Microbial Exposure Research Articles

The Exoproteome and Surfaceome of Toxigenic Corynebacterium diphtheriae 1737 and Its Response to Iron Restriction and Growth on Human Hemoglobin.

Toxin-producing Corynebacterium diphtheriae strains are the etiological agents of the severe upper respiratory disease, diphtheria. A global phylogenetic analysis revealed that biotype gravis is particularly lethal as it produces diphtheria toxin and a range of other virulence factors, particularly when it encounters low levels of iron at sites of infection. To gain insight into how it colonizes its host, we have identified iron-dependent changes in the exoproteome and surfaceome of C. diphtheriae strain 1737 using a combination of whole-cell fractionation, intact cell surface proteolysis, and quantitative proteomics. In total, we identified 1414 of the predicted 2265 proteins (62%) encoded by its reference genome. For each protein, we quantified its degree of secretion and surface exposure, revealing that exoproteases and hydrolases predominate in the exoproteome, while the surfaceome is enriched with adhesins, particularly DIP2093. Our analysis provides insight into how components in the heme-acquisition system are positioned, showing pronounced surface exposure of the strain-specific ChtA/ChtC paralogues and high secretion of the species-conserved heme-binding HtaA protein, suggesting it functions as a hemophore. Profiling the response of the exoproteome and surfaceome after microbial exposure to human hemoglobin and iron limitation reveals potential virulence factors that may be expressed at sites of infection. Data are available via ProteomeXchange with identifier PXD051674.

Occupational health of drilling waste workers as related to microbial exposure and waste treatment methods.

Exposure to microorganisms is a known contributor to occupational disease. This study assessed drilling waste workers' health status and investigated the potential of inhalable bioaerosols to elicit an immune response in vitro and in vivo. Venous blood and self-reported health data were collected from 56 and 73 Norwegian drilling waste workers, respectively. Immunological effects were assessed as Toll-like receptor (TLR) activation potential of personal air samples in vitro and biomarker expression in workers' plasma samples in vivo. Parameters, such as BMI, sex, and smoking habits, were considered along with factors such as purification technology of drilling waste when biomarker expression was interpreted. Symptom prevalence among exposed workers was compared to an unexposed control group. Personal air samples activated TLR signalling in vitro in 90% of all cases. The activation potential correlated significantly with work exposure to microbial agents and total dust. Significant differences in biomarker expression and symptom prevalence were identified between purification technologies and exposure groups. Drilling waste workers had significantly increased OR of skin irritation and respiratory symptoms compared to the control group. Exposure to microorganisms during the treatment of offshore drilling waste is an occupational health concern.

Early life acute infections and risk for cow's milk protein allergy or atopic dermatitis at 6 months of age in high risk for allergy infants

BackgroundEarly life infections (ELIs), encompassing both viral and bacterial types, occur within the first six months of life. Influenced by genetic host factors and environmental conditions, the relationship between ELIs and subsequent allergic manifestations, particularly cow's milk protein allergy (CMPA) and atopic dermatitis (AD), is complex and not fully understood.ObjectiveThe aim of the current study was to examine the potential interplay between nutrition, infections, and allergic manifestations in the first six months of life in infants with a family history of allergies, who were either exclusively breastfed (EBF) or fed a combination of breast milk and standard (SF) or partially hydrolyzed infant formula (pHF).MethodsThe Allergy Reduction Trial (ART) is a multicenter, randomized controlled trial involving 551 participants. From birth, these participants were divided into three groups: Exclusive Breastfeeding (EBF), Partially Hydrolyzed Formula (pHF), and Standard Formula (SF). ELIs, defined as viral and bacterial infections occurring during the first 6 months, and outcomes (AD, CMPA) were recorded through questionnaires (i.e., SCORAD and CоMiSS) and clinical assessments.ResultsThe relative risk (RR) for CMPA in infants with ELIs was 0.20 (95% CI: 0.07–0.58), highlighting a protective effect of ELIs against CMPA development. Notably, the incidence of CMPA was significantly lower in infants who experienced ELIs compared to those without (3% vs. 13.4%, p = 0.001), with no cases of CMPA observed at 6 months in exclusively breastfed (EBF) infants with ELIs. For AD, a trend was observed where the incidence was lower in infants with ELIs who were fed with pHF at 6.5%, compared to those fed with SF at 18.2% (p = 0.092), suggesting a potential protective effect of ELIs in the pHF group against AD development.ConclusionThe study highlights a potential protective role of ELIs in reducing the risk of CMPA, particularly in EBF infants. Furthermore, it suggests a trend towards lower AD incidence in infants fed with pHF, highlighting the complex interplay between early microbial exposures, feeding practices, and immune development. Further research is warranted to unravel this challenging relationship and appropriately inform early life allergy prevention strategies

