Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

Clinical outcomes and immunological response to SARS-CoV-2 infection among people living with HIV.

People living with HIV (PLWH) usually suffer from co-infections and co-morbidities including respiratory tract infections. SARS-CoV-2 has been reported to cause respiratory infections. There are uncertainties in the disease severity and immunological response among PLWH who are co-infected with COVID-19. This review outlines the current knowledge on the clinical outcomes and immunological response to SARS-CoV-2 among PLWH. Literature was searched in Google scholar, Scopus, PubMed, and Science Direct conforming with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines from studies published from January 2020 to June 2023. A total of 81 studies from 25 countries were identified, and RT-PCR was used in confirming COVID-19 in 80 of the studies. Fifty-seven studies assessed risk factors and clinical outcomes in HIV patients co-infected with COVID-19. Thirty-nine of the studies indicated the following factors being associated with severe outcomes in HIV/SARS-CoV-2: older age, the male sex, African American race, smoking, obesity, cardiovascular diseases, low CD4+ count, high viral load, tuberculosis, high levels of inflammatory markers, chronic kidney disease, hypertension, diabetes, interruption, and delayed initiation of ART. The severe outcomes are patients' hospitalization, admission at intensive care unit, mechanical ventilation, and death. Twenty (20) studies, however, reported no difference in clinical presentation among co-infected compared to mono-infected individuals. Immune response to SARS-CoV-2 infection was investigated in 25 studies, with some of the studies reporting high levels of inflammatory markers, T cell exhaustion and lower positive conversion rate of IgG in PLWH. There is scanty information on the cytokines that predisposes to severity among HIV/SARS-CoV-2 co-infected individuals on combined ART. More research work should be carried out to validate co-infection-related cytokines and/or immune markers to SARS-CoV-2 among PLWH.

HPV18 L1 and long control region sequences variation and E6/E7 differential expression in nasopharyngeal and cervical cancers: a comparative study.

BACKGROUND: The role of high-risk human papillomaviruses (hr-HPVs) in cervical cancer (CC) pathogenesis has long been established. Knowledge about the involvement of hr-HPVs in the etiology of nasopharyngeal cancers (NPC) was not well appreciated until the early 2000s when a clear link began to emerge. However, it is not clear whether HPV oncogenesis in the different epithelial cancers is associated with L1 gene and long-control region (LCR) sequences variation. This study aimed to investigate the HPV18 L1 gene and LCR sequences variation in cervical and nasopharyngeal biopsies, and assessed E6 and E7 genes expression level in both cancers. METHOD: Four-hundred and three (403) formalin-fixed paraffin-embedded tissues originating from nasopharyngeal (NPC) (279) and cervical (CC) (124) sites were collected from a pathology laboratory, Pathologist Without Borders, Accra, Ghana. Haematoxylin and eosin staining was carried out to confirm the presence of cancer on prepared biopsy sections. DNA was extracted from the confirmed cancer biopsies, followed by PCR using MY09/GP5+ /6+ primers to detect the presence of HPV and specific primers for the amplification of L1 gene and LCR. Sanger sequencing was carried out to determine HPV genotypes, and L1 and LCR sequences variant of HPV18s in CC and NPC biopsies. The HPV18 E6/E7 mRNA expression pattern in both cancers was determined using RT-qPCR. RESULTS: Most of the NPC (45%) and CC (55%) biopsies were HPV18 positive. Comparison of HPV18 L1 sequences obtained from cervical and nasopharyngeal cancer tissues, the L1 sequences from the NPC were highly dissimilar with a 59-100% variation among themselves, and in relation to the reference strains. However, the L1 sequences from the CC were more similar with a 91.0-100% variation among the amplified sequences. Also, the LCR sequences from CC were quite different relative to that of NPC. Results for the differential expression of E6/E7 in the two cancers showed a higher fold change in E6 expression in the CC tissues than the NPC tissues while a reverse expression pattern was found for E7 gene. CONCLUSION: The current study reports for the first-time variations in HPV18 L1 and LCR sequences, and differential expression of E6/E7 genes in NPC compared to CC, suggesting a possible adaptation mechanism of the virus at different cancer sites.

