Immunomodulation of susceptibility to pneumococcal pneumonia infection in mouse lungs exposed to carbon nanoparticles via dysregulation of innate and adaptive immune responses.

Carbon nanotubes (CNTs) are emerging pollutants of occupational and environmental health concern. While toxicological mechanisms of CNTs are emerging, there is paucity of information on their modulatory effects on susceptibility to infections. Here, we investigated cellular and molecular events underlying the effect of multi-walled CNT (MWCNT) exposure on susceptibility to Streptococcus pneumoniae infection in our 28-day sub-chronic exposure mouse model. Data indicated reduced phagocytic function in alveolar macrophages (AMs) from MWCNT-exposed lungs evidenced by lower pathogen uptake in 1-h infection assay. At 24-h post-infection, intracellular pathogen count in exposed AMs showed 2.5 times higher net increase (2-fold in vehicle- versus 5-fold in MWCNT-treated), indicating a greater rate of intracellular multiplication and/or survival due to MWCNT exposure. AMs from MWCNT-exposed lungs exhibited downregulation of pathogen-uptake receptors CD163, Phosphatidyl-serine receptor (Ptdsr), and Macrophage scavenger receptors class A type 1 (Msr1) and type 2 (MSr2). In whole lung, MWCNT exposure shifted the macrophage polarization state towards the immunosuppressive phenotype M2b and increased the CD11c+ dendritic cell population required to activate the adaptive immune response. Notably, the MWCNT pre-exposure dysregulated T-cell immunity, evidenced by diminished CD4 and Th17 response, and exacerbated Th1 and Treg responses (skewed Th17/Treg ratio), thereby favoring the pneumococcal infection. Overall, these findings indicated that MWCNT exposure compromises both innate and adaptive immunity leading to diminished host lung defense against pneumonia infection. To our knowledge, this is the first report on an immunomodulatory role of CNT pre-exposure on pneumococcal infection susceptibility due to dysregulation of both innate and adaptive immunity targets.

Sequencing the B Cell Receptor Repertoires of Antibody-Deficient Individuals With and Without Infection Susceptibility.

PURPOSE: Most individuals with antibody deficiency (hypogammaglobulinemia) need immunoglobulin replacement therapy (IgG-RT) from healthy plasma donors to stay clear of infections. However, a small subset of hypogammaglobulinemic patients do not require this substitution therapy. We set out to investigate this clinical conundrum by asking whether the peripheral B cell receptor repertoires differ between antibody-deficient patients who do and do not need IgG-RT. METHODS: We sequenced and analyzed IgG and IgM heavy chain B cell receptor repertoires from peripheral blood mononuclear cells (PBMCs) isolated from patients with low serum IgG concentrations who did or did not require IgG-RT. RESULTS: Compared to the patients who did not need IgG-RT, those who needed IgG-RT had higher numbers of IgG antibody clones, higher IgM diversity, and less oligoclonal IgG and IgM repertoires. The patient cohorts had different heavy chain variable gene usage, and the patients who needed IgG-RT had elevated frequencies of IgG clones with higher germline identity (i.e., fewer somatic hypermutations). CONCLUSION: Antibody-deficient patients with infection susceptibility who needed IgG-RT had more diverse peripheral antibody repertoires that were less diverged from germline and thus may not be as optimal for targeting pathogens, possibly contributing to infection susceptibility.

The prevalence and contributing risk factors of coronavirus disease 2019 infection in patients with metabolic syndrome.