Unveiling microbial dynamics: a review of health and immune enhancement in school settings

This review focuses on the role of microorganisms in promoting health and immune function within school environments. Microbes, including bacteria, viruses, fungi, and other microorganisms, constitute the human microbiome and play a crucial role in various bodily functions and immune system development. The complex interactions between microorganisms and the immune system in schools, where children spend a significant amount of time, are not fully understood. While schools have traditionally emphasized hygiene practices to prevent the spread of infectious diseases, recent research has highlighted the potential consequences of reduced microbial exposure during early life. The “hygiene hypothesis” suggests that limited exposure to microbes in infancy may increase the risk of allergies, asthma, and autoimmune diseases in adulthood. This paper explores the microbial diversity found in schools, the benefits of exposure to different microorganisms, and the implications of hygiene practices on immune system development. It also examines current research on microbial intervention strategies and their potential to influence overall health in schools. Understanding the role of microbes in school environments has implications for public health policies and educational practices, aiming to create healthier and more conducive learning environments for the younger generation. By comprehensively exploring this topic, this review contributes to a broader understanding of the significance of microbes in promoting health and immune function in school settings and its relevance to future health research.

Contamination of Dental Surgical Masks by Aerosols Generated During Different Dental Treatments.

The COVID-19 pandemic raised the question about the extent of microbial exposure encountered by dentists during dental therapy. The purpose of this study was to quantify microbial counts on surgical masks related to duration and type of dental therapy, as well as patient oral health variables. Sterile filter papers were fixed on surgical masks used during routine daily dental therapy. Thereafter, the filter papers were pressed onto blood agar plates for 1 min, before the agar plates were incubated with 10% CO2. After 48 h, the colony forming units (CFU) were counted and microorganisms were identified. The dependence of the CFU counts on treatment and patient-related variables was analysed using linear regression. Filter papers obtained from 322 dental treatments (429 masks) were included in the final analysis. On average, 5.41 ± 9.94 CFUs were counted. While mostly oral bacteria were detected, Staphylococcus aureus was also identified on 16 masks. Linear regression, incorporating patient-related and treatment characteristics through step-wise inclusion, revealed statistical significance (p 0.001) only with the variable 'assistance during therapy'. The type of dental treatment exhibited a trend, with fewer CFUs observed in caries treatment compared to periodontal or prosthodontic therapy. Furthermore, after analysing filter papers from masks used by dental assistants in 107 dental treatments, fewer CFUs were found on the masks compared to those used by dentists (p 0.001). The mean number of CFUs observed consistently remained low, highlighting the efficacy of the implemented hygiene measures. Consequently, it is clinically recommended to support dental treatment with precise suction of the generated aerosols.

Exposure to Pseudomonas spp. increases Anopheles gambiae insecticide resistance in a host-dependent manner

The microbiota of mosquitoes influences many aspects of their biology, including developmental processes, mating and sexual reproduction, immune functions, and refractoriness to pathogens. Here, we considered their role in resistance against insecticides. In particular, we assessed how larval infection of a permethrin-resistant and a sensitive colony of Anopheles gambiae by four strains belonging to three different Pseudomonas species affects several life history traits and the impact of the insecticide on adult mortality. Our data showed that all four Pseudomonas strains persisted in adults until death. The bacteria increased the likelihood that mosquitoes survived 24 h after exposure to permethrin by up to twofold. The impact of the bacteria depended on the bacterial strains and the mosquito colony: in the resistant colony, all bacteria increased survival by about twofold, while in the sensitive colony, only two of the four strains increased survival. The benefit concerning insecticide resistance came with little to no impact on the other traits (i.e., larval mortality, developmental time and adult longevity). Altogether, our results highlight the importance of considering environmental microbial exposure and mosquito microbial communities in epidemiological and vector-control studies, while also suggesting a possible role for Pseudomonas spp. as a symbiont in A. gambiae.

Lithification of pelletal grains by microbially mediated organomineralization

Fecal pellets are key components of the biological carbon pump and a source of nutrients. When cohesively bound and cemented, they become the most abundant non-skeletal grains in shallow-water carbonates and an important nucleus for ooid formation. Herein, we describe the mineralization processes contributing to pellet cementation using scanning electron microscopy in conjunction with stable isotope and mineralogical analyses of the bulk sediments on Great Bahama Bank, known for its abundance of peloids and fecal pellets. Results show biogenic signatures consistent with the initial stages of organomineralization. These include, curved-tubular filaments and bacilli bacteria associated with extracellular polymeric substances (EPS); fibrils of EPS binding aragonite needles; and the coexistence of decayed EPS with amorphous calcium carbonate that once it develops, coalesces and crystalizes into aragonite. While δ13Cinorg do not show large variations, slightly higher values are observed in areas where pellets are indurated, likely attributed to photosynthetic activity on the pellets. The δ13Corg values tend to be more elevated in indurated pellets, suggesting that heterotrophs are preferentially using enriched carbon sources. In contrast, friable pellets from nearshore areas show more negative δ13Corg values, suggesting microbial exposure to depleted C3 and CAM plant sources. Fingerprints of nitrogen fixation and denitrification are also documented and supported by δ15Norg values. Altogether, these findings suggest that EPS and a microbial consortium, including gut-microbial flora and free-living surface colonizers, are responsible for inducing early cements, which are later complemented by secondary cements. Microorganisms involved in pellet lithification may subsequently also aid in ooid cortex development.

Redox Oscillation-Driven Production of Reactive Oxygen Species from Black Carbon.

Wildfire and stubble burning release substantial amounts of black carbon (BC) into natural environments that experience frequent redox oscillations, such as wetlands and farmlands. Here, we report that redox oscillations can effectively drive ROS production from BC. Following sequential microbial reduction and air exposure, 6.5 ± 0.2 μM/gC hydrogen peroxide (H2O2) and 285.3 ± 9.5 nM/gC hydroxyl radical (•OH) were produced from BC. Moreover, BC derived from various biomass sources, temperatures, and particle sizes exhibits 111.5-fold variations in ROS production. Electrochemical analyses revealed that both the electron transfer capacity and the ROS production selectivity are critical determinants of ROS generation under redox oscillations. The variation in electron transfer capacity (0.3-5.7 mmol e-/gC) is primarily governed by the abundance of electron-storing moieties such as quinones, while the ROS generation selectivity (26.2-72.0%) is influenced by the presence of competitive sites for oxygen reduction reactions, such as carbon defects. These findings provide insights into ROS production from BC under fluctuating redox conditions, with potential implications for elemental cycles and pollutant dynamics in regions prone to wildfire and stubble burning events and substantial BC deposition (e.g., wetlands and rice paddies).

Microbial exposure during recycling of domestic waste: a cross-sectional study of composition and associations with inflammatory markers

ObjectivesThis study aims to investigate (1) the microbial community composition by work characteristics and (2) the association between microbial genera level and inflammatory markers among recycling workers.MethodsIn this cross-sectional study,...

Non-antibiotic disinfectant synchronously interferes methane production and antibiotic resistance genes propagation during sludge anaerobic digestion: Activation of microbial adaptation and reconfiguration of bacteria-archaea synergies

