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Background Insecticide resistance in malaria vectors is a serious challenge to malaria control and elimination. Elucidation of the role of detoxification genes in resistance is necessary to develop targeted strategies to reduce malaria burden. Glutathione S-transferase epsilon clusters ( GSTe genes) are upregulated in DDT- and pyrethroid-resistant Anopheles funestus mosquitoes across Africa. However, except for GSTe2 , the molecular mechanisms behind this upregulation remain unclear. Here, we established that overexpression and allelic variation of GSTe genes contribute to insecticide resistance in African malaria vector An. funestus s.s. Methods Transcriptomic and genomic analyses of GST e genes were conducted, followed by in silico structural analysis, and functional characterization of GSTe3 , GSTe4 and GSTe6 using metabolic assay and transgenic expression in Drosophila flies. Results Transcriptomic and genomic analyses reveal changes in gene expression and genetic diversity of GSTes cluster in An. funestus across Africa. Cloning of cDNAs of GST es from different regions of Africa detected allelic variants under selection, including A 17 D 26 T 158 -GSTe3, L 135 H 191 A 189 -GSTe4 in West/Central Africa, and T 169 S 201 E 210 - GST e6 present only in West/Southern Africa. Furthermore, in silico analysis of BN-GSTe3, MWI-GSTe3, BN-GSTe4, MWI-GSTe4, CMR-GSTe6 and, BN-GSTe6 alleles revealed that allelic variations increase the binding cavity in the active site of these GST es with stronger affinities observed towards DDT and permethrin. All recombinant GST es significantly metabolize DDT (41–63%) and permethrin (13–25%). Additionally, BN-GSTe4 (L 135 H 191 A 189 -GSTe4) variant significantly metabolizes deltamethrin (28.75%), compared to the wild-type allele (15.99%; p  < 0.05). Transgenic expression of the GST es in Drosophila melanogaster flies revealed reduced DDT mortalities in flies expressing the selected alleles (39–55%; p˂0.001), compared to control group (98%). Similar resistance patterns were observed toward permethrin and deltamethrin. Conclusion These findings established the role of GST es in conferring cross-resistance to pyrethroids and DDT, highlighting the role of these genes in metabolic resistance in An. funestus , which complicates malaria control using the above key insecticides.

Background Insecticide resistance is jeopardising malaria control efforts in Africa. Deciphering the evolutionary dynamics of mosquito populations country-wide is essential for designing effective and sustainable national and subnational tailored strategies to accelerate malaria elimination efforts. Here, we employed genome-wide association studies through pooled template sequencing to compare four eco-geographically different populations of the major vector, Anopheles funestus , across a South North transect in Cameroon, aiming to identify genomic signatures of adaptive responses to insecticides. Results Our analysis revealed limited population structure within Northern and Central regions ( F ST <0.02), suggesting extensive gene flow, while populations from the Littoral/Coastal region exhibited more distinct genetic patterns ( F ST >0.049). Greater genetic differentiation was observed at known resistance-associated loci, resistance-to-pyrethroids 1 (rp1) (2R chromosome) and CYP9 (X chromosome), with varying signatures of positive selection across populations. Allelic variation between variants underscores the pervasive impact of selection pressures, with rp1 variants more prevalent in Central and Northern populations ( F ST >0.3), and the CYP9 associated variants more pronounced in the Littoral/Coastal region ( F ST =0.29). Evidence of selective sweeps was supported by negative Tajima’s D and reduced genetic diversity in all populations, particularly in Central (Elende) and Northern (Tibati) regions. Genomic variant analysis identified novel missense mutations and signatures of complex genomic alterations such as duplications, deletions, transposable element (TE) insertions, and chromosomal inversions, all associated with selective sweeps. A 4.3 kb TE insertion was fixed in all populations with Njombe Littoral/Coastal population, showing higher frequency of CYP9K1 (G454A), a known resistance allele and TE upstream compared to elsewhere. Conclusion Our study uncovered regional variations in insecticide resistance candidate variants, emphasizing the need for a streamlined DNA-based diagnostic assay for genomic surveillance across Africa. These findings will contribute to the development of tailored resistance management strategies crucial for addressing the dynamic challenges of malaria control in Cameroon.