BACKGROUND: Components of metabolic syndrome (MetS) was reported to contribute to severe and worse outcomes of coronavirus disease 2019 (COVID-19). Hereby, we evaluated the association of MetS and its components with susceptibility to COVID-19. METHODS: Here, 1000 subjects with MetS were recruited that were diagnosed via the International Diabetes Federation (IDF) criterion. Real-time PCR was exerted to detect SARS-CoV-2 in the nasopharyngeal swabs. RESULTS: Among the MetS patients, 206 (20.6%) cases were detected to have COVID-19. Smoking (OR = 5.04, 95%CI = 3.53-7.21, P < 0.0001) and CVD (OR = 1.62, 95%CI = 1.09-2.40, P = 0.015) were associated with increased chance of COVID-19 infection in the MetS patients. BMI was significantly higher (P = 0.0001) in MetS cases with COVID-19 than those without COVID-19. Obesity was associated with increased susceptibility to COVID-19 in MetS patients (OR = 2.00, 95%CI = 1.47-2.74, P < 0.0001). Total cholesterol, TG, LDL were significantly higher in the MetS cases with COVID-19 than those without COVID-19. Dyslipidemia was associated with increased chance of COVID-19 (OR = 1.50, 95%CI = 1.10-2.05, P = 0.0104). FBS level was significantly higher in the MetS cases with COVID-19. T2DM was associated with increased risk of COVID-19 in MetS patients (OR = 1.43, 95%CI = 1.01-2.00, P = 0.0384). Hypertension was associated with increased chance of COVID-19 in the MetS patients (OR = 1.44, 95%CI = 1.05-1.98, P = 0.0234). CONCLUSIONS: MetS and its components, like obesity, diabetes, dyslipidemia, cardiovascular complications were associated with increased chance of COVID-19 infection development and probably with aggravated symptoms in such patients.

[Principles of the diagnostics of inborn errors of immunity]. / Grundlagen der Diagnostik primärer Immunstörungen ("inborn errors of immunity").

Inborn errors of immunity (IEI) are a heterogeneous group of nearly 500 diseases characterized by a congenital dysfunction of the immune system. The vast majority of IEIs are rare diseases but all IEIs share a cumulative prevalence of 1:1200-1:2000. In addition to a pathological susceptibility to infections, IEIs can also present with lymphoproliferative, autoimmune or autoinflammatory manifestations. There is often an overlap with classical rheumatic and inflammatory disease patterns. Therefore, a basic knowledge of the clinical presentation and the diagnostics of IEIs is also relevant for the practicing rheumatologist.

Variation and expression of HLA-DPB1 gene in HBV infection.

Hepatitis B virus (HBV) affects approximately 68 million people in China, and 10-15% of adults infected with HBV develop chronic hepatitis B, liver cirrhosis, liver failure or hepatocellular carcinoma (HCC). HLA-DPB1 gene polymorphism and expression have been shown to be associated with HBV infection susceptibility and spontaneous clearance. The aim of this study is to evaluate the role of HLA-DPB1 gene polymorphism in HBV infection. HLA-DPB1 and rs9277535 polymorphisms were investigated in 259 patients with HBV infection and 442 healthy controls (HCs) using sequence-based typing. The mRNA of HLA-DPB1 was measured by real-time polymerase chain reaction. HLA-DPB1 genes and rs9277535 polymorphisms were all associated with HBV infection in the Sichuan Han population. rs9277535A and HLA-DPB1*04:02 played a protective role against HBV infection. rs9277535G and DPB1*05:01 were associated with susceptibility to HBV infection. rs9277535GG had significantly higher HLA-DPB1 mRNA expression in the HBV infection group compared with the HC group. HLA-DPB1*05:01 and HLA-DPB1*21:01 had significantly lower mRNA expression in the HBV infection group compared with the HC group. The meta-analysis revealed that HLA-DPB1*02:01, HLA-DPB1*02:02, HAL-DPB1*04:01 and HLA-DPB1*04:02 protected against HBV infection, while HLA-DPB1*05:01, HLA-DPB1*09:01, and HLA-DPB1*13:01 were risk factors for susceptibility to HBV infection. HLA-DPB1*02:01, HLA-DPB1*02:02, and HLA-DPB1*04:01 were associated with HBV spontaneous clearance, while HLA-DPB1*05:01 was associated with chronic HBV infection. HLA-DPB1 alleles and rs9277535 have a major effect on the risk of HBV infection, and HBV infection is associated with lower HLA-DPB1 expression. HLA-DPB1 alleles have an important role in HBV susceptibility and spontaneous clearance.

HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy.

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson's coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson's coefficients between -0.47 and -0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1-35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1-41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.

Shift Work and Respiratory Infections in Health-Care Workers.

Recently, there has been interest in whether shift work may enhance susceptibility to infection. Our aim was to determine whether shift workers in the health-care field have a higher incidence, duration, and/or severity of influenza-like illness (ILI) and acute respiratory infection (ARI) than non-shift workers. From September 2016 to June 2017, 501 rotating and/or night-shift workers and 88 non-shift workers from the Klokwerk+ Study (the Netherlands, 2016-2017) registered the occurrence of ILI/ARI symptoms daily using a smartphone application. The incidence rate of ILI/ARI (defined as ≥2 symptoms on the same day/≥1 symptom on 2 consecutive days), the mean duration of each episode, and the incidence rate of severe episodes were compared between shift workers and non-shift workers using negative binomial regression and linear mixed-model analysis. In total, participants completed 110,347 diaries. Shift workers' incidence rate of ILI/ARI was 1.20 (95% confidence interval (CI): 1.01, 1.43) times higher than that of non-shift workers, and for severe ILI/ARI episodes, shift workers' incidence rate was 1.22 (95% CI: 1.01, 1.49) times higher. The mean duration of an ILI/ARI episode did not differ (ratio between means = 1.02, 95% CI: 0.87, 1.19). In conclusion, shift workers in health care had more ILI/ARI episodes and more severe ILI/ARI episodes than non-shift workers, but with a similar duration. Insight into underlying mechanisms connecting shift work and infection susceptibility will contribute to the design of preventive initiatives.

Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients.

The double edge to parasite escape: invasive host is less infected but more infectable.

Nonnative species that escape their native-range parasites may benefit not only from reduced infection pathology, but also from relaxed selection on costly immune defenses, promoting reallocation of resources toward growth or reproduction. However, benefits accruing from a reduction in defense could come at the cost of increased infection susceptibility. We conducted common garden studies of the shore crab Hemigrapsus sanguineus from highly parasitized native (Japan) populations and largely parasite-free invasive (USA) populations to test for differences in susceptibility to infection by native-range rhizocephalan parasites, and to explore differences in host resource allocation. Nonnative individuals showed at least 1.8 times greater susceptibility to infection than their native counterparts, and had reduced standing metabolic rates, suggesting that less of their energy was spent on physiological self-maintenance. Our results support an indirect advantage to parasite escape via the relaxation of costly physiological defenses. However, this advantage comes at the cost of heightened susceptibility, a trade-off of parasite escape that is seldom considered.

Klokwerk + study protocol: An observational study to the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects.

BACKGROUND: Night-shift work may cause severe disturbances in the worker's circadian rhythm, which has been associated with the onset of health problems and diseases. As a substantial part of the workforce is exposed to night-shift work, harmful aspects of night-shift work should not be overlooked. The aim of the Klokwerk + study is to study the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects. First, we will study the relation between night-shift work exposure and body weight and between night-shift work exposure and infection susceptibility. Second, we will examine the mechanisms linking night-shift work exposure to body weight and infection susceptibility, with a specific focus on sleep, physical activity, diet, light exposure, vitamin D level, and immunological factors. Lastly, we will focus on the identification of biomarkers for chronic circadian disturbance associated with night-shift work. METHODS/DESIGN: The design of this study is a prospective observational cohort study consisting of 1,960 health care workers aged 18-65 years. The study population will consist of a group of night-shift workers and an equally sized group of non-night-shift workers. During the study, there will be two measurement periods. As one of the main outcomes of this study is infection susceptibility, the measurement periods will take place at approximately the first (September/October) (T0) and the last month (April/May) (T1, after 6 months) of the flu season. The measurements will consist of questionnaires, anthropometric measurements, a smartphone application to determine infection susceptibility, food diaries, actigraphy, light sensors, and blood sample analyses. DISCUSSION: The Klokwerk + study will contribute to the current need for high-quality data on the health effects of night-shift work and its underlying behavioral and physiological mechanisms. The findings can be the starting point for the development of interventions that prevent negative health effects caused by night-shift work. In addition, the identification of biomarkers indicative of loss of homeostasis due to circadian disturbance may be an important asset in monitoring the effects of such interventions.