Extracellular matrix metalloproteinases inducer gene polymorphism and reduced serum matrix metalloprotease-2 activity in preeclampsia patients.

Preeclampsia increases the risk of pregnancy-related complications, nevertheless a successful spiral vessel remodeling, and trophoblast invasion reduces disorders of pregnancy. Matrix metalloproteinase-2 (MMP-2) clears the path for trophoblast invasion, and activation of MMP-2 largely depends on extracellular matrix metalloproteinases inducer (EMMPRIN) protein. This study aimed to investigate EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia patients. Archival whole blood and serum samples of 74 preeclampsia and 66 normotensive pregnant women age-matched were used in this case-control study. Genomic DNA was extracted from the whole blood samples and EMMPRIN gene amplified with specific primers following fragments sequence mutation analysis. Serum MMP-2 activity was determined using enzyme-linked immunosorbent assay (ELISA) and socio-demographic data of participants retrieved from the database. Age of preeclampsia patients (32.78 ± 6.39) years and body mass index (BMI) (33.09 ± 7.27) kg/m2 compared with the normotensive counterparts (32.33 ± 5.56) years and (32.33 ± 5.56) kg/m2,respectively, were not statistically significant (P > 0.05). Serum matrix metalloprotease-2 (MMP-2) activity was significantly reduced in preeclampsia group (16.34 ± 7.07) compared with the normotensives (25.63 ± 4.56) (P < 0.001), and rs424243T/G variant (55.6%) was overrepresented among the cases compared with the normotensives (16.7%). The single-nucleotide polymorphism T/G was found to be associated with preeclampsia (odds ratio [OR] = 7.63; 95% confidence interval [CI] = 3.95-14.75; P < 0.0001). Decreased activity of MMP-2 and rs424243T/G SNP of EMMPRIN gene was reported in preeclampsia. These preliminary data warrant a further investigation into the relationship between EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia.

Development of an Affordable ELISA Targeting the SARS-CoV-2 Nucleocapsid and Its Application to Samples from the Ongoing COVID-19 Epidemic in Ghana.

INTRODUCTION: The true nature of the population spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in populations is often not fully known as most cases, particularly in Africa, are asymptomatic. Finding the true magnitude of SARS-CoV-2 spread is crucial to provide actionable data about the epidemiological progress of the disease for researchers and policymakers. This study developed and optimized an antibody enzyme-linked immunosorbent assay (ELISA) using recombinant nucleocapsid antigen expressed in-house using a simple bacterial expression system. METHODS: Nucleocapsid protein from SARS-CoV-2 was expressed and purified from Escherichia coli. Plasma samples used for the assay development were obtained from Ghanaian SARS-CoV-2 seropositive individuals during the pandemic, while seronegative controls were plasma samples collected from blood donors before the coronavirus disease 2019 (COVID-19) pandemic. Another set of seronegative controls was collected during the COVID-19 pandemic. Antibody detection and levels within the samples were validated using commercial kits and Luminex. Analyses were performed using GraphPad Prism, and the sensitivity, specificity and background cut-off were calculated. RESULTS AND DISCUSSION: This low-cost ELISA (£0.96/test) assay has a high prediction of 98.9%, and sensitivity and specificity of 97% and 99%, respectively. The assay was subsequently used to screen plasma from SARS-CoV-2 RT-PCR-positive Ghanaians. The assay showed no significant difference in nucleocapsid antibody levels between symptomatic and asymptomatic, with an increase of the levels over time. This is in line with our previous publication. CONCLUSION: This study developed a low-cost and transferable assay that enables highly sensitive and specific detection of human anti-SARS-CoV-2 IgG antibodies. This assay can be modified to include additional antigens and used for continuous monitoring of sero-exposure to SARS-CoV-2 in West Africa.

Circulation of multiple hepatitis B virus genotypes in individual pregnant women seeking antenatal care in northern Ghana.

