SUMMARYAdvances in modern medical therapies for many previously intractable human diseases have improved patient outcomes. However, successful disease treatment outcomes are often prevented due to invasive fungal infections caused by the environmental mold Aspergillus fumigatus. As contemporary antifungal therapies have not experienced the same robust advances as other medical therapies, defining mechanisms of A. fumigatus disease initiation and progression remains a critical research priority. To this end, the World Health Organization recently identified A. fumigatus as a research priority human fungal pathogen and the Centers for Disease Control has highlighted the emergence of triazole-resistant A. fumigatus isolates. The expansion in the diversity of host populations susceptible to aspergillosis and the complex and dynamic A. fumigatus genotypic and phenotypic diversity call for a reinvigorated assessment of aspergillosis pathobiological and drug-susceptibility mechanisms. Here, we summarize recent advancements in the field and discuss challenges in our understanding of A. fumigatus heterogeneity and its pathogenesis in diverse host populations.

Piscirickettsia salmonis is a globally distributed aquatic bacterium and a component of the normal salmon microbiome. It has significant biological and economic impact on Chilean salmon aquaculture due to the highly fatal disease, piscirickettsiosis. Unsuccessful attempts to prevent and treat this disease have resulted in heavy use of antimicrobials with adverse effects on the aquatic environment and piscine and human health. Evidence suggests P. salmonis could be a bacterium with relative pathogenic potential on farmed salmonids and other fishes that triggers piscirickettsiosis under particular conditions in the salmon and its environment. Application of a damage-response framework analysis could define the steps from asymptomatic P. salmonis infection to symptomatic disease, help tailor improved approaches to disease prevention and management, and, in turn, help avoid heavy use of antimicrobials which have global effects on animal health, human health, and environmental biodiversity (the One Health concept).

A quarter of a century ago, Liise-anne Pirofski and Arturo Casadevall shared their concepts of microbial pathogenesis through the lens of a damage-response framework (DRF), which characterizes disease by assessing the dynamic interactions between the host and pathogen as reflected by damage as the readout. This framework has evolved to be a powerful tool for understanding the biology of complex infectious diseases, analyzing emerging and reemerging microbes, and developing therapeutic approaches to combat infections. The DRF is also frequently used to explain research at scientific meetings and to teach microbial pathogenesis to diverse learners. This mGem reviews how the DRF came to be and provides an overview of how it is used. Without a doubt, the scientific community will continue to leverage the DRF to advance research and innovate therapeutic approaches, which is especially important as new and reemerging infectious diseases threaten global health.

Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.

We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival.

Participants with CSF leukocytes ≥50/microliter had a higher probability of 18-week survival compared with those with ≤50 cells/microliter (68% (52/77 vs. 52% (151/292); Hazard Ratio = 1.63, 95% confidence interval 1.14-2.23; p = 0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein and immune parameters (interferon-gamma (IFN-γ), IL-17A, tumor necrosis factor alpha (TNF)-α, and circulating CD4+ and CD8+ T cells).

18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival and may support potential pathways for adjunctive immune therapy in HIV-associated cryptococcal meningitis.

Extraintestinal pathogenic Escherichia coli (ExPEC) can cause systemic infections in livestock and poultry. Flagellin, a classical virulence factor, acts as a promoter of cell adhesion and invasion, as well as an inducer of inflammatory responses during intestinal pathogen infection. Further understanding is needed regarding the interaction between flagellin and host within the extra-intestinal ecological niche to facilitate a deeper comprehension of ExPEC infection mechanisms. In this study, we constructed a FliC mutant strain (ΔfliC) of ExPEC XM which exhibited reduced motility and enhanced biofilm formation in vitro assays. The ΔfliC strain also demonstrated diminished adherence and invasion capabilities on hBMEC cells while inducing decreased levels of apoptosis. In vivo experiments with BALB/c mice revealed that the ΔfliC strain displayed enhanced pathogenicity compared to wild-type strains, resulting in an earlier time to death, higher tissue load, severe bacteremia, and more intense inflammatory response observed in serum and tissues. These results suggest that the flagellar protein FliC plays different roles for extraintestinal pathogens compared to enteric pathogens. This study further elucidates the functional role of FliC in ExPEC infection while providing a research basis for exploring pathogenic mechanisms and prevention/control strategies for systemic infectious bacterial diseases.

This study aims to utilize the FDA's Adverse Event Reporting System (FAERS) for data analysis to explore the potential adverse events associated with Droxidopa in real-world settings, thereby providing reference information for clinical practice.

Adverse event reports where Droxidopa was the primary suspected drug were collected from the FAERS database from the third quarter of 2014 to the fourth quarter of 2023. Multiple signal quantification techniques were employed, including ROR, PRR, BCPNN, and MGPS.

A total of 19,295 reports directly related to Droxidopa were screened, encompassing 94 Preferred Terms and involving 27 System Organ Classes. In addition to the adverse events already mentioned in the drug's labeling, this study identified new and valuable adverse event signals, such as Gastrointestinal disorders, Infections and infestations, and Musculoskeletal and connective tissue disorders. Notably, Urinary tract infection, Urinary tract infection pseudomonal, and Pneumonia aspiration were associated with Infections and infestations, indicating the need for heightened vigilance when using Droxidopa in clinical settings. These new signals provide a basis and direction for future research.

This study highlights new potential adverse events related to Droxidopa, emphasizing the need for caution, especially concerning Infections and infestations. Further research is warranted to validate these findings.