If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it?

Either immune selection or stochastic processes may have influenced the frequency of highly polymorphic genes such as mannose-binding lectin 2 (MBL2). This pattern recognition receptor of the innate immune system recognizes and binds to pathogenic microorganisms and apoptotic cells leading to lectin pathway complement killing or clearance. In almost all of a large number of studies in different ethnic groups worldwide there is 20-25% carriage of low MBL2 haplotypes, with 8-10% of each population having no MBL detectable in the blood. The source of this high variability of MBL2 remains cryptic. It arises from six main snps in the prompter and exon regions of the gene that assort into seven common haplotypes under linkage disequilibrium. While global studies of MBL2 show that it is not under immune selection pressure, these results are not the same when the same population genetic tools are used on large national studies. Other analyses point to the silenced MBL1 pseudogene and development of promoter polymorphisms in humans as evidence of selection pressure favouring low-producing haplotypes. While these analyses cannot be reconciled readily, there are two processes by which MBL heterozygosity could have been advantageous in an evolutionary sense; protection against adverse effects of various infectious diseases and lethal manifestations of atherosclerosis - a disease that now seems to have a more ancient history than assumed previously. Ultimately, consideration of the context for possible future therapeutic manipulation of MBL means that this can proceed independently of resolution of the evolutionary forces that have shaped MBL2 polymorphism.

Impact of CCR5Δ32 on the risk of infection, Staphylococcus aureus carriage, and plasma concentrations of chemokines in Danish blood donors.

BACKGROUND: The CC chemokine receptor 5 (CCR5) is a suggested receptor for Staphylococcus aureus leukotoxin ED. Homozygosity for the Δ32 deletion (CCR5Δ32) protects against human immunodeficiency virus infection and possibly also against leukotoxin ED. We examined the impact of CCR5Δ32 on the susceptibility to S. aureus infection, all-cause infections, and S. aureus nasal carriage, respectively, and on the concentrations of circulating chemokines in blood donors. METHODS: We included 95,406 participants from the Danish Blood Donor Study (DBDS) genotyped for >650,000 single nucleotide polymorphisms. The CCR5Δ32 (rs333, MAF: 0.12) was imputed from a reference panel and validated. Infectious outcomes were identified by diagnosis codes and redeemed prescription of antibiotics in national health registers. Data on S. aureus nasal carriage and forty-seven inflammatory biomarkers were available for 6721 and 7811 participants, respectively. Cox, logistic, and linear regression models adjusted for relevant confounders were used to explore said associations. FINDINGS: During more than 700,000 person-years of observation, we found that CCR5Δ32 was associated with neither an increased risk of redeemed dicloxacillin, hospital-treated S. aureus-associated infection (replicated in 345,996 Icelanders), redeemed antibiotics, all-cause infection, and nor with S. aureus nasal carriage. We discovered an association between CCR5Δ32 and elevated CCL4 concentrations, which were 1.26-fold higher in Δ32-heterozygotes (95%-CI: 1.23-1.30) and 2.64-fold higher in Δ32-homozygotes (95%-CI: 2.41-2.90) compared with wildtype homozygotes. Conversely, concentrations of CCL2, CXCL-10, and CCL11 were slightly lower among Δ32-heterozygotes. INTERPRETATION: Results from this CCR5Δ32 high-prevalent cohort do not support the idea that CCR5Δ32 affects the risk of S. aureus carriage or infection to any relevant degree, in this northern European context. CCL4 was the main chemokine affected by CCR5Δ32 and was observed in higher concentration among Δ32-carriers. This study cannot rule out that S. aureus is a previous driver of CCR5Δ32 selection. FUNDING: The Health Research Fund of Central Denmark Region, Aarhus University, Danish Administrative Regions, Bio- and Genome Bank Denmark, Danish Blood Donor Research Foundation, Aase & Ejnar Danielsens Foundation, Højmosegård Grant, National Institute of Allergy and Infectious Diseases, and A.P. Møller Foundation for the Advancement of Medical Science.