BACKGROUND: Identification and monitoring of HBV genotype variations is important, since that can help forecast the likelihood of developing serious liver disease and how well patients respond to antiviral medication. Given that HBV genotyping tests are not widely available in our healthcare system, this study characterized HBV genotypes in pregnant women seeking prenatal treatment in northern Ghana. METHOD: By a cross-sectional approach, 2071 pregnant women seeking antenatal care in health facilities in northern Ghana were screened for HBV infection using hepatitis B surface antigen (HBsAg) rapid diagnostic test kit. The women were aged between 17 and 41 years, were of varying gravidae (primigravidae and multigravidae) and gestational age (first, second and third trimesters). A confirmatory PCR assay was used to detect HBsAg, and the distribution of HBV genotypes was determined using a nested PCR assay. RESULTS: Three HBV genotypes (A, D and E) were detected among the pregnant women, of which 175 (91.6%) had genotype E, 9 (4.7%) had mixed genotypes A and E, 5 (2.6%) had mixed genotypes D and E, and 2 (1.1) had mixed genotypes A, D and E. The proportions of women with the different HBV genotypes were independent of age (p = 0.925), gravidity (p = 0.193, χ2 = 4.729) and gestational age (p = 0.227, χ2 = 8.152). CONCLUSION: This study for the first-time characterized circulating HBV genotypes in pregnant women in northern Ghana, which reveals genotypes A and D are found in mixed infections with genotype E. The findings have clinical implications on the management of chronic HBV infection among pregnant women in northern Ghana.

Cryptolepine Suppresses Colorectal Cancer Cell Proliferation, Stemness, and Metastatic Processes by Inhibiting WNT/ß-Catenin Signaling.

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths globally. Evidence shows that over 90% of CRC cases are initiated by a deregulated Wingless Integrated Type-1 (WNT)/ß-catenin signaling pathway. The WNT/ß-catenin pathway also promotes CRC cell proliferation, stemness, and metastasis. Therefore, modulators of the WNT/ß-catenin pathway may serve as promising regimens for CRC. This study investigated the effect of cryptolepine-a plant-derived compound-on the WNT/ß-catenin pathway in CRC. Two CRC cell lines, COLO205 and DLD1, were treated with cryptolepine or XAV 939 (a WNT inhibitor) in the presence or absence of WNT3a (a WNT activator). Using a tetrazolium-based assay, cryptolepine was found to reduce cell viability in a dose- and time-dependent manner and was a more potent inhibitor of viability than XAV 939. RT-qPCR analyses showed that cryptolepine reverses WNT3a-induced expression of ß-catenin, c-MYC, and WISP1, suggesting that cryptolepine inhibits WNT3a-mediated activation of WNT/ß-catenin signaling. Cryptolepine also repressed WNT3a-induced OCT4 and CD133 expression and suppressed colony formation of the cells, indicating that cryptolepine inhibits the stemness of CRC cells. Additionally, cryptolepine inhibited WNT3a-induced epithelial-to-mesenchymal transition by reducing the expression of SNAI1 and TWIST1 genes. In a wound healing assay, cryptolepine was found to suppress cell migration under unstimulated and WNT3a-stimulated conditions. Moreover, cryptolepine downregulated WNT3a-induced expression of MMP2 and MMP9 genes, which are involved in cancer cell invasion. Altogether, cryptolepine suppresses CRC cell proliferation, stemness, and metastatic properties by inhibiting WNT3a-mediated activation of the WNT/ß-catenin signaling pathway. These findings provide a rationale for considering cryptolepine as a potential WNT inhibitor in CRC.

Epstein-Barr virus genotype-1 and Mediterranean + strain in gastric cancer biopsies of Ghanaian patients.

Gastric cancer (GC) prevalence is on the increase in Ghana, and Epstein-Barr virus (EBV) is one of the factors that have been implicated in the etiology of the cancer. It is therefore important to know the contribution of EBV genotype and strains that are associated with GC. In this study, we aimed at genotyping EBV and determining predominant strains in GC biopsies in Ghanaian patients. Genomic DNA was extracted from 55 GC biopsies (cases) and 63 normal gastric tissues (controls) were amplified by polymerase chain reaction (PCR) using specific primers for EBV detection and genotyping followed by PCR fragments sequencing. Epstein-Barr virus positivity were 67.3% and 49.2% in the GC and normal biopsies, respectively. Both cases and controls had the Mediterranean + strain of EBV. The predominant genotype of the virus in the GC cases was genotype-1 (75.7%) compared to 66.7% of genotype-2 among the control group. Infection was associated with GC in the study population (OR = 2.11, P = 0.014, 95% CI: 1.19 - 3.75), and EBV genotype-1 significantly increased the risk of GC (OR = 5.88, P < 0.0001, 95% CI: 3.18-10.88). The mean EBV load in the cases (3.507 ± 0.574) was significantly higher than in the controls (2.256 ± 0.756) (P < 0.0001). We conclude that EBV, especially Mediterranean + genotype-1, was the predominant strain in GC biopsies and GC type or progression is independent of the viral load.