The frequency of emerging disease is growing with ongoing human activity facilitating new host-pathogen interactions. Novel infection outcomes can also be shaped by the host microbiota. Caenorhabditis elegans nematodes experimentally colonised by a wild microbiota community and infected by the widespread animal pathogen, Staphylococcus aureus, have been shown to suffer higher mortality than those infected by the pathogen alone. Understanding the host responses to such microbiota-pathogen ecological interactions is key to pinpointing the mechanism underlying severe infection outcomes. We conducted transcriptomic analyses of C. elegans colonised by its native microbiota, S. aureus and both in combination. Correlations between altered collagen gene expression and heightened mortality in co-colonised hosts suggest the microbiota modified host resistance to infection. Furthermore, microbiota colonised hosts showed increased expression of immunity genes and variable expression of stress response genes during infection. Changes in host immunity and stress response could encompass both causes and effects of severe infection outcomes. 'Re-wilding' this model nematode host with its native microbiota indicated that typically commensal microbes can mediate molecular changes in the host that are costly when challenged by a novel emerging pathogen.

The purpose of this Editorial is to expose the gaps in the knowledge created by a decision by the World Workshop Consensus Conference (WWCC), held in 2017, which was focused on the re-classification of periodontal diseases [...].

Different theoretical frameworks have been invoked to guide the study of virus evolution. Three of the more prominent ones are (i) the evolution of virulence, (ii) life history theory, and (iii) the generalism-specialism dichotomy. All involve purported tradeoffs between traits that define the evolvability and constraint of virus-associated phenotypes. However, as popular as these frameworks are, there is a surprising paucity of direct laboratory tests of the frameworks that support their utility as broadly applicable theoretical pillars that can guide our understanding of disease evolution. In this study, we conduct a meta-analysis of direct experimental evidence for these three frameworks across several widely studied virus-host systems: plant viruses, fungal viruses, animal viruses, and bacteriophages. We extracted 60 datasets from 28 studies and found a range of relationships between traits in different analysis categories (e.g., frameworks, virus-host systems). Our work demonstrates that direct evidence for relationships between traits is highly idiosyncratic and specific to the host-virus system and theoretical framework. Consequently, scientists researching viral pathogens from different taxonomic groups might reconsider their allegiance to these canons as the basis for expectation, explanation, or prediction. Future efforts could benefit from consistent definitions, and from developing frameworks that are compatible with the evidence and apply to particular biological and ecological contexts.

Aggregatibacter actinomycetemcomitans ApiA is a trimeric autotransporter outer membrane protein (Omp) that participates in multiple functions, enabling A. actinomycetemcomitans to adapt to a variety of environments. The goal of this study is to identify regions in the apiA gene responsible for three of these functions: auto-aggregation, buccal epithelial cell binding, and complement resistance. Initially, apiA was expressed in Escherichia coli. Finally, wild-type A. actinomycetemcomitans and an apiA-deleted version were tested for their expression in the presence and absence of serum and genes related to stress adaptation, such as oxygen regulation, catalase activity, and Omp proteins. Sequential deletions in specific regions in the apiA gene as expressed in E. coli were examined for membrane proteins, which were confirmed by microscopy. The functional activity of epithelial cell binding, auto-aggregation, and complement resistance were then assessed, and regions in the apiA gene responsible for these functions were identified. A region spanning amino acids 186-217, when deleted, abrogated complement resistance and Factor H (FH) binding, while a region spanning amino acids 28-33 was related to epithelial cell binding. A 13-amino-acid peptide responsible for FH binding was shown to promote serum resistance. An apiA deletion in a clinical isolate (IDH781) was created and tested in the presence and/or absence of active and inactive serum and genes deemed responsible for prominent functional activity related to A. actinomycetemcomitans survival using qRT-PCR. These experiments suggested that apiA expression in IDH781 is involved in global regulatory mechanisms that are serum-dependent and show complement resistance. This is the first study to identify specific apiA regions in A. actinomycetemcomitans responsible for FH binding, complement resistance, and other stress-related functions. Moreover, the role of apiA in overall gene regulation was observed.

Cryptococcal meningitis causes an estimated 112,000 global deaths per annum. Genomic and phenotypic features of the infecting strain of Cryptococcus spp. have been associated with outcomes from cryptococcal meningitis. Additionally, population-level pharmacokinetic variability is well documented in these patient cohorts. The relative contribution of these factors to clinical outcomes is unknown. Based in Malawi, we conducted a sub-study of the phase 3 Ambition-CM trial (ISRCTN72509687), collecting plasma and cerebrospinal fluid at serial time points during the first 14 days of antifungal therapy. We explored the relative contribution of pathogen genotype, drug resistance phenotype, and pharmacokinetics on clinical outcomes including lumbar opening pressure, pharmacodynamic effect, and mortality. We report remarkable genomic homogeneity among infecting strains of Cryptococcus spp., within and between patients. There was no evidence of acquisition of antifungal resistance in our isolates. Genotypic features of the infecting strain were not consistently associated with adverse or favorable clinical outcomes. However, baseline fungal burden and early fungicidal activity (EFA) were associated with mortality. The strongest predictor of EFA was the level of exposure to amphotericin B. Our analysis suggests the most effective means of improving clinical outcomes from HIV-associated cryptococcal meningitis is to optimize exposure to potent antifungal therapy.

HIV-associated cryptococcal meningitis is associated with a high burden of mortality. Research into the different strain types causing this disease has yielded inconsistent findings in terms of which strains are associated with worse clinical outcomes. Our study suggests that the exposure of patients to potent anti-cryptococcal drugs has a more significant impact on clinical outcomes than the strain type of the infecting organism. Future research should focus on optimizing drug exposure, particularly in the context of novel anticryptococcal drugs coming into clinical use.

Microbiologists, like scientists in any other biomedical field, are too engrossed in writing research papers. Aided by both expanding research programs and shrinking resources, this will continue for the foreseeable time. In this editorial, I discuss a compelling need for all microbiologists to dedicate some time to writing non-research publications such as minireviews, perspectives, commentary, opinion/hypothesis, and other non-research article types. I also list the benefits to the field, of review articles and how they can have the potential to change the field. I have provided a handful of classic examples of reviews that clearly changed the field in a remarkable way as well as a number of reviews that clarified the field and facilitated future research.