Deciphering the evolutionary forces controlling insecticide resistance in malaria vectors remains a prerequisite to designing molecular tools to detect and assess resistance impact on control tools. Here, we demonstrate that a 4.3kb transposon-containing structural variation is associated with pyrethroid resistance in central/eastern African populations of the malaria vector Anopheles funestus . In this study, we analysed Pooled template sequencing data and direct sequencing to identify an insertion of 4.3kb containing a putative retro-transposon in the intergenic region of two P450s CYP6P5 - CYP6P9b in mosquitoes of the malaria vector Anopheles funestus from Uganda. We then designed a PCR assay to track its spread temporally and regionally and decipher its role in insecticide resistance. The insertion originates in or near Uganda in East Africa, where it is fixed and has spread to high frequencies in the Central African nation of Cameroon but is still at low frequency in West Africa and absent in Southern Africa. A marked and rapid selection was observed with the 4.3kb-SV frequency increasing from 3% in 2014 to 98% in 2021 in Cameroon. A strong association was established between this SV and pyrethroid resistance in field populations and is reducing pyrethroid-only nets’ efficacy. Genetic crosses and qRT-PCR revealed that this SV enhances the expression of CYP6P9a/b but not CYP6P5 . Within this structural variant (SV), we identified putative binding sites for transcription factors associated with the regulation of detoxification genes. An inverse correlation was observed between the 4.3kb SV and malaria parasite infection, indicating that mosquitoes lacking the 4.3kb SV were more frequently infected compared to those possessing it. Our findings highlight the underexplored role and rapid spread of SVs in the evolution of insecticide resistance and provide additional tools for molecular surveillance of insecticide resistance.

There are uncertainties about the global epidemiological data of infections due to Crimean-Congo hemorrhagic fever virus (CCHFV). We estimated the global case fatality rate (CFR) of CCHFV infections and the prevalence of CCHFV in humans, ticks and other animal species. We also explored the socio-demographic and clinical factors that influence these parameters. In this systematic review with meta–analyses we searched publications from database inception to 03 rd February 2020 in Pubmed, Scopus, and Global Index Medicus. Studies included in this review provided cross-sectional data on the CFR and/or prevalence of one or more targets used for the detection of CCHFV. Two independent investigators selected studies to be included. Data extraction and risk of bias assessment were conducted independently by all authors. Data collected were analysed using a random effect meta-analysis. In all, 2345 records were found and a total of 312 articles (802 prevalence and/or CFR data) that met the inclusion criteria were retained. The overall CFR was 11.7% (95% CI = 9.1–14.5), 8.0% (95% CI = 1.0–18.9), and 4.7% (95% CI = 0.0–37.6) in humans with acute, recent, and past CCHFV infections respectively. The overall CCHFV acute infections prevalence was 22.5% (95% CI = 15.7–30.1) in humans, 2.1% (95% CI = 1.3–2.9) in ticks, and 4.5% (95% CI = 1.9–7.9) in other animal species. The overall CCHFV recent infections seroprevalence was 11.6% (95% CI = 7.9–16.4) in humans and 0.4% (95% CI = 0.0–2.9) in other animal species. The overall CCHFV past infections seroprevalence was 4.3% (95% CI = 3.3–5.4) in humans and 12.0% (95% CI = 9.9–14.3) in other animal species. CFR was higher in low-income countries, countries in the WHO African, South-East Asia and Eastern Mediterranean regions, in adult and ambulatory patients. CCHFV detection rate in humans were higher in CCHFV suspected cases, healthcare workers, adult and hospitalized patients, ticks of the genus Ornithodoros and Amblyomma and in animals of the orders Perissodactyla and Bucerotiformes . This review highlights a significant disease burden due to CCHFV with a strong disparity according to country income levels, geographic regions, various human categories and tick and other animal species. Preventive measures in the light of these findings are expected.

Background Malaria prevention still relies greatly on vector control interventions. However, increasing levels of resistance to pyrethroids across Africa have significantly reduced the efficacy of pyrethroid-based interventions leading to an increase of malaria burden. Consequently, it is imperative to characterize the extent and molecular basis of this resistance. Methods This study was conducted from 2020 to 2021 in a South-North transect across Cameroon. WHO tube assay was used to assess the susceptibility profile of Anopheles funestus to the four main classes of insecticides. The efficacy of bed nets was evaluated using cone assay. Known genetic resistance markers and gene expression were determined using PCR and quantitative PCR techniques, respectively. Taqman assay and nested polymerase chain reaction (PCR) were used to determine Plasmodium sporozoite infection. Results High pyrethroid resistance intensity was noticed in all sites with mortalities ranging from 80–93.9%, 84.9–96.7% and 82% for permethrin, deltamethrin and alphacypermethrin at 10 × concentration respectively. This high level of resistance led to dramatic inefficacy of pyrethroid-only nets with 0–17% mortality recorded 24-h post exposure while PBO-based nets displayed optimal efficacy. Sporozoite infection rates ranged from 0–16.5% across the study sites. However, there was no clear relationship between the infection rate and the intensity of pyrethroid resistance. The L119F- GSTe2 allele was higher in the South (56–68%) compared to the North (20–37%) meanwhile the P450-linked 4.3 kb structural variant was fixed contrasting with the absence of the CYP6P9a/b-R , 6.5 kb insertion and N485I- Ace1 alleles. Furthermore, the L119F- GSTe2 allele confers significant ability to mosquito to survive permethrin. In addition, the CYP325A, CYP6P5, CYP6P9a/b, and the Carb2514 were the most overexpressed genes in pyrethroid resistant mosquitoes. However, no further association was noticed between these alleles/genes and increasing doses of pyrethroids. Conclusion This study confirms the escalation of pyrethroid resistance across Cameroon and the inefficacy of pyrethroid-only nets and highlights genes potentially implicated in the aggravation of insecticide resistance with implications on vector control strategies.