Serum Metabolome Signatures Characterizing Co-Infection of Plasmodium falciparum and HBV in Pregnant Women.

Plasmodium falciparum (P. falciparum) and hepatitis B virus (HBV) co-infection is on the rise among pregnant women in northern Ghana. Mono-infection with either of these two pathogens results in unique metabolic alterations. Thus, we aimed to explicate the effects of this co-infection on the metabolome signatures of pregnant women, which would indicate the impacted metabolic pathways and provide useful prognostic or diagnostic markers. Using an MS/MS-based targeted metabolomic approach, we determined the serum metabolome in pregnant women with P. falciparum mono-infection, HBV mono-infection, P. falciparum, and HBV co-infection and in uninfected (control) women. We observed significantly decreased sphingolipid concentrations in subjects with P. falciparum mono-infection, whereas amino acids and phospholipids were decreased in subjects with HBV mono-infection. Co-infections were found to be characterized distinctively by reduced concentrations of phospholipids and hexoses (mostly glucose) as well as altered pathways that contribute to redox homeostasis. Overall, PC ae C40:1 was found to be a good discriminatory metabolite for the co-infection group. PC ae C40:1 can further be explored for use in the diagnosis and treatment of malaria and chronic hepatitis B co-morbidity as well as to distinguish co-infections from cases of mono-infections.

Analysis of dengue fever disease in West Africa.

Dengue fever disease (DFD) which is caused by four antigenically distinct dengue viruses (DENV) presents a global health threat, with tropical and subtropical regions at a greater risk. The paucity of epidemiological data on dengue in West African subregion endangers efforts geared toward disease control and prevention. A systematic search of DFD prevalence, incidence, and DENV-infected Aedes in West Africa was conducted in PubMed, Scopus, African Index Medicus, and Google Scholar in line with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. A total of 58 human prevalence studies involving 35,748 people from 8 countries were identified. Two incidence and six DENV-infected studies were also reviewed. Nigeria and Burkina Faso contributed the majority of the prevalence studies which spanned between 1968 and 2018, with a considerable variation in coverage among the countries reviewed in this study. An average prevalence of 20.97% was observed across both general prevalence and acute DENV infection study categories, ranging between 0.02% and 93%. The majority of these studies were conducted in acute febrile patients with a prevalence range of 0.02-93% while 19% (n = 11) of all studies were general population-based studies and reported a prevalence range of 17.2-75.8%. DENV-infected Aedes aegypti were reported in four out of the five countries with published reports; with DENV-2 found circulating in Cape Verde, Senegal, and Burkina Faso while DENV-3 and DENV-4 were also reported in Senegal and Cape Verde, respectively. High prevalence of DFD in human populations and the occurrence of DENV-infected A. aegypti have been reported in West Africa, even though weaknesses in study design were identified. Epidemiological data from most countries and population in the subregion were scarce or non-existent. This study highlights the epidemic risk of DFD in West Africa, and the need for research and surveillance to be prioritized to fill the data gap required to enact effective control measures.

Risk of Heavy Metal Poisoning From Consuming Grasscutter Digesta in Ghana.

Grasscutter (cane rat/Thryonomys swinderianus) digesta is used as a spice in Ghana. Research shows that heavy metals from the environment may accumulate in the internal organs of grasscutters, which raises concerns about the possible contamination of grasscutter digesta, too, with heavy metals. Although grasscutter meat in Ghana has been described as safe for consumption, information is lacking on the health risks associated with ingesting the digesta. This study, therefore, aimed to assess the knowledge and perceptions of a merchant and a consumer about the safety of ingesting grasscutter digesta and to evaluate potential health risks from exposure to heavy metals from the spice. A total of 12 digesta samples were analyzed to evaluate potential health risks from exposure to Cd, Fe, Hg, and Mn using a Varian AA240FS Atomic Absorption Spectrometer. The levels of Cd, Hg, and Mn were below the detection limit of 0.01 mg/kg digesta. Also, the estimated daily intake of Fe (0.02 mg/kg) was less than the maximum allowable dose recommended by the US EPA (0.7 mg/kg). The hazard indices of Fe for daily and weekly consumption were <1, suggesting that the consumers may be safe from iron poisoning. Because grasscutter digesta is a relatively expensive spice, it is unlikely to be consumed daily by the average Ghanaian. Moreover, if 10 g of digesta is consumed daily, it can be safely ingested about 971 times in a month. Domestication of grasscutters may be a useful approach to monitor their diet and consequently the quality of their digesta.

Thyroid hormone profile in preeclampsia patients: a case control study.

Objective: Preeclamptic women are reported to have a higher incidence of thyroid dysfunction that correlates with the severity of preeclampsia. The aim of this study was to assess thyroid hormone profiles in in pregnant women with preeclampsia and gestational hypertension and the risk for thyroid dysfunction.Methods: In this study, age-matched pregnant females in the second trimester of pregnancy, diagnosed with preeclampsia (PE), gestational hypertension (GH), as cases, and apparently healthy normotensive (NT) pregnant woman as controls were recruited. Blood samples were drawn for the assessment of thyroid hormone (TSH, FT3 and FT4) levels and thyroid dysfunction.Results: Out of the total of 133 pregnant women recruited for this study, sub-clinical hypothyroidism was the only thyroid dysfunction common to all study groups, with a prevalence of 3.3% in both PE and NT groups, and 4.3% in the GH group. 1% of women in the PE group had sub-clinical hyperthyroidism, compared to 3.3% in the NT group. Although TSH and FT3 were elevated in normotensives, mean differences between the three groups were not statistically significant. However, mean FT4 levels in the GH group (12.99 ± 1.24) and PE group (12.33 ± 2.26), when compared to the control group (11.55 ± 1.94), were significantly higher (p < 0.05).Conclusion: Undiagnosed subclinical hypothyroidism was found in all the categories of pregnant women studied, which if uncontrolled, could increase the risk of pregnancy-related complications, especially in pregnant women with preeclampsia and gestational hypertension.

Altered Faecal Microbiota Composition and Structure of Ghanaian Children with Acute Gastroenteritis.

Acute gastroenteritis (AGE) is a disease of global public health importance. Recent studies show that children with AGE have an altered gut microbiota relative to non-AGE controls. Yet, how the gut microbiota differs in Ghanaian children with and without AGE remains unclear. Here, we explore the 16S rRNA gene-based faecal microbiota profiles of Ghanaian children five years of age and younger, comprising 57 AGE cases and 50 healthy controls. We found that AGE cases were associated with lower microbial diversity and altered microbial sequence profiles relative to the controls. The faecal microbiota of AGE cases was enriched for disease-associated bacterial genera, including Enterococcus, Streptococcus, and Staphylococcus. In contrast, the faecal microbiota of controls was enriched for potentially beneficial genera, including Faecalibacterium, Prevotella, Ruminococcus, and Bacteroides. Lastly, distinct microbial correlation network characteristics were observed between AGE cases and controls, thereby supporting broad differences in faecal microbiota structure. Altogether, we show that the faecal microbiota of Ghanaian children with AGE differ from controls and are enriched for bacterial genera increasingly associated with diseases.

Structure-Based Identification of Natural-Product-Derived Compounds with Potential to Inhibit HIV-1 Entry.

Broadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4-binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserved CD4-binding regions may serve as a new generation of HIV-1 entry inhibitors by being broadly reactive and potently neutralizing. This study aimed to identify compounds that mimic VRC01 by interacting with the CD4-bs of HIV-1 gp120 and thereby inhibiting viral entry into target cells. Libraries of purchasable natural products were virtually screened against clade A/E recombinant 93TH057 (PDB: 3NGB) and clade B (PDB ID: 3J70) HIV-1 env protein. Protein-ligand interaction profiling from molecular docking and dynamics simulations showed that the compounds had intermolecular hydrogen and hydrophobic interactions with conserved amino acid residues on the CD4-binding site of recombinant clade A/E and clade B HIV-1 gp120. Four potential lead compounds, NP-005114, NP-008297, NP-007422, and NP-007382, were used for cell-based antiviral infectivity inhibition assay using clade B (HXB2) env pseudotype virus (PV). The four compounds inhibited the entry of HIV HXB2 pseudotype viruses into target cells at 50% inhibitory concentrations (IC50) of 15.2 µM (9.7 µg/mL), 10.1 µM (7.5 µg/mL), 16.2 µM (12.7 µg/mL), and 21.6 µM (12.9 µg/mL), respectively. The interaction of these compounds with critical residues of the CD4-binding site of more than one clade of HIV gp120 and inhibition of HIV-1 entry into the target cell demonstrate the possibility of a new class of HIV entry inhibitors.

The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways.

Type 1 interferons (IFN-1) are pleiotropic cytokines with well-established anticancer and antiviral properties, particularly in mucosal tissues. Hence, natural IFN-1-inducing treatments are highly sought after in the clinic. Here, we report for the first time that cryptolepine, a pharmacoactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, is a potent IFN-1 pathway inducer. Cryptolepine increased the transcript levels of JAK1, TYK2, STAT1, STAT2, IRF9, and OAS3, as well as increased the accumulation of STAT1 and OAS3 proteins, similar to recombinant human IFN-α. Cryptolepine effects were observed in multiple cell types including a model of human macrophages. This response was maintained in MAVS and STING-deficient cell lines, suggesting that cryptolepine effects are not mediated by nucleic acids released upon nuclear or organelle damage. In agreement, cryptolepine did not affect cell viability in concentrations that triggered potent IFN-1 activation. In addition, we observed no differences in the presence of a pharmacological inhibitor of TBK1, a pleiotropic kinase that is a converging point for Toll-like receptors (TLRs) and nucleic acid sensors. Together, our results demonstrate that cryptolepine is a strong inducer of IFN-1 response and suggest that cryptolepine-based medications such as C. sanguinolenta extract could be potentially tested in resource-limited regions of the world for the management of chronic viral infections as well as cancers.

Live-attenuated YF17D-vectored COVID-19 vaccine protects from lethal yellow fever virus infection in mouse and hamster models.

BACKGROUND: The live-attenuated yellow fever vaccine YF17D holds great promise as alternative viral vector vaccine platform, showcased by our previously presented potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate YF-S0. Besides protection from SARS-CoV-2, YF-S0 also induced strong yellow fever virus (YFV)-specific immunity, suggestive for full dual activity. A vaccine concomitantly protecting from SARS-CoV-2 and YFV would be of great benefit for those living in YFV-endemic areas with limited access to current SARS-CoV-2 vaccines. However, for broader applicability, pre-existing vector immunity should not impact the potency of such YF17D-vectored vaccines. METHODS: The immunogenicity and efficacy of YF-S0 against YFV and SARS-CoV-2 in the presence of strong pre-existing YFV immunity were evaluated in mouse and hamster challenge models. FINDINGS: Here, we show that a single dose of YF-S0 is sufficient to induce strong humoral and cellular immunity against YFV as well as SARS-CoV-2 in mice and hamsters; resulting in full protection from vigorous YFV challenge in either model; in mice against lethal intracranial YF17D challenge, and in hamsters against viscerotropic infection and liver disease following challenge with highly pathogenic hamster-adapted YFV-Asibi strain. Importantly, strong pre-existing immunity against the YF17D vector did not interfere with subsequent YF-S0 vaccination in mice or hamsters; nor with protection conferred against SARS-CoV-2 strain B1.1.7 (Alpha variant) infection in hamsters. INTERPRETATION: Our findings warrant the development of YF-S0 as dual SARS-CoV-2 and YFV vaccine. Contrary to other viral vaccine platforms, use of YF17D does not suffer from pre-existing vector immunity. FUNDING: Stated in the acknowledgments.