This review addresses the recent World Workshop Consensus Conference (WWCC) decision to eliminate Localized Aggressive Periodontitis (LAgP) in young adults as a distinct form of periodontitis. A "Consensus" implies widespread, if not unanimous, agreement among participants. However, a significant number of attendees were opposed to the elimination of the LAgP classification. The substantial evidence supporting a unique diagnosis for LAgP includes the (1) incisor/molar pattern of disease, (2) young age of onset, (3) rapid progression of attachment and bone loss, (4) familial aggregation across multiple generations, and (5) defined consortium of microbiological risk factors including Aggregatibacter actinomycetemcomitans. Distinctive clinical signs and symptoms of LAgP are presented, and the microbial subgingival consortia that precede the onset of signs and symptoms are described. Using Bradford-Hill guidelines to assess causation, well-defined longitudinal studies support the unique microbial consortia, including A. actinomycetemcomitans as causative for LAgP. To determine the effects of the WWCC elimination of LAgP on research, we searched three publication databases and discovered a clear decrease in the number of new publications addressing LAgP since the new WWCC classification. The negative effects of the WWCC guidelines on both diagnosis and treatment success are presented. For example, due to the localized nature of LAgP, the practice of averaging mean pocket depth reduction or attachment gain across all teeth masks major changes in disease recovery at high-risk tooth sites. Reinstating LAgP as a distinct disease entity is proposed, and an alternative or additional way of measuring treatment success is recommended based on an assessment of the extension of the time to relapse of subgingival re-infection. The consequences of the translocation of oral microbes to distant anatomical sites due to ignoring relapse frequency are also discussed. Additional questions and future directions are also presented.

Our work investigated the antimicrobial and prebiotic properties of basil, mint, oregano, rosemary, savory, and thyme honey. The potential antimicrobial action, assessed against the pathogens Acinetobacter baumannii, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus, evidenced the capacity of the honey to influence the pathogenic hydrophobicity and hemolytic activities. Honey inhibited pathogen biofilms, acting especially on the mature biofilms, with inhibition rates of up to 81.62% (caused by the presence of mint honey on L. monocytogenes). S. aureus biofilms were the most susceptible to the presence of honey, with inhibition rates up of to 67.38% in the immature form (caused by basil honey) and up to 80.32% in the mature form (caused by mint honey). In some cases, the amount of nuclear and proteic material, evaluated by spectrophotometric readings, if also related to the honey's biofilm inhibitory activity, let us hypothesize a defective capacity of building the biofilm scaffold or bacterial membrane damage or an incapability of producing them for the biofilm scaffold. The prebiotic potentiality of the honey was assessed on Lacticaseibacillus casei Shirota, Lactobacillus gasseri, Lacticaseibacillus paracasei subsp. paracasei, and Lacticaseibacillus rhamnosus and indicated their capacity to affect the whole probiotic growth and in vitro adhesive capacity, as well as the antioxidant and cytotoxic abilities, and to inhibit, mainly in the test performed with the L. casei Shirota, L. gasseri, and L. paracasei supernatants, the immature biofilm of the pathogens mentioned above.

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

The adverse outcomes of fungal infection in mammalian hosts depend on the complex interactions between the host immune system and pathogen virulence-associated traits. The main clinical problems arise when the host response is either too weak to effectively eliminate the pathogen or overly aggressive, resulting in host tissue damage rather than protection. This article will highlight current knowledge regarding the virulence attributions and mechanisms involved in the dual-sided role of the host immune system in the immunopathogenesis of the thermally dimorphic fungus Talaromyces marneffei through the lens of the damage response framework (DRF) of microbial pathogenesis model.

Microbial virulence and biofilm formation stand as a big concern against the goal of achieving a green and sustainable future. Microbial pathogenesis is the process by which the microbes (bacterial, fungal, and viral) cause illness in their respective host organism. 'Nanotechnology' is a state-of-art discipline to address this problem. The use of conventional techniques against microbial proliferation has been challenging against the environment. To tackle this problem, there has been a revolution in this multi-disciplinary field, to address the aspect of bioinspired nanomaterials in the antibiofilm and antimicrobial sector. Bioinspired nanomaterials prove to be a potential antibiofilm and antimicrobial agent as they are non-hazardous to the environment and mostly synthesized using a single-step reduction protocol. They exhibit synergistic effects against bacterial, fungal, and viral pathogens and thereby, control the virulence. In this literature review, we have elucidated the potential of bioinspired nanoparticles as well as nanomaterials as a promising anti-microbial treatment pedagogy and throw light on the advancements in how smart photo-switchable platforms have been designed to exhibit both bacterial releasing as well as bacterial-killing properties. Certain limitations and possible outcomes of these bio-based nanomaterials have been discussed in the hope of achieving a green and sustainable ecosystem.

Recent phylogenetic profiling of pneumococcal serotype 3 (Pn3) isolates revealed a dynamic interplay among major lineages with the emergence and global spread of a variant termed clade II. The cause of Pn3 clade II dissemination along with epidemiological and clinical ramifications are currently unknown. Here, we sought to explore biological characteristics of dominant Pn3 clades in a mouse model of pneumococcal invasive disease and carriage. Carriage and virulence potential were strain dependent with marked differences among clades. We found that clinical isolates from Pn3 clade II are less virulent and less invasive in mice compared to clade I isolates. We also observed that clade II isolates are carried for longer and at higher bacterial densities in mice compared to clade I isolates. Taken together, our data suggest that the epidemiological success of Pn3 clade II could be related to alterations in the pathogen's ability to cause invasive disease and to establish a robust carriage episode.

The aim of this prospective, randomized, controlled, single-centered, examiner-blinded clinical trial was to evaluate the effectiveness of a personalized and visual oral health education program in addition to conventional oral hygiene education.

Fifty-six non-smoker, right-handed participants (aged 30.34 ± 11.46 years) without clinical signs of periodontitis were randomly grouped: the intervention group (n = 28) received a personalized visualized oral health education combined with conventional oral hygiene education, and the control group (n = 28) received conventional oral hygiene education only. All participants were assessed for improved periodontal parameters (PI, GI, BOP, and PPD) at baseline, first month, and third month.