Meta-analyses conducted so far on the association between diabetes mellitus (DM) and the tuberculosis (TB) development risk did not sufficiently take confounders into account in their estimates. The objective of this systematic review was to determine whether DM is associated with an increased risk of developing TB with a sensitivity analyses incorporating a wider range of confounders including age, gender, alcohol consumption, smoke exposure, and other comorbidities. Pubmed, Embase, Web of Science and Global Index Medicus were queried from inception until October 2020. Without any restriction to time of study, geographical location, and DM and TB diagnosis approaches, all observational studies that presented data for associations between DM and TB were included. Studies with no abstract or complete text, duplicates, and studies with wrong designs (review, case report, case series, comment on an article, and editorial) or populations were excluded. The odds ratios (OR) and their 95% confidence intervals were estimated by a random-effect model. The electronic and manual searches yielded 12,796 articles of which 47 were used in our study (23 case control, 14 cross-sectional and 10 cohort studies) involving 503,760 cases (DM or TB patients) and 3,596,845 controls. The size of the combined effect of TB risk in the presence of DM was OR = 2.3, 95% CI = [2.0-2.7], I2 = 94.2%. This statistically significant association was maintained in cohort (OR = 2.0, CI 95% = [1.5-2.4], I2 = 94.3%), case control (OR = 2.4, CI 95% = [2.0-2.9], I2 = 93.0%) and cross-sectional studies (OR = 2.5, CI 95% = [1.8-3.5], I2 = 95.2%). The association between DM and TB was also maintained in the sensitivity analysis including only studies with similar proportions of confounders between cases and controls. The substantial heterogeneity observed was mainly explained by the differences between geographic regions. DM is associated with an increased risk of developing latent and active TB. To further explore the role of DM in the development of TB, more investigations of the biological mechanisms by which DM increases the risk of TB are needed. PROSPERO, CRD42021216815.

Consideration of confounding factors about the association between Lower Respiratory Tract Infections (LRTI) in childhood and the development of subsequent wheezing has been incompletely described. We determined the association between viral LRTI at ≤ 5 years of age and the development of wheezing in adolescence or adulthood by a meta-analysis and a sensitivity analysis including comparable studies for major confounding factors. We performed searches through Pubmed and Global Index Medicus databases. We selected cohort studies comparing the frequency of subsequent wheezing in children with and without LRTI in childhood regardless of the associated virus. We extracted the publication data, clinical and socio-demographic characteristics of the children, and confounding factors. We analyzed data using random effect model. The meta-analysis included 18 publications (22 studies) that met the inclusion criteria. These studies showed that viral LRTI in children ≤ 3 years was associated with an increased risk of subsequent development of wheezing (OR = 3.1, 95% CI = 2.4-3.9). The risk of developing subsequent wheezing was conserved when considering studies with comparable groups for socio-demographic and clinical confounders. When considering studies with comparable groups for most confounding factors, our results provided strong evidence for the association between neonatal viral LRTI and the subsequent wheezing development. Further studies, particularly from lower-middle income countries, are needed to investigate the role of non-bronchiolitis and non-HRSV LRTI in the association between viral LRTI in childhood and the wheezing development later. In addition, more studies are needed to investigate the causal effect between childhood viral LRTI and the wheezing development later. Review registration: PROSPERO, CRD42018116955; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018116955.

Accurate data on the Lassa virus (LASV) human case fatality rate (CFR) and the prevalence of LASV in humans, rodents and other mammals are needed for better planning of actions that will ultimately reduce the burden of LASV infection in sub-Saharan Africa. In this systematic review with meta-analysis, we searched PubMed, Scopus, Africa Journal Online, and African Index Medicus from 1969 to 2020 to obtain studies that reported enough data to calculate LASV infection CFR or prevalence. Study selection, data extraction, and risk of bias assessment were conducted independently. We extracted all measures of current, recent, and past infections with LASV. Prevalence and CFR estimates were pooled using a random-effect meta-analysis. Factors associated with CFR, prevalence, and sources of between-study heterogeneity were determined using subgroup and metaregression analyses. This review was registered with PROSPERO, CRD42020166465. We initially identified 1,399 records and finally retained 109 reports that contributed to 291 prevalence records from 25 countries. The overall CFR was 29.7% (22.3-37.5) in humans. Pooled prevalence of LASV infection was 8.7% (95% confidence interval: 6.8-10.8) in humans, 3.2% (1.9-4.6) in rodents, and 0.7% (0.0-2.3) in other mammals. Subgroup and metaregression analyses revealed a substantial statistical heterogeneity explained by higher prevalence in tissue organs, in case-control, in hospital outbreak, and surveys, in retrospective studies, in urban and hospital setting, in hospitalized patients, and in West African countries. This study suggests that LASV infections is an important cause of death in humans and that LASV are common in humans, rodents and other mammals in sub-Saharan Africa. These estimates highlight disparities between sub-regions, and population risk profiles. Western Africa, and specific key populations were identified as having higher LASV CFR and prevalence, hence, deserving more attention for cost-effective preventive interventions.

Africa denotes unique facies for hepatocellular carcinoma (HCC) characterized by a conjunction of low sensitization, restricted access to diagnosis and treatment and associated with the highest incidence and mortality in the world. We investigated whether hepatitis B (HBV), C (HCV) and D (VHD) viruses were etiological agents of HCC in Africa. Relevant articles were searched in PubMed, Web of Science, African Index Medicus, and African Journal Online databases, as well as manual searches in relevant reviews and included articles. Analytical studies from Africa evaluating the association between HCC development and HBV, HCV, and HDV were included. Relevant studies were selected, data extracted, and the risk of bias assessed independently by at least 2 investigators. The association was estimated using odds ratios (OR) and their 95% confidence interval (95% CI) determined by a random-effects model. Sources of heterogeneity were determined by subgroup analyses. A total of 36 case-control studies were included. With controls having non-hepatic disease, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBeAg (OR = 19.9; 95% CI = [3.7-105.2]), HBsAg (OR = 9.9; 95%) CI = [6.2-15.6]) and DNA (OR = 8.9; 95% CI = [5.9-13.4]); HCV (Anti-HCV (OR = 9.4; 95% CI = [6.3-14.0]) and RNA (OR = 16.5; 95% CI = [7.8-34.6]); HDV (Anti-VHD, (OR = 25.8; 95% CI = [5.9-112.2]); and HBV/HCV coinfections (HBV DNA/HCV RNA (OR = 22.5; 95% CI = [1.3-387.8]). With apparently healthy controls, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBsAg, (OR = 8.9; 95% CI = [6.0-13.0]); HCV (Anti-HCV, (OR = 7.7; 95% CI = [5.6-10.6]); and HBV/HCV coinfections (HBsAg/Anti-HCV (OR = 7.8; 95% CI = [4.4-13.6]) Substantial heterogeneity and the absence of publication bias were recorded for these results. In Africa, HBV/HCV coinfections and HBV, HCV, and HDV infections are associated with an increased risk of developing HCC. The implementation of large-scale longitudinal and prospective studies including healthy participants to search for early biomarkers of the risk of progression to HCC is urgently needed.

Aggravation of pyrethroid resistance threatens malaria control; yet, its molecular basis remains elusive. This study used a comprehensive multi-omics framework integrating 7-year gap temporal RNA-Seq, PoolSeq Whole Genome, and functional analyses, to uncover resistance escalation mechanisms in Anopheles funestus Africa-wide. Spatiotemporal analyses (2014–2021) reveal massive overexpression of novel genes (V-ATPase, tubulin alpha-1, transposase), alongside canonical resistance genes (P450s, cuticular proteins, chemosensory). Epigenetic regulators (histone H3/4, glycine N-methyltransferase) were greatly overexpressed in highly resistant mosquitoes, suggesting resistance modulation. P450-based signatures of selective sweep were detected with a drastic change in the rp1 and the P450 CYP9K1 in Central Africa. Noticeably, genomic variations at the cytochrome P450 reductase (CPR) gene were selected including a N70I mutation in Malawi [0% (2009)–80% (2021)] and a 5.9 kb promoter duplication in Ghana. Transgenic expression in Drosophila confirmed CPR-70I enhances pyrethroid resistance when co-expressed with P450-CYP6P9a, uncovering a novel CPR-mediated mechanism in intensely resistant mosquitoes. This study highlights novel candidate genes for marker development to track the spread of intensely resistant mosquitoes across Africa.