Casual effects of gut microbiota on risk of infections: a two-sample Mendelian randomization study.

Background: The correlation between gut microbiota and infections has garnered significant attention in previous studies; nevertheless, our understanding of the causal relationships and mechanisms between specific microbial species and infections remains limited. Methods: This study aimed to employ Mendelian randomization (MR) using single-nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) data of European ancestry to explore the genetic-level relationships between distinct types of gut microbiota and susceptibility to infections. Our analysis encompassed three prevalent infections: intestinal infections, pneumonia, and urinary tract infections, while concurrently examining various types of gut microbiota. Results: We identified 18 protective gut microbiotas alongside 13 associated with increased infection risk. Particularly noteworthy are certain microbial communities capable of producing butyrate, such as the Ruminococcaceae and Lachnospiraceae families, which exhibited both favorable and unfavorable effects. Additionally, we observed a few certain communities linked to infection susceptibility, including ErysipelotrichaceaeUCG003 (OR = 0.13, 95% CI: 0.054-0.33, p = 1.24E-05), Collinsella (OR = 3.25, 95% CI: 2.00-5.27, p = 1.87E-06), and NB1n (OR = 1.24, 95% CI: 1.09-1.40, p = 1.12E-03). Conclusion: This study reveals complex relationships between gut microbiota and various infections. Our findings could potentially offer new avenues for exploring prevention and treatment strategies for infectious diseases.

MBL2 gene polymorphisms related to HIV-1 infection susceptibility and treatment response.

Human Mannose-binding lectin (MBL) is a protein encoded by MBL2 gene involved in the activation of the lectin-complement pathway. Several studies emphasized the role of MBL2 gene in several infectious diseases' susceptibility, including HIV-1 infection. We aim to investigate the impact of 10 MBL2 gene polymorphisms located in the promoter, 5'UTR and exon 1 regions on HIV-1 physiopathology. The polymorphisms genotyping of 400 individuals, which 200 were HIV-1 positive patients and 200 were controls, was performed by PCR-sequencing. Our results showed that rs503037 and rs1800451 polymorphisms are associated with a high risk of HIV-1 infection susceptibility while rs7096206 and rs11003123 showed a protective effect. A significant association between haplotype CGA and HIV-1 infection susceptibility was also found in the exon 1 region. Moreover, rs11003124, rs7084554, rs36014597 and rs11003123 polymorphisms revealed an association with treatment response outcome as measured by RNA viral load. This study highlights the importance of MBL2 polymorphisms in the modulation of HIV-1 infection susceptibility and the contribution to treatment response outcomes among Moroccan subjects.

Night-shift work is associated with increased susceptibility to SARS-CoV-2 infection.

Night-shift workers experience disturbances of their circadian rhythm and sleep, which may make them more susceptible to infectious diseases. Therefore, we studied whether night-shift workers are at higher risk of testing positive for SARS-CoV-2 infection than day workers. In this prospective study, data were used from 20 questionnaire rounds of the Dutch Lifelines COVID-19 cohort that was initiated in March 2020. In the different questionnaire rounds, 2285 night-shift workers and 23,766 day workers reported whether they had tested positive for SARS-CoV-2. Cox proportional hazards regression models adjusted for demographic, work, and health covariates were used to compare SARS-CoV-2 incidence between night-shift and day workers. From March 2020-January 2021, 3.4% of night-shift workers and 2.2% of day workers reported to have tested positive for SARS-CoV-2 (p < .001). After adjustment for covariates, night-shift workers had a 37% higher risk of testing positive for SARS-CoV-2 (hazard ratio: 1.37, 95% confidence interval: 1.05-1.77). In this study, we show that night-shift workers were more likely to test positive for SARS-CoV-2 than day workers, which adds to the growing evidence that night-shift work may influence the complex processes involved in infection susceptibility. Further mechanistic insight is needed to understand the relation between night-shift work and (SARS-CoV-2) infection susceptibility.