A significant reduction (p < 0.001) was observed in PI, GI, and BOP during two follow-up sessions compared to the baseline for the two groups. No differences were found for inter-group (p > 0.05) or intra-group (p = 1) comparison of PPD. PI (p = 0.012), GI (p = 0.032), and BOP (p = 0.024) scores were significantly reduced at the third-month follow-up assessment in the intervention group compared to the control group.

Clinical outcomes of periodontal health were significantly enhanced by the personalized and visual oral health education program applied in this study compared to the conventional oral hygiene education program.

Numerous studies reported additional interventions to the oral hygiene education program. However, we did not find any published studies investigating the role of patients' intra-oral photographs in oral care. This study's results demonstrated that a visually aided education program for oral hygiene motivation may help improve oral health.

Registration number is "NCT06316505" and date of registration is 18/03/2024.

Endosymbionts are widespread in arthropods, living in host cells with effects that extend from parasitic to mutualistic. Newly acquired endosymbionts tend to be parasitic, but vertical transmission favors coevolution toward mutualism, with hosts sometimes developing dependency. Endosymbionts negatively affecting host fitness may still spread by impacting host reproductive traits, referred to as reproductive "manipulation," although costs for hosts are often assumed rather than demonstrated. For cytoplasmic incompatibility (CI) that involves endosymbiont-mediated embryo death, theory predicts directional shifts away from "manipulation" toward reduced CI strength; moreover, CI-causing endosymbionts need to increase host fitness to initially spread. In nature, endosymbiont-host interactions and dynamics are complex, often depending on environmental conditions and evolutionary history. We advocate for capturing this complexity through appropriate datasets, rather than relying on terms like "manipulation." Such imprecision can lead to the misclassification of endosymbionts along the parasitism-mutualism continuum.

The field of microbial pathogenesis seeks to identify the agents and mechanisms responsible for disease causation. Since Robert Koch introduced postulates that were used to guide the characterization of microbial pathogens, technological advances have substantially increased the capacity to rapidly identify a causative infectious agent. Research efforts currently focus on causation at the molecular level with a search for virulence factors (VFs) that contribute to different stages of the infectious process. We note that the quest to identify and characterize VFs sometimes lacks scientific rigor, and this suggests a need to examine the epistemology of VF characterization. We took this premise as an opportunity to explore the epistemology of VF characterization. In this perspective, we discuss how the characterization of various gene products that evolved to facilitate bacterial survival in the broader environment have potentially been prematurely mischaracterized as VFs that contribute to pathogenesis in the context of human biology. Examples of the reasoning that can affect misinterpretation, or at least a premature assignment of mechanistic causation, are provided. Our aim is to refine the categorization of VFs by emphasizing a broader biological view of their origin.

Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models.

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range of therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy of those approaches often remains controversial or compromised by viral evolution. Uncertainties still persist regarding the best therapies for high-risk patients, and the drug pipeline is suffering fatigue and shortage of funding. In this article, we review the antiviral activity, mechanism of action, pharmacokinetics, and safety of COVID-19 antiviral therapies. Additionally, we summarize the evidence from randomized controlled trials on efficacy and safety of the various COVID-19 antivirals and discuss unmet needs which should be addressed.

Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.

We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival.

Participants with CSF leukocytes ≥50/μL, had higher probability 68% (52/77) of 18-week survival compared with 52% (151/292) 18-week survival in those with ≤50 cells/μL (Hazard Ratio=1.63, 95% confidence intervals 1.14-2.23; p=0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein, interferon-gamma (IFN-γ), IL-17A, tumor necrosis factor (TNF)-α, and peripheral blood CD4+ and CD8+ T cells expression.

18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival with HIV-associated cryptococcal meningitis.

The antibiotic resistance (ABR) crisis is an urgent global health priority. Staphylococci are among the problematic bacteria contributing to this emergency owing to their recalcitrance to many clinically important antibiotics. Staphylococcal pathogenesis is further complicated by the presence of small colony variants (SCVs), a bacterial subpopulation displaying atypical characteristics including retarded growth, prolific biofilm formation, heightened antibiotic tolerance, and enhanced intracellular persistence. These capabilities severely impede current chemotherapeutics, resulting in chronic infections, poor patient outcomes, and significant economic burden. Tackling ABR requires alternative measures beyond the conventional options that have dominated treatment regimens over the past 8 decades. Non-antibiotic therapies are gaining interest in this arena, including the use of honey, which despite having ancient therapeutic roots has now been reimagined as an alternative treatment beyond just traditional topical use, to include the treatment of an array of difficult-to-treat staphylococcal infections. This literature review focused on Manuka honey (MH) and its efficacy as an anti-staphylococcal treatment. We summarized the studies that have used this product and the technologies employed to study the antibacterial mechanisms that render MH a suitable agent for the management of problematic staphylococcal infections, including those involving staphylococcal SCVs. We also discussed the status of staphylococcal resistance development to MH and other factors that may impact its efficacy as an alternative therapy to help combat ABR.

The human gut flora comprises a dynamic network of bacterial species that coexist in a finely tuned equilibrium. The interaction with intestinal bacteria profoundly influences the host's development, metabolism, immunity, and overall health. Furthermore, dysbiosis, a disruption of the gut microbiota, can induce a variety of diseases, not exclusively associated with the intestinal tract. The increased consumption of animal protein, high-fat and high-sugar diets in Western countries has been implicated in the rise of chronic and inflammatory illnesses associated with dysbiosis. In particular, this diet leads to the overgrowth of sulfide-producing bacteria, known as sulfidogenic bacteria, which has been linked to inflammatory bowel diseases and colorectal cancer, among other disorders. Sulfidogenic bacteria include sulfate-reducing bacteria (Desulfovibrio spp.) and Bilophila wadsworthia among others, which convert organic and inorganic sulfur compounds to sulfide through the dissimilatory sulfite reduction pathway. At high concentrations, sulfide is cytotoxic and disrupts the integrity of the intestinal epithelium and mucus barrier, triggering inflammation. Besides producing sulfide, B. wadsworthia has revealed significant pathogenic potential, demonstrated in the ability to cause infection, adhere to intestinal cells, promote inflammation, and compromise the integrity of the colonic mucus layer. This review delves into the mechanisms by which taurine and sulfide-driven gut dysbiosis contribute to the pathogenesis of sulfidogenic bacteria, and discusses the role of these gut microbes, particularly B. wadsworthia, in human diseases.

