelerated X-Y differentiation. CONCLUSIONS: The evidence presented here is consistent with differential evolution of proto-Y chromosomes in Aaa and SenAae

Shotgun Sequencing Analysis of Trypanosoma cruzi I Sylvio X10/1 and Comparison with T. cruzi VI CL Brener

Trypanosoma cruzi is the causative agent of Chagas disease, which affects more than 9 million people in Latin America. We have generated a draft genome sequence of the TcI strain Sylvio X10/1 and compared it to the TcVI reference strain CL Brener to identify lineage-specific features. We found virtually no differences in the core gene content of CL Brener and Sylvio X10/1 by presence/absence analysis, but 6 open reading frames from CL Brener were missing in Sylvio X10/1. Several multicopy gene families, including DGF, mucin, MASP and GP63 were found to contain substantially fewer genes in Sylvio X10/1, based on sequence read estimations. 1,861 small insertion-deletion events and 77,349 nucleotide differences, 23% of which were non-synonymous and associated with radical amino acid changes, further distinguish these two genomes. There were 336 genes indicated as under positive selection, 145 unique to T. cruzi in comparison to T. brucei and Leishmania. This study provides a framework for further comparative analyses of two major T. cruzi lineages and also highlights the need for sequencing more strains to understand fully the genomic composition of this parasite

Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis

Background The infection-fatality ratio (IFR) is a metric that quantifies the likelihood of an individual dying once infected with a pathogen. Understanding the determinants of IFR variation for COVID-19, the disease caused by the SARS-CoV-2 virus, has direct implications for mitigation efforts with respect to clinical practice, non-pharmaceutical interventions, and the prioritisation of risk groups for targeted vaccine delivery. The IFR is also a crucial parameter in COVID-19 dynamic transmission models, providing a way to convert a population's mortality rate into an estimate of infections.Methods We estimated age-specific and all-age IFR by matching seroprevalence surveys to total COVID-19 mortality rates in a population. The term total COVID-19 mortality refers to an estimate of the total number of deaths directly attributable to COVID-19. After applying exclusion criteria to 5131 seroprevalence surveys, the IFR analyses were informed by 2073 all-age surveys and 718 age-specific surveys (3012 age-specific observations). When seroprevalence was reported by age group, we split total COVID-19 mortality into corresponding age groups using a Bayesian hierarchical model to characterise the non-linear age pattern of reported deaths for a given location. To remove the impact of vaccines on the estimated IFR age pattern, we excluded age-specific observations of seroprevalence and deaths that occurred after vaccines were introduced in a location. We estimated age-specific IFR with a non-linear meta-regression and used the resulting age pattern to standardise all-age IFR observations to the global age distribution. All IFR observations were adjusted for baseline and waning antibody-test sensitivity. We then modelled age-standardised IFR as a function of time, geography, and an ensemble of 100 of the top-performing covariate sets. The covariates included seven clinical predictors (eg, age-standardised obesity prevalence) and two measures of health system performance. Final estimates for 190 countries and territories, as well as subnational locations in 11 countries and territories, were obtained by predicting age-standardised IFR conditional on covariates and reversing the age standardisation.Findings We report IFR estimates for April 15, 2020, to January 1, 2021, the period before the introduction of vaccines and widespread evolution of variants. We found substantial heterogeneity in the IFR by age, location, and time. Age-specific IFR estimates form a J shape, with the lowest IFR occurring at age 7 years (0-0023%, 95% uncertainty interval [UI] 0-0015-0-0039) and increasing exponentially through ages 30 years (0-0573%, 0-0418-0-0870), 60 years (1-0035%, 0-7002-1-5727), and 90 years (20-3292%, 14-6888-28-9754). The countries with the highest IFR on July 15, 2020, were Portugal (2-085%, 0-946-4-395), Monaco (1-778%, 1-265-2-915), Japan (1-750%, 1-302-2-690), Spain (1-710%, 0-991-2-718), and Greece (1-637%, 1-155-2-678). All-age IFR varied by a factor of more than 30 among 190 countries and territories.After age standardisation, the countries with the highest IFR on July 15, 2020, were Peru (0-911%, 0-636-1-538), Portugal (0-850%, 0-386-1-793), Oman (0-762%, 0-381-1-399), Spain (0-751%, 0-435-1-193), and Mexico (0-717%, 0-426-1-404). Subnational locations with high IFRs also included hotspots in the UK and southern and eastern states of the USA. Sub-Saharan African countries and Asian countries generally had the lowest all-age and age-standardised IFRs. Population age structure accounted for 74% of logit-scale variation in IFRs estimated for 39 in-sample countries on July 15, 2020. A post-hoc analysis showed that high rates of transmission in the care home population might account for higher IFRs in some locations. Among all countries and territories, we found that the median IFR decreased from 0-466% (interquartile range 0-223-0-840) to 0-314% (0-143-0-551) between April 15, 2020, and Jan 1, 2021.Interpretation Estimating the IFR for global populations helps to identify relative vulnerabilities to COVID-19. Information about how IFR varies by age, time, and location informs clinical practice and non-pharmaceutical interventions like physical distancing measures, and underpins vaccine risk stratification. IFR and mortality risk form a J shape with respect to age, which previous research, such as that by Glynn and Moss in 2020, has identified to be a common pattern among infectious diseases. Understanding the experience of a population with COVID-19 mortality requires consideration for local factors; IFRs varied by a factor of more than 30 among 190 countries and territories in this analysis. In particular, the presence of elevated age-standardised IFRs in countries with well resourced health-care systems indicates that factors beyond health-care capacity are important. Potential extenuating circumstances include outbreaks among care home residents, variable burdens of severe cases, and the population prevalence of comorbid conditions that increase the severity of COVID-19 disease. During the pre-vaccine period, the estimated 33% decrease in median IFR over 8 months suggests that treatment for COVID-19 has improved over time. Estimating IFR for the pre-vaccine era provides an important baseline for describing the progression of COVID-19 mortality patterns.Funding Bill &amp; Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

Pregnancy Outcome and Placenta Pathology in Plasmodium berghei ANKA Infected Mice Reproduce the Pathogenesis of Severe Malaria in Pregnant Women

Pregnancy-associated malaria (PAM) is expressed in a range of clinical complications that include increased disease severity in pregnant women, decreased fetal viability, intra-uterine growth retardation, low birth weight and infant mortality. The physiopathology of malaria in pregnancy is difficult to scrutinize and attempts were made in the past to use animal models for pregnancy malaria studies. Here, we describe a comprehensive mouse experimental model that recapitulates many of the pathological and clinical features typical of human severe malaria in pregnancy. We used P. berghei ANKA-GFP infection during pregnancy to evoke a prominent inflammatory response in the placenta that entails CD11b mononuclear infiltration, up-regulation of MIP-1 alpha chemokine and is associated with marked reduction of placental vascular spaces. Placenta pathology was associated with decreased fetal viability, intra-uterine growth retardation, gross post-natal growth impairment and increased disease severity in pregnant females. Moreover, we provide evidence that CSA and HA, known to mediate P. falciparum adhesion to human placenta, are also involved in mouse placental malaria infection. We propose that reduction of maternal blood flow in the placenta is a key pathogenic factor in murine pregnancy malaria and we hypothesize that exacerbated innate inflammatory responses to Plasmodium infected red blood cells trigger severe placenta pathology. This experimental model provides an opportunity to identify cell and molecular components of severe PAM pathogenesis and to investigate the inflammatory response that leads to the observed fetal and placental blood circulation abnormalities

Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?

The sequestration of Plasmodium falciparum–infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration