Phenome-wide analysis reveals epistatic associations between APOL1 variants and chronic kidney disease and multiple other disorders.

BACKGROUND: APOL1 variants G1 and G2 are common in populations with recent African ancestry. They are associated with protection from African sleeping sickness, however homozygosity or compound heterozygosity for these variants is associated with chronic kidney disease (CKD) and related conditions. What is not clear is the extent of associations with non-kidney-related disorders, and whether there are clusters of diseases associated with individual APOL1 genotypes. METHODS: Using a cohort of 7462 UK Biobank participants with recent African ancestry, we conducted a phenome-wide association study investigating associations between individual APOL1 genotypes and conditions identified by the International Classification of Disease phenotypes. FINDINGS: We identified 27 potential associations between individual APOL1 genotypes and a diverse range of conditions. G1/G2 compound heterozygotes were specifically associated with 26 of these conditions (all deleteriously), with an over-representation of infectious diseases (including hospitalisation and death resulting from COVID-19). The analysis also exposed complexities in the relationship between APOL1 and CKD that are not evident when risk variants are grouped together: G1 homozygosity, G2 homozygosity, and G1/G2 compound heterozygosity were each shown to be associated with distinct CKD phenotypes. The multi-locus nature of the G1/G2 genotype means that its associations would go undetected in a standard genome-wide association study. INTERPRETATION: Our findings have implications for understanding health risks and better-targeted detection, intervention, and therapeutic strategies, particularly in populations where APOL1 G1 and G2 are common such as in sub-Saharan Africa and its diaspora. FUNDING: This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004).

SARS-CoV-2 seroprevalence at urban and rural sites in Kaduna State, Nigeria, during October/November 2021, immediately prior to detection of the Omicron variant.

BACKGROUND: Nigeria is Africa's most populated country. By November 2021 it had experienced three waves of SARS-CoV-2 infection. Peer-reviewed seroprevalence data assessing the proportion of the Nigerian population that have been infected were extremely limited. METHODS: We conducted a serosurvey in one urban site (n = 400) and one rural site (n = 402) in Kaduna State, Nigeria between 11 October 2021 and 8 November 2021. Z-tests were used to compare seroprevalence across age groups, locations and sexes. T tests were used to determine whether age or household size are associated with seropositivity. Associations between seropositivity and recent history of common Covid-19 symptoms were tested using logistic regression. RESULTS: SARS-CoV-2 antibodies were detected in 42.5% an 53.5% of participants at the urban and rural sites, respectively The overall age- and sex- stratified seroprevalence was 43.7% (42.2% for unvaccinated individuals). The data indicate an infection rate in Kaduna State ≥359-fold the rate derived from polymerase chain reaction-confirmed cases. In the urban site, seroprevalence among females and participants aged <20 was lower than other groups. Reporting loss of sense of taste and/or smell was strongly associated with seropositive status. Associations with seropositivity were also found for the reporting of dry cough, fever, headache, nausea and sore throat. CONCLUSIONS: This study provides baseline SARS-CoV-2 seroprevalence in Kaduna State, Nigeria, immediately prior to the spread of the Omicron variant. It indicates that in October/November 2021, approximately 56% of the population did not have detectable antibodies, and population subgroups with particularly low seroprevalence remain. It highlights limitations in using PCR-confirmed cases to estimate infection rates. The data will inform public health strategies in Nigeria and other sub-Saharan African countries with limited SARS-CoV-2 seroprevalence data.

Distemper, extinction, and vaccination of the Amur tiger.

Canine distemper virus (CDV) has recently emerged as an extinction threat for the endangered Amur tiger (Panthera tigris altaica). CDV is vaccine-preventable, and control strategies could require vaccination of domestic dogs and/or wildlife populations. However, vaccination of endangered wildlife remains controversial, which has led to a focus on interventions in domestic dogs, often assumed to be the source of infection. Effective decision making requires an understanding of the true reservoir dynamics, which poses substantial challenges in remote areas with diverse host communities. We carried out serological, demographic, and phylogenetic studies of dog and wildlife populations in the Russian Far East to show that a number of wildlife species are more important than dogs, both in maintaining CDV and as sources of infection for tigers. Critically, therefore, because CDV circulates among multiple wildlife sources, dog vaccination alone would not be effective at protecting tigers. We show, however, that low-coverage vaccination of tigers themselves is feasible and would produce substantive reductions in extinction risks. Vaccination of endangered wildlife provides a valuable component of conservation strategies for endangered species.

Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom.

UNLABELLED: The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE: Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes of this variation, we studied genetic changes in virus isolates from individual hospitalized patients. There were no consistent differences between these viruses and those circulating in the community, but we found multiple evolutionary changes that in combination over time increased the virus's ability to infect human cells. These adaptations may explain the remarkable ability of A(H1N1)pdm09 virus to continue to circulate despite widespread immunity and the apparent increase in severity of influenza over successive waves of infection.

Prevalence of influenza A (H1N1) seropositivity in unvaccinated healthcare workers in Scotland at the height of the global pandemic.

BACKGROUND: We set out to identify the level of previous exposure to influenza A (H1N1) in unvaccinated healthcare workers (HCWs) at the peak of the pandemic outbreak in the UK, with control samples collected prior to the outbreak. METHODS: Cross-sectional study (seroprevalence assessed before and at pandemic peak, with questionnaire data collected at peak of outbreak) in HCWs in Scotland. RESULTS: The prevalence of seropositivity in 493 HCWs at pandemic peak was 10.3%, which was higher than the prepandemic level by 3.7 percentage points (95% CI 0.3% to 7.3%, P = 0.048). Seropositivity rates for frontline and nonfrontline HCWs were similar. CONCLUSION: At pandemic peak, only 10.3% of HCWs were seropositive for influenza A (H1N1), so the great majority were still susceptible to infection at the introduction of the vaccination programme. Few studies have reported on seroprevalence in unvaccinated and asymptomatic participants, so our findings may have relevance to the wider population.

Mutational analysis of the herpes simplex virus triplex protein VP19C.

Herpes simplex virus type 1 (HSV-1) capsids have an icosahedral structure with capsomers formed by the major capsid protein, VP5, linked in groups of three by distinctive structures called triplexes. Triplexes are heterotrimers formed by two proteins in a 1:2 stoichiometry. The single-copy protein is called VP19C, and the dimeric protein is VP23. We have carried out insertional and deletional mutagenesis on VP19C and have examined the effects of the mutations on virus growth and capsid assembly. Insertional mutagenesis showed that the N-terminal approximately 100 amino acids of the protein, which correspond to a region that is poorly conserved among herpesviruses, are insensitive to disruption and that insertions into the rest of the protein had various effects on virus growth. Some, but not all, severely disabled mutants were compromised in the ability to bind VP23 or VP5. Analysis of deletion mutants revealed the presence of a nuclear localization signal (NLS) near the N terminus of VP19C, and this was mapped to a 33-amino-acid region by fusion of specific sequences to a green fluorescent protein marker. By replacing the endogenous NLS with that from the simian virus 40 large T antigen, we were able to show that the first 45 amino acids of VP19C were not essential for assembly of functional capsids and infectious virus particles. However, removing the first 63 amino acids resulted in formation of aberrant capsids and prevented virus growth, suggesting that the poorly conserved N-terminal sequences have some as-yet-unidentified function.