Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation.

BACKGROUND: Tuberculosis (TB) remains a major public health problem globally, even compared to COVID-19. Genome-wide studies have failed to discover genes that explain a large proportion of genetic risk for adult pulmonary TB, and even fewer have examined genetic factors underlying TB severity, an intermediate trait impacting disease experience, quality of life, and risk of mortality. No prior severity analyses used a genome-wide approach. METHODS AND FINDINGS: As part of our ongoing household contact study in Kampala, Uganda, we conducted a genome-wide association study (GWAS) of TB severity measured by TBScore, in two independent cohorts of culture-confirmed adult TB cases (n = 149 and n = 179). We identified 3 SNPs (P<1.0 x 10-7) including one on chromosome 5, rs1848553, that was GWAS significant (meta-analysis p = 2.97x10-8). All three SNPs are in introns of RGS7BP and have effect sizes corresponding to clinically meaningful reductions in disease severity. RGS7BP is highly expressed in blood vessels and plays a role in infectious disease pathogenesis. Other genes with suggestive associations defined gene sets involved in platelet homeostasis and transport of organic anions. To explore functional implications of the TB severity-associated variants, we conducted eQTL analyses using expression data from Mtb-stimulated monocyte-derived macrophages. A single variant (rs2976562) associated with monocyte SLA expression (p = 0.03) and subsequent analyses indicated that SLA downregulation following MTB stimulation associated with increased TB severity. Src Like Adaptor (SLAP-1), encoded by SLA, is highly expressed in immune cells and negatively regulates T cell receptor signaling, providing a potential mechanistic link to TB severity. CONCLUSIONS: These analyses reveal new insights into the genetics of TB severity with regulation of platelet homeostasis and vascular biology being central to consequences for active TB patients. This analysis also reveals genes that regulate inflammation can lead to differences in severity. Our findings provide an important step in improving TB patient outcomes.

Correction: Fraik et al. The Impacts of Dam Construction and Removal on the Genetics of Recovering Steelhead (Oncorhynchus mykiss) Populations across the Elwha River Watershed. Genes 2021, 12, 89.

In the original publication [...].

Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide Association Study.

BACKGROUND: Pulmonary tuberculosis (TB) is one of the most deadly pathogens on earth. However, the majority of people have resistance to active disease. Further, some individuals, termed resisters (RSTRs), do not develop traditional latent tuberculosis (LTBI). The RSTR phenotype is important for understanding pathogenesis and preventing TB. The host genetic underpinnings of RSTR are largely understudied. METHODS: In a cohort of 908 Ugandan subjects with genome-wide data on single nucleotide polymorphisms, we assessed the heritability of the RSTR phenotype and other TB phenotypes using restricted maximum likelihood estimation (REML). We then used a subset of 263 RSTR and LTBI subjects with high quality phenotyping and long-term follow-up to identify DNA variants genome-wide associated with the RSTR phenotype relative to LTBI subjects in a case-control GWAS design and annotated and enriched these variants to better understand their role in TB pathogenesis. RESULTS: The heritability of the TB outcomes was very high, at 55% for TB vs. LTBI and 50.4% for RSTR vs. LTBI among HIV- subjects, controlling for age and sex. We identified 27 loci associated with the RSTR phenotype (P<5e-05) and our annotation and enrichment analyses suggest an important regulatory role for many of them. INTERPRETATION: The heritability results show that the genetic contribution to variation in TB outcomes is very high and our GWAS results highlight variants that may play an important role in resistance to infection as well as TB pathogenesis as a whole.

Interaction between M. tuberculosis Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB.

Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and Mycobacterium tuberculosis (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothesize that long-term coexistence between human genomes and MTBC lineages modulates disease to affect its severity. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which we identified three MTBC lineages, of which one, L4.6-Uganda, is clearly derived and hence recent. We quantified TB severity using the Bandim TBscore and examined the interaction between MTBC lineage and human single-nucleotide polymorphisms (SNPs) genome-wide, in two independent cohorts of TB cases (n = 149 and n = 127). We found a significant interaction between an SNP in PPIAP2 and the Uganda lineage (combined p = 4 × 10-8). PPIAP2 is a pseudogene that is highly expressed in immune cells. Pathway and eQTL analyses indicated potential roles between coevolving SNPs and cellular replication and metabolism as well as platelet aggregation and coagulation. This finding provides further evidence that host-pathogen interactions affect clinical presentation differently than host and pathogen genetic variation independently, and that human-MTBC coevolution is likely to explain patterns of disease severity.

The Impacts of Dam Construction and Removal on the Genetics of Recovering Steelhead (Oncorhynchus mykiss) Populations across the Elwha River Watershed.

Dam construction and longitudinal river habitat fragmentation disrupt important life histories and movement of aquatic species. This is especially true for Oncorhynchus mykiss that exhibits both migratory (steelhead) and non-migratory (resident rainbow) forms. While the negative effects of dams on salmonids have been extensively documented, few studies have had the opportunity to compare population genetic diversity and structure prior to and following dam removal. Here we examine the impacts of the removal of two dams on the Elwha River on the population genetics of O. mykiss. Genetic data were produced from >1200 samples collected prior to dam removal from both life history forms, and post-dam removal from steelhead. We identified three genetic clusters prior to dam removal primarily explained by isolation due to dams and natural barriers. Following dam removal, genetic structure decreased and admixture increased. Despite large O. mykiss population declines after dam construction, we did not detect shifts in population genetic diversity or allele frequencies of loci putatively involved in migratory phenotypic variation. Steelhead descendants from formerly below and above dammed populations recolonized the river rapidly after dam removal, suggesting that dam construction did not significantly reduce genetic diversity underlying O. mykiss life history strategies. These results have significant evolutionary implications for the conservation of migratory adaptive potential in O. mykiss populations above current anthropogenic barriers.

Shifting food web structure during dam removal-Disturbance and recovery during a major restoration action.

We measured food availability and diet composition of juvenile salmonids over multiple years and seasons before and during the world's largest dam removal on the Elwha River, Washington State. We conducted these measurements over three sediment-impacted sections (the estuary and two sections of the river downstream of each dam) and compared these to data collected from mainstem tributaries not directly affected by the massive amount of sediment released from the reservoirs. We found that sediment impacts from dam removal significantly reduced invertebrate prey availability, but juvenile salmon adjusted their foraging so that the amount of energy in diets was similar before and during dam removal. This general pattern was seen in both river and estuary habitats, although the mechanisms driving the change and the response differed between habitats. In the estuary, the dietary shifts were related to changes in invertebrate assemblages following a hydrological transition from brackish to freshwater caused by sediment deposition at the river's mouth. The loss of brackish invertebrate species caused fish to increase piscivory and rely on new prey sources such as plankton. In the river, energy provided to fish by Ephemeroptera, Plecoptera, and Trichoptera taxa before dam removal was replaced first by terrestrial invertebrates, and then by sediment-tolerant taxa such as Chironomidae. The results of our study are consistent with many others that have shown sharp declines in invertebrate density during dam removal. Our study further shows how those changes can move through the food web and affect fish diet composition, selectivity, and energy availability. As we move further along the dam removal response trajectory, we hypothesize that food web complexity will continue to increase as annual sediment load now approaches natural background levels, anadromous fish have recolonized the majority of the watershed between and above the former dams, and revegetation and microhabitats continue to develop in the estuary.

Estimating the prevalence and risk of COVID-19 among international travelers and evacuees of Wuhan through modeling and case reports.

