Vitamin D Status and SARS-CoV-2 Infection in a Cohort of Kidney Transplanted Patients

Background: Recently the protective role of 25-hydroxyvitamin D (25(OH)D) against viral infections has been hypothesized. We evaluated the association between vitamin D status and SARS-CoV-2 infection susceptibility and severity in a cohort of kidney transplanted patients (KTxp). Methods: A total of 61 KTxp with SARS-CoV-2 infection (COV+) were matched with 122 healthy KTxp controls (COV−). Main biochemical parameters at 1, 6, and 12 months before SARS-CoV-2 infection were recorded. Vitamin D status was considered as the mean of two 25(OH)D measures obtained 6 ± 2 months apart during the last year. The severity of SARS-CoV-2 infection was based on the need for hospitalization (HOSP+) and death (D+). Results: 25(OH)D levels were lower in COV+ than in controls [19(12–26) vs. 23(17–31) ng/mL, p = 0.01]. No differences among the other biochemical parameters were found. The SARS-CoV-2 infection discriminative power of 25(OH)D was evaluated by ROC-curve (AUC 0.61, 95% CI 0.5–0.7, p = 0.01). 25(OH)D was not significantly different between HOSP+ and HOSP− [17(8–25) vs. 20(15–26) ng/mL, p = 0.19] and between D+ and D− [14(6–23) vs. 20(14–26) ng/mL, p = 0.22] and had no significant correlation with disease length. Conclusions: During the year preceding the infection, 25(OH)D levels were lower in COV+ KTxp in comparison with controls matched for demographic features and comorbidities. No significant association between vitamin D status and SARS-CoV-2 infection related outcomes was found.

Dengue Infection Susceptibility of Five Aedes aegypti Populations from Manaus (Brazil) after Challenge with Virus Serotypes 1–4

The successful spread and maintenance of the dengue virus (DENV) in mosquito vectors depends on their viral infection susceptibility, and parameters related to vector competence are the most valuable for measuring the risk of viral transmission by mosquitoes. These parameters may vary according to the viral serotype in circulation and in accordance with the geographic origin of the mosquito population that is being assessed. In this study, we investigated the effect of DENV serotypes (1–4) with regards to the infection susceptibility of five Brazilian Ae. aegypti populations from Manaus, the capital of the state of Amazonas, Brazil. Mosquitoes were challenged by oral infection with the DENV serotypes and then tested for the presence of the arbovirus using quantitative PCR at 14 days post-infection, which is the time point that corresponds to the extrinsic incubation period of Ae. aegypti when reared at 28 °C. Thus, we were able to determine the infection patterns for DENV-1, -2, -3 and -4 in the mosquito populations. The mosquitoes had both interpopulation and inter-serotype variation in their viral susceptibilities. All DENV serotypes showed a similar tendency to accumulate in the body in a greater amount than in the head/salivary gland (head/SG), which does not occur with other flaviviruses. For DENV-1, DENV-3, and DENV-4, the body viral load varied among populations, but the head/SG viral loads were similar. Differently for DENV-2, both body and head/SG viral loads varied among populations. As the lack of phenotypic homogeneity represents one of the most important reasons for the long-term fight against dengue incidence, we expect that this study will help us to understand the dynamics of the infection patterns that are triggered by the distinct serotypes of DENV in mosquitoes.

Precision medicine in bronchiectasis

Bronchiectasis, due to its highly heterogenous nature, requires an individualised approach to therapy. Patients experience symptoms and exacerbations driven by a combination of impaired mucociliary clearance, airway inflammation and airway infection. Treatment of bronchiectasis aims to enhance airway clearance and to address the underlying causes of inflammation and infection susceptibility. Bronchiectasis has multiple causes and so the pathophysiology leading to individual symptoms and exacerbations are different between individuals. Standardised investigations are recommended by international guidelines to identify the underlying causes of bronchiectasis. The process of identifying the underlying biology within an individual is called “endotyping” and is an emerging concept across chronic diseases. Endotypes that have a specific treatment are referred to as “treatable traits” and a treatable traits approach to managing patients with bronchiectasis in a holistic and evidence-based manner is the key to improved outcomes. Bronchiectasis is an area of intense research. Endotyping allows identification of subsets of patients to allow medicines to be tested differently in the future where trials, rather than trying to achieve a “one size fits all” solution, can test efficacy in subsets of patients where the treatment is most likely to be efficacious.

CD46 Genetic Variability and HIV-1 Infection Susceptibility

CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by complement, a strategy shared by viruses of other families. We sought to determine the association between CD46 gene variants and HIV-1 acquired through intravenous drug use (IDU) and sexual routes (n = 823). Study subjects were of European ancestry and were HIV-1 infected (n = 438) or exposed but seronegative (n = 387). Genotyping of the rs2796265 SNP located in the CD46 gene region was done by allele-specific real-time PCR. A meta-analysis merging IDU and sexual cohorts indicates that the minor genotype (CC) was associated with increased resistance to HIV-1 infection OR= 0.2, 95% CI (0.07–0.61), p = 0.004. The HIV-1-protective genotype is correlated with reduced CD46 expression and alterations in the ratio of CD46 mRNA splicing isoforms.

Transient Receptor Potential Vanilloid Subtype 1: Potential Role in Infection, Susceptibility, Symptoms and Treatment of COVID-19

The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P<5×10-6, one of which was genome-wide significant (P<5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

A Biological Insight into the Susceptibility to Influenza Infection in Junior Rats by Comprehensive Analysis of lncRNA Profiles

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.

COVID-19 vaccines that reduce symptoms but do not block infection need higher coverage and faster rollout to achieve population impact

Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VEDIS). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection susceptibility (VESUSC) or development of symptoms after infection (VESYMP). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VESYMP and VESUSC) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VESUSC and VESYMP resulting in up to 100% VEDIS. We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VEDIS are projected to prevent 23–46% of infections and 31–46% of deaths over 1 year. In comparison, vaccines with 90% VEDIS are projected to prevent 37–64% of infections and 46–64% of deaths over 1 year. In both cases, there is a greater reduction if VEDIS is mediated mostly by VESUSC. The use of a “symptom reducing” vaccine will require twice as many people vaccinated than a “susceptibility reducing” vaccine with the same 90% VEDIS to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.