Waste activated sludge (WAS) presents both resource recovery potential and pollution risks, making its efficient treatment challenging. Anaerobic digestion is broadly recognized as a green and sustainable approach to WAS treatment, whose efficiency is easily impacted by the exogeneous pollutants in WAS. However, the impact of polyhexamethylene guanidine (PHMG), as a widely-used non-antibiotic disinfectant, on WAS digestion under semi-continuous flow conditions remains unclear. In this study, CH4 production decreased from 16.1 mL/g volatile suspended solids (VSS) in the control to 13.2 mL/g VSS and 0.3 mL/g VSS under low and high PHMG exposure, respectively, while PHMG increased the number of antibiotic resistance gene (ARG) copies per bacterium by 4.6-12.7 %. Molecular docking analysis revealed that PHMG could spontaneously bind to and disintegrate WAS (binding energy:2.35 and -9.62 kcal/mol), increasing the likelihood of microbial exposure to PHMG. This led to an increase in bacterial abundance and a reduction in archaeal populations, resulting in bacterial dominance in ecological niches. The network topology index in PHMG-treated reactors was consistently lower than in the control, with a higher proportion of negatively correlated links, indicating a more antagonistic relationship between bacteria and archaea. Consequently, PHMG significantly interfered with key genes involved in CH4 biosynthesis (e.g., mch and mtd). Interestingly, methanogenic activity and archaeal chemotaxis (e.g., rfk and cheA) partially recovered under low PHMG exposure due to archaeal adaptation through quorum sensing and two-component systems. However, this adaptation process also contributed to the propagation of ARGs through horizontal gene transfer, facilitated by the enhancement of mobile genetic elements and ARGs hosts. These findings confirm the ecological risks of PHMG and highlight the need for effective WAS disposal strategies.

Moving beyond species: fungal function in house dust provides novel targets for potential indicators of mold growth in homes

BackgroundIncreased risk of asthma and other respiratory diseases is associated with exposures to microbial communities growing in damp and moldy indoor environments. The exact causal mechanisms remain unknown, and occupant health effects have not been consistently associated with any species-based mold measurement methods. We need new quantitative methods to identify homes with potentially harmful fungal growth that are not dependent upon species. The goal of this study was to identify genes consistently associated with fungal growth and associated function under damp conditions for use as potential indicators of mold in homes regardless of fungal species present. A de novo metatranscriptomic analysis was performed using house dust from across the US, incubated at 50%, 85%, or 100% equilibrium relative humidity (ERH) for 1 week.ResultsGene expression was a function of moisture (adonis2 p < 0.001), with fungal metabolic activity increasing with an increase in moisture condition (Kruskal–Wallis p = 0.003). Genes associated with fungal growth such as sporulation (n = 264), hyphal growth (n = 62), and secondary metabolism (n = 124) were significantly upregulated at elevated ERH conditions when compared to the low 50% ERH (FDR-adjusted p ≤ 0.001, log2FC ≥ 2), indicating that fungal function is influenced by damp conditions. A total of 67 genes were identified as consistently associated with the elevated 85% or 100% ERH conditions and included fungal developmental regulators and secondary metabolite genes such as brlA (log2FC = 7.39, upregulated at 100% compared to 85%) and stcC (log2FC = 8.78, upregulated at 85% compared to 50%).ConclusionsOur results demonstrate that moisture conditions more strongly influence gene expression of indoor fungal communities compared to species presence. Identifying genes indicative of microbial growth under damp conditions will help develop robust monitoring techniques for indoor microbial exposures and improve understanding of how dampness and mold are linked to disease.-X5AkW-U2mftBzktcaxDSrVideo

Survivability and life support in sealed mini-ecosystems with simulated planetary soils

Establishing a sustainable life-support system for space exploration is a formidable challenge due to the vast distances, high costs, and environmental differences from Earth. Building upon the lessons from the Biosphere 2 experiment, we introduce the novel “Ecosphere” and “Biosealed” systems, self-sustaining ecosystems within customizable, enclosed containers. These systems incorporate terrestrial ecosystems and groundwater layers, offering a potential model for transplanting Earth-like biomes to extraterrestrial environments. Over 4 years, we conducted rigorous experiments and analyses to understand the dynamics of these enclosed ecosystems. We successfully mitigated moisture deficiency, a major obstacle to plant growth, by incorporating groundwater layers. Additionally, we quantified microbial communities proliferating in specific soils, including simulated lunar and Ryugu asteroid regolith, enhance plant cultivation in space environments. Metagenomic analysis of these simulated space soils revealed diverse microbial populations and their crucial role in plant growth and ecosystem stability. Notably, we identified symbiotic relationships between plants and Cyanobacteria, enhancing oxygen production, and demonstrated the potential of LED lighting as an alternative light source for plant cultivation in sun-limited space missions. We also confirmed the survival of fruit flies within these systems, relying on plant-produced oxygen and photosynthetic bacteria. Our research provides a comprehensive framework for developing future space life-support systems. The novelty of our work lies in the unique design of our enclosed ecosystems, incorporating groundwater layers and simulated extraterrestrial soils, and the detailed analysis of microbial communities within these systems. These findings offer valuable insights into the challenges and potential solutions for establishing sustainable human habitats in space, including the importance of microbial management and potential health concerns related to microbial exposure.

Experimental models of antibiotic exposure and atopic disease.

In addition to numerous clinical studies, research using experimental models have contributed extensive evidence to the link between antibiotic exposure and atopic disease. A number of mouse models of allergy have been developed and used to uncover the specific effects of various microbiota members and perturbations on allergy development. Studies in mice that lack microbes entirely have also demonstrated the various components of the immune system that require microbial exposure. The importance of the early-life period and the mechanisms by which atopy "protective" species identified in human cohorts promote immune development have been elucidated in mice. Finally, non-animal models involving human-derived cells shed light on specific effects of bacteria on human epithelial and immune responses. When considered alongside clinical cohort studies, experimental model systems have provided crucial evidence for the link between the neonatal gut microbiota and allergic disease, immensely supporting the stewardship of antibiotic administration in infants. The following review aims to describe the range of experimental models used for studying factors that affect the relationship between the gut microbiota and allergic disease and summarize key findings that have come from research in animal and in vitro models.

The role of early life factors and green living environment in the development of gut microbiota in infancy: Population-based cohort study

ObjectiveEarly life microbial exposure influences the composition of gut microbiota. We investigated how early life factors, and the green living environment around infants’ homes, influence the development of gut microbiota during infancy by utilizing data from the Steps to Healthy Development follow-up study (the STEPS study). MethodsThe gut microbiota was analyzed at early (∼3 months, n = 959), and late infancy (∼13 months, n = 984) using 16S rRNA amplicon sequencing, and combined with residential green environment, measured as (1) Normalized Difference Vegetation Index, (2) Vegetation Cover Diversity, and (3) Naturalness Index within a 750 m radius. We compared gut microbiota diversity and composition between early and late infancy, identified significant individual and family level early life factors influencing gut microbiota, and determined the role of the residential green environment measures on gut microbiota development. ResultsAlpha diversity (t-test, p < 0.001) and beta diversity (PERMANOVA, R2 = 0.095, p < 0.001) differed between early and late infancy. Birth mode was the strongest contributor to the gut microbiota community composition in early infancy (PERMANOVA, R2 = 0.005, p < 0.01) and the presence of siblings in late infancy (PERMANOVA, R2 = 0.007, p < 0.01). Residential green environment showed no association with community composition, whereas time spend outdoors did (PERMANOVA, R2 = 0.002, p < 0.05). Measures of greenness displayed a statistically significant association with alpha diversity during early infancy, not during late infancy (glm, p < 0.05). In adjusted analysis, the associations remained only with the Naturalness Index, where higher human impact on living environment was associated with decreased species richness (glm, Observed richness, p < 0.05). ConclusionsThe role of the residential green environment to the infant gut microbiota is especially important in early infancy, however, other early life factors, such as birth mode and presence of sibling, had a more significant effect on the overall community composition.

Gestational diabetes exacerbates intrauterine microbial exposure induced intestinal microbiota change in offspring contributing to increased immune response.

maternal health during pregnancy can affect the intestinal microbial community of offspring, but currently the impact of intrauterine environmental changes resulting from gestational diabetes mellitus (GDM) on the microbiota of offspring as well as its interaction with the immune system remains unclear. to explore the impact of intrauterine microbial exposure during pregnancy of gestational diabetes mellitus on the development of neonate's intestinal microbiota and activation of immune responses. Levels of lipopolysaccharides in cord blood from GDM and expression of microbial recognition-related proteins in the placenta were measured. To evaluate embryonic intestinal colonization, pregnant mice with GDM were administered with labeled Escherichia coli or Lactobacillus. The intestinal colonization of pups was analyzed through 16S rRNA gene sequencing and labeled microbial culture. Additionally, memory T lymphocyte and dendritic cell co-culture experiments were conducted to elucidate the immune memory of intestinal microbes during the embryonic stages. Gestational diabetes mellitus led to elevated umbilical cord blood LPS level and increased GFP labeled Escherichia coli in the offspring's intestine after gestational microbial exposure. The mouse model of GDM exhibited increased immune markers including TLR4, TLR5, IL-22 and IL-23 in the placenta and a recall response from memory T cells in offspring's intestines, with similar observations found in human experiments. Furthermore, reduced intestinal microbiome diversity and an increased ratio of Firmicutes/Bacteroidetes was found in GDM progeny, with the stability of bacterial colonization been interfered. Our investigation has revealed a noteworthy correlation between gestational diabetes and intrauterine microbial exposure, as well as alterations in the neonatal microbiota and activation of immune responses. These findings highlight the gestational diabetes's role on offspring's gut microbiota and immune system interactions with early-life pathogen exposure.

Microbial exposure at birth and the development of behavioral temperament during the first three years of childhood.

We investigated cross-sectional and longitudinal associations between neonate microbial exposure and emerging behavioral temperament measures at the ages of 1, 2, and 3 years. Infants and mothers (n = 335) were extracted from the Kuopio Birth Cohort Study. Temperament was assessed using the Infant Behavioral and Early Childhood Behavioral Questionnaires. Microbial samples were collected from oral cavity at birth and the bacterial profiles were assessed using 16S rRNA gene sequencing. Microbial diversity was characterized using alpha and beta diversity metrics. Analyses were performed for the most abundant genera. The sample was analyzed as a whole, as well as divided into subgroups representing no antibiotic use during birth (n = 198) and those with antibiotic use during birth (n = 137). No significant associations were observed between microbial profiles and behavioral measures after Bonferroni corrections. Nevertheless, our pre-correction results indicated an association between increased behavioral temperament surgency in the first year and beta diversity (high abundance of Bacteroides, Faecalibacterium and Blautia, low abundance of Lactobacillus) in the antibiotic use group. Additionally, pre-corrections, a high relative abundance of Staphylococcus was associated with increased surgency through years 1, 2, and 3 in the no antibiotics group, prompting consideration into a possible link between antibiotic use and emerging behavioral temperament.

Department-specific patterns of bacterial communities and antibiotic resistance in hospital indoor environments

The hospital indoor environment has a crucial impact on the microbial exposures that humans encounter. Resistance to antibiotics is a mechanism used by bacteria to develop resilience in indoor environments, and the widespread use of antibiotics has led to changes in the ecological function of resistance genes and their acquisition by pathogens. By integrating the 16S rRNA Illumina sequencing and high-throughput-quantitative PCR approaches with water and air dust samples across seven departments in Peking University Shenzhen Hospital, China, this study yields intriguing findings regarding the department-specific variations, correlations and source tracing of bacteria, antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) within the hospital indoor environment. A notable observation was the pivotal role played by seasonal variations in shaping the bacterial composition across the entire hospital indoor environment. Another department-specific finding was the correlation between ARGs and MGEs abundance, which was evident in the overall hospital indoor environment, but not found in the blood test room, ophthalmology, and gynecology departments. Notably, as an important source of bacteria and ARGs/MGEs for the blood test room, the gynecology department also presented a close link between bacterial communities and the presence of ARGs/MGEs. Additionally, the results reiterate the importance of surveillance and monitoring of antibiotic resistance, specifically in Legionella spp. in man-made water systems, and highlight the significance of understanding genetic elements like Tp614 involved in gene transfer and recombination, and their impact on antimicrobial treatment efficacy. Key points•The department-specific variations, correlations and source tracing of bacteria, ARGs, and MGEs were uncovered in the hospital’s indoor environment.•Although each department exhibited consistent seasonal impacts on bacterial compositions, the co-occurrence between the presence of ARGs and MGEs was exclusively evident in the emergency, surgery, pneumology and otolaryngology departments.•The gynecology department emerged as a crucial source of bacteria, ARGs and MGEs within the hospital. Additionally, it was found to exhibit a significant correlation between bacterial communities and the presence of ARGs and MGEs.