Coronavirus disease 2019 (COVID-19) started in Wuhan, China and has spread through other provinces and countries through infected travelers. On January 23rd, 2020, China issued a quarantine and travel ban on Wuhan because travelers from Wuhan were thought to account for the majority of exported COVID-19 cases to other countries. Additionally, countries evacuated their citizens from Wuhan after institution of the travel ban. Together, these two populations account for the vast majority of the "total cases with travel history to China" as designated by the World Health Organization (WHO). The current study aims to assess the prevalence and risk of COVID-19 among international travelers and evacuees of Wuhan. We first used case reports from Japan, Singapore, and Korea to investigate the date of flights of infected travelers. We then used airline traveler data and the number of infected exported cases to correlate the cases with the number of travelers for multiple countries. Our findings suggest that the risk of COVID-19 infection is highest among Wuhan travelers between January 19th and 22nd, 2020, with an approximate infection rate of up to 1.3% among international travelers. We also observed that evacuee infection rates varied heavily between countries and propose that the timing of the evacuation and COVID-19 testing of asymptomatic evacuees played significant roles in the infection rates among evacuees. These findings suggest COVID-19 cases and infectivity are much higher than previous estimates, including numbers from the WHO and the literature, and that some estimates of the infectivity of COVID-19 may need re-assessment.

Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.

Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches.

Tuberculosis is the most lethal infectious disease globally, but the vast majority of people who are exposed to the primary causative pathogen, Mycobacterium tuberculosis (MTB), do not develop active disease. Most people do, however, show signs of infection that remain throughout their lifetimes. In this review, we develop a framework that describes several possible transitions from pathogen exposure to TB disease and reflect on the genetics studies to address many of these. The evidence strongly supports a human genetic component for both infection and active disease, but many of the existing studies, including some of our own, do not clearly delineate what transition(s) is being explicitly examined. This can make interpretation difficult in terms of why only some people develop active disease. Nonetheless, both linkage peaks and associations with either active disease or latent infection have been identified. For transition to active disease, pathways defined as active TB altered T and B cell signaling in rheumatoid arthritis and T helper cell differentiation are significantly associated. Pathways that affect transition from exposure to infection are less clear-cut, as studies of this phenotype are less common, and a primary response, if it exists, is not yet well defined. Lastly, we discuss the role that interaction between the MTB lineage and human genetics can play in TB disease, especially severity. Severity of TB is at present the only way to study putative co-evolution between MTB and humans as it is impossible in the absence of disease to know the MTB lineage(s) to which an individual has been exposed. In addition, even though severity has been defined in multiple heterogeneous ways, it appears that MTB-human co-evolution may shape pathogenicity. Further analysis of co-evolution, requiring careful analysis of paired samples, may be the best way to completely assess the genetic basis of TB.

Increased sediment load during a large-scale dam removal changes nearshore subtidal communities.

The coastal marine ecosystem near the Elwha River was altered by a massive sediment influx-over 10 million tonnes-during the staged three-year removal of two hydropower dams. We used time series of bathymetry, substrate grain size, remotely sensed turbidity, scuba dive surveys, and towed video observations collected before and during dam removal to assess responses of the nearshore subtidal community (3 m to 17 m depth). Biological changes were primarily driven by sediment deposition and elevated suspended sediment concentrations. Macroalgae, predominantly kelp and foliose red algae, were abundant before dam removal with combined cover levels greater than 50%. Where persistent sediment deposits formed, macroalgae decreased greatly or were eliminated. In areas lacking deposition, macroalgae cover decreased inversely to suspended sediment concentration, suggesting impacts from light reduction or scour. Densities of most invertebrate and fish taxa decreased in areas with persistent sediment deposition; however, bivalve densities increased where mud deposited over sand, and flatfish and Pacific sand lance densities increased where sand deposited over gravel. In areas without sediment deposition, most invertebrate and fish taxa were unaffected by increased suspended sediment or the loss of algae cover associated with it; however, densities of tubeworms and flatfish, and primary cover of sessile invertebrates increased suggesting benefits of increased particulate matter or relaxed competition with macroalgae for space. As dam removal neared completion, we saw evidence of macroalgal recovery that likely owed to water column clearing, indicating that long-term recovery from dam removal effects may be starting. Our results are relevant to future dam removal projects in coastal areas and more generally to understanding effects of increased sedimentation on nearshore subtidal benthic communities.