One of the main challenges in aquaculture is pathogenic bacterial control. Streptococcus iniae stands out for its ability to cause high mortality rates in populations of commercially important fish populations and its recent recognition as an emerging zoonotic pathogen. The rise in identifying over 80 strains some displaying antibiotic resistance coupled with the emerging occurrence of infections in marine mammal species and wild fish underscores the urgent need of understanding pathogenesis, virulence and drug resistance mechanisms of this bacterium. This understanding is crucial to ensure effective control strategies. In this context, the present review conducts a bibliometric analysis to examine research trends related to S. iniae, extending into the mechanisms of infection, virulence, drug resistance and control strategies, whose relevance is highlighted on vaccines and probiotics to strengthen the host immune system. Despite the advances in this field, the need for developing more efficient identification methods is evident, since they constitute the basis for accurate diagnosis and treatment.

Circadian rhythms are intrinsic 24-hour oscillations found in nearly all life forms. They orchestrate key physiological and behavioral processes, allowing anticipation and response to daily environmental changes. These rhythms manifest across entire organisms, in various organs, and through intricate molecular feedback loops that govern cellular oscillations. Recent studies describe circadian regulation of pathogens, including parasites, bacteria, viruses, and fungi, some of which have their own circadian rhythms while others are influenced by the rhythmic environment of hosts. Pathogens target specific tissues and organs within the host to optimize their replication. Diverse cellular compositions and the interplay among various cell types create unique microenvironments in different tissues, and distinctive organs have unique circadian biology. Hence, residing pathogens are exposed to cyclic conditions, which can profoundly impact host-pathogen interactions. This review explores the influence of circadian rhythms and mammalian tissue-specific interactions on the dynamics of pathogen-host relationships. Overall, this demonstrates the intricate interplay between the body's internal timekeeping system and its susceptibility to pathogens, which has implications for the future of infectious disease research and treatment.

Foodborne pathogens compromise food safety and public health, and Salmonella spp. are among the major pathogenic bacteria that cause outbreaks worldwide. Proper surveillance through timely and cost-effective detection methods across the food animal production chain is crucial to prevent Salmonella outbreaks and agricultural losses. Traditional culture methods are labor- and resource-intensive, with lengthy turnaround times. Meanwhile, conventional molecular tools, such as PCR and qPCR, are expensive and require technical skills and equipment. Loop-mediated isothermal amplification (LAMP) is a simple, rapid, inexpensive, highly sensitive, and specific molecular assay that does not require expensive equipment. Hence, this study developed and optimized a closed-tube, calcein-based LAMP assay to detect Salmonella using the invA gene and performed evaluation and validation against conventional PCR. The LAMP assay showed high specificity and sensitivity. It showed 10-fold higher sensitivity than conventional PCR, at <1 ng/μL DNA concentrations. Meanwhile, for CFU/mL, LAMP assay showed 1000-fold higher sensitivity than conventional PCR at 4.8 × 103 cells/mL than 4.8 × 107 cells/mL, respectively. For parallel testing of 341 raw meat samples, after conventional culture enrichment (until Rappaport-Vassiliadis broth), the optimized LAMP assay showed 100% detection on all samples while conventional PCR showed 100%, 99.04%, and 96.64% for raw chicken, beef, and pork samples, respectively. Meanwhile, a shortened enrichment protocol involving 3-h incubation in buffered peptone water only, showed lower accuracy in tandem with the optimized LAMP assay ranging from 55 to 75% positivity rates among samples. These suggest that the optimized LAMP assay possesses higher sensitivity over conventional PCR for invA gene detection when coupled with conventional enrichment culture methods. Hence, this assay has potential as a powerful complementary or alternative Salmonella detection method to increase surveillance capacity and protect consumer food safety and public health worldwide.

Sporothrix schenckii is one of the etiological agents of sporotrichosis, a cutaneous and subcutaneous infection distributed worldwide. Like other medically relevant fungi, its cell wall is a molecular scaffold to display virulence factors, such as protective pigments, hydrolytic enzymes, and adhesins. Cell wall proteins with adhesive properties have been previously reported, but only a handful of them have been identified and characterized. One of them is Gp70, an abundant cell wall protein mainly found on the surface of yeast-like cells. Since the protein also has a role in the activity of 3-carboxy-cis,cis-muconate cyclase and its abundance is low in highly virulent strains, its role in the Sporothrix-host interaction remains unclear. Here, a set of GP70-silenced strains was generated, and the molecular and phenotypical characterization was performed. The results showed that mutants with high silencing levels showed a significant reduction in the adhesion to laminin and fibrinogen, enzyme activity, and defects in the cell wall composition, which included reduced mannose, rhamnose, and protein content, accompanied by an increment in β-1,3-glucans levels. The cell wall N-linked glycan content was significantly reduced. These strains induced poor TNFα and IL-6 levels when interacting with human peripheral blood mononuclear cells in a dectin-1-, TLR2-, and TLR4-dependent stimulation. The IL-1β and IL-10 levels were significantly higher and were stimulated via dectin-1. Phagocytosis and stimulation of neutrophil extracellular traps by human granulocytes were increased in highly GP70-silenced strains. Furthermore, these mutants showed virulence attenuation in the invertebrate model Galleria mellonella. Our results demonstrate that Gp70 is a versatile protein with adhesin properties, is responsible for the activity of 3-carboxy-cis,cis-muconate cyclase, and is relevant for the S. schenckii-host interaction.