The snapshot of metabolic health in evaluating micronutrient status, the risk of infection and clinical outcome of COVID-19.

COVID-19 has re-established the significance of analyzing the organism through a metabolic perspective to uncover the dynamic interconnections within the biological systems. The role of micronutrient status and metabolic health emerge as pivotal in COVID-19 pathogenesis and the immune system's response. Metabolic disruption, proceeding from modifiable factors, has been proposed as a significant risk factor accounting for infection susceptibility, disease severity and risk for post-COVID complications. Metabolomics, the comprehensive study and quantification of intermediates and products of metabolism, is a rapidly evolving field and a novel tool in biomarker discovery. In this article, we propose that leveraging insulin resistance biomarkers along with biomarkers of micronutrient deficiencies, will allow for a diagnostic window and provide functional therapeutic targets. Specifically, metabolomics can be applied as: a. At-home test to assess the risk of infection and propose nutritional support, b. A screening tool for high-risk COVID-19 patients to develop serious illness during hospital admission and prioritize medical support, c(i). A tool to match nutritional support with specific nutrient requirements for mildly ill patients to reduce the risk for hospitalization, and c(ii). for critically ill patients to reduce recovery time and risk of post-COVID complications, d. At-home test to monitor metabolic health and reduce post-COVID symptomatology. Metabolic rewiring offers potential virtues towards disease prevention, dissection of high-risk patients, taking actionable therapeutic measures, as well as shielding against post-COVID syndrome.

Infection's Sweet Tooth: How Glycans Mediate Infection and Disease Susceptibility.

Glycans form a highly variable constituent of our mucosal surfaces and profoundly affect our susceptibility to infection and disease. The diversity and importance of these surface glycans can be seen in individuals who lack a functional copy of the fucosyltransferase gene, FUT2. Representing around one-fifth of the population, these individuals have an altered susceptibility to many bacterial and viral infections and diseases. The mediation of host-pathogen interactions by mucosal glycans, such as those added by FUT2, is poorly understood. We highlight, with specific examples, important mechanisms by which host glycans influence infection dynamics, including by: acting as pathogen receptors (or receptor-decoys), promoting microbial stability, altering the physical characteristics of mucus, and acting as immunological markers. We argue that the effect glycans have on infection dynamics has profound implications for many aspects of healthcare and policy, including clinical management, outbreak control, and vaccination policy.

Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan.

Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory-referred to as the "open window" hypothesis-and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1-2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances-rather than suppresses-immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.

Impact of tumor necrosis factor receptor p55 deficiency in susceptibility of C57BL/6 mice to infection with Leishmania (Leishmania) amazonensis.

Tumor necrosis factor (TNF) is involved in host resistance to several intracellular pathogens. Although the critical role of TNF receptor (TNFR)p55 in Leishmania (Leishmania) major infection has been demonstrated, the impact of TNFRp55 deficiency on L. (L.) amazonensis infection has not been explored. L. (L.) amazonensis-infected TNFRp55(-/-) mice failed to resolve lesions, whereas C57BL/6 wild-type mice completely healed. The susceptibility of the TNFRp55(-/-) mice was characterized by higher lesion size and histopathological damage in comparison with the wild-type mice. A marked increased of the splenic index was observed in the TNFRp55(-/-) mice after 15 weeks infection. These results show that in the absence of TNFRp55, L. (L.) amazonensis-infected knockout mice fail to resolve lesions, whereas wild-type mice completely heal.

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.