Occurrence of influenza and bacterial infections in cancer patients receiving radiotherapy in Ghana.

BACKGROUND: Influenza co-infection with bacteria is a leading cause of influenza-related deaths and severe respiratory infections, especially among high-risk groups like cancer patients undergoing treatment. However, acute respiratory infection (ARI)-like symptoms developed by upper-torso cancer (UTC) patients receiving radiotherapy are considered as side-effects of the radiation. Hence influenza and bacterial pathogens implicated in ARI are not investigated. METHODS: This prospective cohort study examined 85 in-patients with upper-torso cancers undergoing radiotherapy at the National Radiotherapy, Oncology and Nuclear Medicine Centre (NRONMC) of Korle-Bu Teaching Hospital (KBTH) in Accra, Ghana. Eligible patients who consented were recruited into the study from September 2018 to April 2019. Influenza viruses A and B in addition to the following bacteria species Streptococcus pneumonia, Haemophilus influenzae, Neisseria meningitidis and Staphylococcus aureus were detected from oropharyngeal and nasopharyngeal swab specimens collected at three different time points. Presence of respiratory pathogens were investigated by influenza virus isolation in cell culture, bacterial culture, polymerase chain reaction (PCR) and next generation sequencing (NGS) assays. RESULTS: Of the 85 eligible participants enrolled into the study, 87% were females. Participants were 17 to 77 years old, with a median age of 49 years. Most of the participants (88%) enrolled had at least one pathogen present. The most prevalent pathogen was N. meningitidis (63.4%), followed by H. influenzae (48.8%), Influenza viruses A and B (32.9%), S. pneumoniae (32.9%) and S. aureus (12.2%). Approximately, 65% of these participants developed ARI-like symptoms. Participants with previous episodes of ARI, did not live alone, HNC and total radiation less than 50 Gy were significantly associated with ARI. All treatment forms were also significantly associated with ARI. CONCLUSION: Data generated from the study suggests that ARI-like symptoms observed among UTC patients receiving radiotherapy in Ghana, could be due to influenza and bacterial single and co-infections in addition to risk factors and not solely the side-effects of radiation as perceived. These findings will be prime importance for diagnosis, prevention, treatment and control for cancer patients who present with such episodes during treatment.

Paradox of COVID-19 in pregnancy: are pregnant women more protected against or at elevated risk of severe COVID-19?

Many underlying medical conditions have been linked to worse COVID-19 prognosis. Based on reports on SARS-CoV-1 and Middle East respiratory syndrome infections, pregnancy has been considered a predisposing factor to severe COVID-19, with pregnant women being a high-risk group for several physiological reasons. Specifically, pregnant women undergo physiological adaptations that predispose them to severe respiratory viral diseases, including SARS-CoV-2. However, a significant amount of evidence suggests that the clinical outcome of COVID-19 among pregnant women is not different from the general population. In view of this, this report discusses the physiological conditions in pregnant women that adversely affect their immunity, cardiovascular homeostasis, and their endothelial and coagulopathic functions, thereby making them more prone to severe viral infections. We also discuss how these physiological adaptations appear to paradoxically offer protection against severe COVID-19 among pregnant women.

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes.

We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.

Genetic associations in chronic hepatitis B infection: toward developing polygenic risk scores.

Chronic hepatitis B (CHB) infection results in multiple clinical phenotypes of varying severity. One of the critical gaps in CHB management is the lack of a genetic-based tool to aid existing hepatocellular carcinoma and cirrhosis risk stratification models for patients with active CHB. Such individual predictive models for CHB are plagued by an inherent limitation of discriminatory power that clearly indicates the need for their improvement. In this article, we highlight genetic association studies in CHB that identified HLA and cytokine genetic susceptibility loci to CHB. We advance the position that translating CHB genetic susceptibility loci into polygenic risk scores will be a welcome addendum to the current arsenal of CHB outcome predictive models. We conclude with comments on hurdles that future research efforts should address within the research enclave of CHB and advocate for increased genetic data representation from sub-Saharan Africa.