MAD-microbial (origin of) Alzheimer's disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems.

Microbes have been suspected to cause Alzheimer's disease since at least 1908, but this has generally remained unpopular in comparison to the amyloid hypothesis and the dominance of Aβ and Tau. However, evidence has been accumulating to suggest that these earlier theories are but a manifestation of a common cause that can trigger and interact with all the major molecular players recognized in AD. Aβ, Tau and ApoE, in particular appear to be molecules with normal homeostatic functions but also with alternative antimicrobial functions. Their alternative functions confer the non-immune specialized neuron with some innate intracellular defenses that appear to be re-appropriated from their normal functions in times of need. Indeed, signs of infection of the neurons by biofilm-forming microbial colonies, in synergy with herpes viruses, are evident from the clinical and preclinical studies we discuss. Furthermore, we attempt to provide a mechanistic understanding of the AD landscape by discussing the antimicrobial effect of Aβ, Tau and ApoE and Lactoferrin in AD, and a possible mechanistic link with deficiency of vital copper-based systems. In particular, we focus on mitochondrial oxidative respiration via complex 4 and ceruloplasmin for iron homeostasis, and how this is similar and possibly central to neurodegenerative diseases in general. In the case of AD, we provide evidence for the microbial Alzheimer's disease (MAD) theory, namely that AD could in fact be caused by a long-term microbial exposure or even long-term infection of the neurons themselves that results in a costly prolonged antimicrobial response that disrupts copper-based systems that govern neurotransmission, iron homeostasis and respiration. Finally, we discuss potential treatment modalities based on this holistic understanding of AD that incorporates the many separate and seemingly conflicting theories. If the MAD theory is correct, then the reduction of microbial exposure through use of broad antimicrobial and anti-inflammatory treatments could potentially alleviate AD although this requires further clinical investigation.

Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination.

Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond changes in the immune responses, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight the potential importance of considering prior microbial exposures when investigating vaccine responses.

Investigations of microbial adaptation to singular, binary, and fully formulated quaternary ammonium compounds.

The study was conducted to inform risk assessments concerning microbial exposure to quaternary ammonium biocides (QUATs) by investigating their effects on 10 microbial strains of hygiene relevance. Biocides were divided into three categories: simple aqueous solutions, biocide mixtures, and formulated biocides. Organisms were grown in the presence of biocides for 10 generations and then subsequently for another 10 generations in biocide-free media. Control organisms were passaged 20 times in biocide-free media. Strains were then assessed for biocide and antibiotic susceptibility, changes in growth dynamics, and single nucleotide polymorphisms (SNPs). Biocide mixtures demonstrated greater antimicrobial potency than singular and formulated biocides. Susceptibility changes of under twofold were observed for all biocides tested. Susceptibility decreased significantly for organisms passaged with singular biocides (1.29- to 4.35-fold) and biocide mixtures (1.4- to 1.5-fold), but not for formulated biocides (1.3- to 1.84-fold) compared to controls. Antibiotic susceptibility both increased and decreased in passaged organisms, with heightened susceptibility occurring more frequently in the singular biocide group. Changes in susceptibility and growth dynamics were similar in the passaged and unexposed controls for fitness measures of adapted bacteria; there were no significant differences between biocide groups, but significantly lower generation and doubling times in organisms exposed to singular biocides. Similar frequencies in SNPs occurred for the three biocide groups and unexposed controls. While some adaptations occurred, particularly with singular biocides, the impact on antibiotic resistance and genomic mutations was limited. These findings suggest that the use of formulated QUATs may pose a comparatively lower risk for antimicrobial resistance.IMPORTANCEBiocides are used globally to control microbial growth and effective assessment of the risks and benefits of their use is therefore a high priority. Much of the data used to assess risk has been based on sub-lethal exposure of bacteria to singular biocides in simple aqueous solutions. This work builds on limited prior realism-based studies to demonstrate enhanced potency in biocidal mixtures; the mitigation of resistance selection by formulations and inconsistent cross-resistance effects with both increases and decreases in susceptibility for a wide range of antibiotics. These data can be used to better inform risk assessments of biocide deployment.