Several studies have established an association between the blood group type and susceptibility to infections. This study aimed to evaluate a correlation between the blood group type and the susceptibility to infection. A total of 558 patients were enrolled in this study who attended at the Althawra Hospital, Ibb City, from March to August 2018. Blood samples were analyzed for complete blood count and blood group. We observed a high frequency of infections affecting the digestive system (26.4%), while the least affected system was the urogenital system 5.9%. Patients with A blood group exhibit an increased probability to be infected by viruses than they do for bacteria (odds ratio [OR] = 1.430; 95% confidence interval [CI] = 1.005 to 2.035; P = 0.05 and OR = 0.098; 95% CI = 0.064 to 0.148; P < 0.0001, respectively). It was observed that blood group A individuals were more susceptible to infection with hepatitis B virus than were the other groups (P = 0.041; OR = 1.704, 95% CI = 1.053-2.773). The liklihood of O blood group patients experiencing urogenital infections was less than that of non-O blood group patients one third (OR = 0.353, 95% CI = 0.158-0.789; P = 0.014). This study corroborates previous findings that demonstrated that certain blood groups are more prone to infection by one agent than are patients with other blood groups.

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

Vibrio mediterranei, a bacterial pathogen of bivalves, has exhibited strain-dependent virulence. The mechanisms behind the variations in bivalve pathogenicity between V. mediterranei strains have remained unclear. However, a preliminary analysis of the extracellular product (ECP) proteomes has revealed differences in protein compositions between low- and high-virulence strains; in addition to 1265 shared proteins, 127 proteins have been identified to be specific to one low-virulence strain and 95 proteins to be specific to two high-virulence strains. We further studied the ECP proteins of the three V. mediterranei strains from functional perspectives using integrated genomics and proteomics approaches. The results showed that lipid metabolism, transporter activity and membrane transporter pathways were more enriched in the ECPs of the two high-virulence strains than in those of the low-virulence strain. Additionally, 73 of the 95 high-virulence strain-specific proteins were found to have coding genes in the genome but were not expressed in the low-virulence strain. Moreover, comparisons with known virulence factors in the Virulence Factor Database (VFDB) and the Pathogen-Host Interactions Database (PHI-base) allowed us to predict more than 10 virulence factors in the categories of antimicrobial activity/competitive advantage, the effector delivery system and immune modulation, and the high-virulence strain-specific ECP proteins consisted of a greater percentage of known virulence factors than the low-virulence strain. Particularly, two virulence factors, MtrC and KatG, were identified in the ECPs of the two high-virulence strains but not in those of the low-virulence strain. Most coding genes of the ECP proteins including known virulence factors were identified on chromosome 1 of V. mediterranei. Our findings indicate that variations in virulence factor composition in the bacterial ECPs may partially account for the differences in the bivalve pathogenicity between V. mediterranei strains.

Host-microbe interactions constitute dynamical systems that can be represented by mathematical formulations that determine their dynamic nature and are categorized as deterministic, stochastic, or chaotic. Knowing the type of dynamical interaction is essential for understanding the system under study. Very little experimental work has been done to determine the dynamical characteristics of host-microbe interactions, and its study poses significant challenges. The most straightforward experimental outcome involves an observation of time to death upon infection. However, in measuring this outcome, the internal parameters and the dynamics of each particular host-microbe interaction in a population of interactions are hidden from the experimentalist. To investigate whether a time-to-death (time-to-event) data set provides adequate information for searching for chaotic signatures, we first determined our ability to detect chaos in simulated data sets of time-to-event measurements and successfully distinguished the time-to-event distribution of a chaotic process from a comparable stochastic one. To do so, we introduced an inversion measure to test for a chaotic signature in time-to-event distributions. Next, we searched for chaos in the time-to-death of Caenorhabditis elegans and Drosophila melanogaster infected with Pseudomonas aeruginosa or Pseudomonas entomophila, respectively. We found suggestions of chaotic signatures in both systems but caution that our results are preliminary and highlight the need for more fine-grained and larger data sets in determining dynamical characteristics. If validated, chaos in host-microbe interactions would have important implications for the occurrence and outcome of infectious diseases, the reproducibility of experiments in the field of microbial pathogenesis, and the prediction of microbial threats.IMPORTANCEIs microbial pathogenesis a predictable scientific field? At a time when we are dealing with coronavirus disease 2019, there is intense interest in knowing about the epidemic potential of other microbial threats and new emerging infectious diseases. To know whether microbial pathogenesis will ever be a predictable scientific field requires knowing whether a host-microbe interaction follows deterministic, stochastic, or chaotic dynamics. If randomness and chaos are absent from virulence, there is hope for prediction in the future regarding the outcome of microbe-host interactions. Chaotic systems are inherently unpredictable, although it is possible to generate short-term probabilistic models, as is done in applications of stochastic processes and machine learning to weather forecasting. Information on the dynamics of a system is also essential for understanding the reproducibility of experiments, a topic of great concern in the biological sciences. Our study finds preliminary evidence for chaotic dynamics in infectious diseases.

Streptococcus pyogenes, or Group A Streptococcus, is an exclusively human pathogen that causes a wide variety of diseases ranging from mild throat and skin infections to severe invasive disease. The pathogenesis of S. pyogenes infection has been extensively studied, but the pathophysiology, especially of the more severe infections, is still somewhat elusive. One key feature of S. pyogenes is the expression of secreted, surface-associated, and intracellular enzymes that directly or indirectly affect both the innate and adaptive host immune systems. Undoubtedly, S. pyogenes is one of the major bacterial sources for immunomodulating enzymes. Major targets for these enzymes are immunoglobulins that are destroyed or modified through proteolysis or glycan hydrolysis. Furthermore, several enzymes degrade components of the complement system and a group of DNAses degrade host DNA in neutrophil extracellular traps. Additional types of enzymes interfere with cellular inflammatory and innate immunity responses. In this review, we attempt to give a broad overview of the functions of these enzymes and their roles in pathogenesis. For those enzymes where experimentally determined structures exist, the structural aspects of the enzymatic activity are further discussed. Lastly, we also discuss the emerging use of some of the enzymes as biotechnological tools as well as biological drugs and vaccines.

Infectious diseases are the leading cause of morbidity and mortality worldwide. Causative pathogenic microbes readily mutate their genome and lead to outbreaks, challenging the healthcare and the medical support. Understanding how certain symptoms manifest clinically is integral for therapeutic decisions and vaccination efficacy/protection. Notably, the interaction between infecting pathogens, host response and co-presence of microbes influence the trajectories of disease progression and clinical outcome. The spectrum of observed symptomatic patients (mild, moderate and severe) and the asymptomatic infections highlight the challenges and the potential for understanding the factors driving protection/susceptibility. With the increasing repertoire of high-throughput tools, such as cutting-edge multi-omics profiling and next-generation sequencing, genetic drivers of factors linked to heterogeneous disease presentations can be investigated in tandem. However, such strategies are not without limits in terms of effectively integrating host-pathogen interactions. Nonetheless, an integrative genomics method (for example, RNA sequencing data) for exploring multiple layers of complexity in host-pathogen interactions could be another way to incorporate findings from high-throughput data. We further propose that a Holo-transcriptome-based technique to capture transcriptionally active microbial units can be used to elucidate functional microbiomes. Thus, we provide holistic perspective on investigative methodologies that can harness the same genomic data to investigate multiple seemingly independent but deeply interconnected functional domains of host-pathogen interaction that modulate disease severity and clinical outcomes.

Worldwide, over 694 million people have been infected with SARS-CoV-2, with an estimated 55-60% of those infected developing COVID-19. Since the beginning of the pandemic in December 2019, different variants of concern have appeared and continue to occur. With the emergence of different variants, an increasing rate of vaccination and previous infections, the acute neurological symptomatology of COVID-19 changed. Moreover, 10-45% of individuals with a history of SARS-CoV-2 infection experience symptoms even 3 months after disease onset, a condition that has been defined as 'post-COVID-19' by the World Health Organization and that occurs independently of the virus variant. The pathomechanisms of COVID-19-related neurological complaints have become clearer during the past 3 years. To date, there is no overt - that is, truly convincing - evidence for SARS-CoV-2 particles in the brain. In this Review, we put special emphasis on discussing the  methodological difficulties of viral detection in CNS tissue and discuss immune-based (systemic and central) effects contributing to COVID-19-related CNS affection. We sequentially review the reported changes to CNS cells in COVID-19, starting with the blood-brain barrier and blood-cerebrospinal fluid barrier - as systemic factors from the periphery appear to primarily influence barriers and conduits - before we describe changes in brain parenchymal cells, including microglia, astrocytes, neurons and oligodendrocytes as well as cerebral lymphocytes. These findings are critical to understanding CNS affection in acute COVID-19 and post-COVID-19 in order to translate these findings into treatment options, which are still very limited.

Healthy marine ecosystems are paramount for Earth's biodiversity and are key to sustaining the global economy and human health. The effects of anthropogenic activity represent a pervasive threat to the productivity of marine ecosystems, with intensifying environmental stressors such as climate change and pollution driving the occurrence and severity of microbial diseases that can devastate marine ecosystems and jeopardise food security. Despite the potentially catastrophic outcomes of marine diseases, our understanding of host-pathogen interactions remains an understudied aspect of both microbiology and environmental research, especially when compared to the depth of information available for human and agricultural systems. Here, we identify three avenues of research in which we can advance our understanding of marine disease in the context of global change, and make positive steps towards safeguarding marine communities for future generations.

Aeromonas sp. is a Gram-negative, non-spore-forming, rod-shaped, oxidase-positive, facultative anaerobic bacterium and a natural contaminant found in aquatic environments. Some species can invade, colonize, and damage host cells due to the presence of virulence factors, such as flagella, elastase, hemolysins, aerolysins, adhesins, enterotoxins, phospholipases and lipases, that lead to pathogenic activities. Consequently, can cause many health disorders that range from gastrointestinal problems, enteric infections, and ulcers to hemorrhagic septicemia. Aeromonas has been isolated and identified from a variety of sources, including drinking water and ready-to-eat foods (fish, meat, fresh vegetables, dairy products, and others). Some species of this opportunistic pathogen are resistant to several commercial antibiotics, including some used as a last resort for treatment, which represents a major challenge in the clinical segment. Antimicrobial resistance can be attributed to the indiscriminate use of antibiotics by society in aquaculture and horticulture. In addition, antibiotic resistance is attributed to plasmid transfer between microorganisms and horizontal gene transfer. This review aimed to (i) verify the occurrence of Aeromonas species in water and food intended for human consumption; (ii) identify the methods used to detect Aeromonas species; (iii) report on the virulence genes carried by different species; and (iv) report on the antimicrobial resistance of this genus in the last 5 years of research. Additionally, we present the existence of Aeromonas spp. resistant to antimicrobials in food and drinking water represents a potential threat to public health.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe and often fatal infections. MRSA epidemics have occurred in waves, whereby a previously successful lineage has been replaced by a more fit and better adapted lineage. Selection pressures in both hospital and community settings are not uniform across the globe, which has resulted in geographically distinct epidemiology. This review focuses on the mechanisms that trigger the establishment and maintenance of current, dominant MRSA lineages across the globe. While the important role of antibiotic resistance will be mentioned throughout, factors which influence the capacity of S. aureus to colonize and cause disease within a host will be the primary focus of this review. We show that while MRSA possesses a diverse arsenal of toxins including alpha-toxin, the success of a lineage involves more than just producing toxins that damage the host. Success is often attributed to the acquisition or loss of genetic elements involved in colonization and niche adaptation such as the arginine catabolic mobile element, as well as the activity of regulatory systems, and shift metabolism accordingly (e.g., the accessory genome regulator, agr). Understanding exactly how specific MRSA clones cause prolonged epidemics may reveal targets for therapies, whereby both core (e.g., the alpha toxin) and acquired virulence factors (e.g., the Panton-Valentine leukocidin) may be nullified using anti-virulence strategies.

Co-infections can affect the transmission of a pathogen within a population and the pathogen's virulence, ultimately affecting the disease's dynamics. In addition, co-infections can potentially affect the host's immunological responses, clinical outcomes, survival, and disease control efficacy. Co-infections significantly impact fish production and can change several fish diseases' progression and severity. However, the effect of co-infection has only recently garnered limited attention in aquatic animals such as fish, and there is currently a dearth of studies on this topic. This study, therefore, presents an in-depth summary of the dynamics of co-infection in fish. This study reviewed the co-infection of fish pathogens, the interaction of pathogens and fish, clinical outcomes and impacts on fish immune responses, and fish survival. Most studies described the prevalence of co-infections in fish, with various parameters influencing their outcomes. Bacterial co-infection increased fish mortality, ulcerative dermatitis, and intestinal haemorrhage. Viral co-infection resulted in osmoregulatory effects, increased mortality and cytopathic effect (CPE). More severe histological alterations and clinical symptoms were related to the co-infection of fish than in single-infected fish. In parasitic co-infection, there was increased mortality, high kidney swelling index, and severe necrotic alterations in the kidney, liver, and spleen. In other cases, there were more severe kidney lesions, cartilage destruction and displacement. There was a dearth of information on mitigating co-infections in fish. Therefore, further studies on the mitigation strategies of co-infections in fish will provide valuable insights into this research area. Also, more research on the immunology of co-infection specific to each fish pathogen class (bacteria, viruses, fungi, and parasites) is imperative. The findings from such studies would provide valuable information on the relationship between fish immune systems and targeted responses.

Bacterial coldwater disease (BCWD), caused by Flavobacterium psychrophilum, results in significant losses among multiple salmonid (family Salmonidae) species. Molecular epidemiology and serotyping studies have suggested that some variants are host specific; however, these associations have not been evaluated by cross-challenging fish species with putatively host-associated F. psychrophilum isolates via more natural (i.e. immersion) exposure routes. To this end, F. psychrophilum isolates US19-COS, US62-ATS and US87-RBT, each originally recovered from diseased coho salmon (Oncorhynchus kisutch), Atlantic salmon (Salmo salar) or rainbow trout (O. mykiss), and belonging to a host-associated multilocus sequence typing clonal complex (e.g. CC-ST9, CC-ST232 or CC-ST10), were PCR-serotyped, evaluated for proteolytic activity, and used to challenge adipose fin-clipped 4-month old Atlantic salmon, coho salmon and rainbow trout via immersion. Findings showed US87-RBT caused disease and mortality only in rainbow trout (e.g. 56.7% survival probability). US19-COS and US62-ATS caused more mortality in coho salmon and Atlantic salmon but also caused disease in both other host species, albeit to a lesser extent. Observed survival differences may be due to variant antigenic/virulence determinants as differences in serotype and proteolytic activity were discovered. Collectively, results highlight the intricacies of F. psychrophilum-host interactions and provide further in vivo evidence that some F. psychrophilum MLST variants are host specific, which may have implications for the development of BCWD prevention and control strategies.

Host-microbe interactions constitute dynamical systems that can be represented by mathematical formulations that determine their dynamic nature, and are categorized as deterministic, stochastic, or chaotic. Knowing the type of dynamical interaction is essential for understanding the system under study. Very little experimental work has been done to determine the dynamical characteristics of host-microbe interactions and its study poses significant challenges. The most straightforward experimental outcome involves an observation of time to death upon infection. However, in measuring this outcome, the internal parameters, and the dynamics of each particular host-microbe interaction in a population of interactions are hidden from the experimentalist. To investigate whether a time-to-death (time to event) dataset provides adequate information for searching for chaotic signatures, we first determined our ability to detect chaos in simulated data sets of time-to-event measurements and successfully distinguished the time-to-event distribution of a chaotic process from a comparable stochastic one. To do so, we introduced an inversion measure to test for a chaotic signature in time-to-event distributions. Next, we searched for chaos, in time-to-death of Caenorhabditis elegans and Drosophila melanogaster infected with Pseudomonas aeruginosa or Pseudomonas entomophila, respectively. We found suggestions of chaotic signatures in both systems, but caution that our results are preliminary and highlight the need for more fine-grained and larger data sets in determining dynamical characteristics. If validated, chaos in host-microbe interactions would have important implications for the occurrence and outcome of infectious diseases, the reproducibility of experiments in the field of microbial pathogenesis and the prediction of microbial threats.

The abundance of gut commensals has historically been associated with health-promoting effects despite the fact that the definition of good or bad microbiota remains condition-specific. The beneficial or pathogenic nature of microbiota is generally dictated by the dimensions of host-microbiota and microbe-microbe interactions. With the increasing popularity of gut microbiota in human health and disease, emerging evidence suggests opportunistic infections promoted by those gut bacteria that are generally considered beneficial. Therefore, the current review deals with the opportunistic nature of the gut commensals and aims to summarise the concepts behind the occasional commensal-to-pathogenic transformation of the gut microbes. Specifically, relevant clinical and experimental studies have been discussed on the overgrowth and bacteraemia caused by commensals. Three key processes and their underlying mechanisms have been summarised to be responsible for the opportunistic nature of commensals, viz. improved colonisation fitness that is dictated by commensal-pathogen interactions and availability of preferred nutrients; pathoadaptive mutations that can trigger the commensal-to-pathogen transformation; and evasion of host immune response as a survival and proliferation strategy of the microbes. Collectively, this review provides an updated concept summary on the underlying mechanisms of disease causative events driven by gut commensal bacteria.