Mucosal Infections Research Articles

Functionalization of cationic porphyrins with peripheral platinum(II) complexes to optimize photodynamic therapy against Candida-associated infections: a focus on denture stomatitis and burn wounds

ABSTRACT Candida spp. are opportunistic pathogens associated with mucosal and cutaneous infections. Its increased resistance to antifungals has instigated the development of adjunct treatments, such as antimicrobial photodynamic therapy (aPDT). This study evaluated the antifungal effects of aPDT mediated by two tetra-cationic porphyrins with peripheral platinum(II) complexes (3-Pt and 4-Pt). A thorough investigation was performed using in vitro and in vivo assays to determine their antifungal activity on Candida albicans and toxicity in human cells. Next, specific models were employed to search for understanding of the action of aPDT on Candida-associated infections. As a result, a MIC value of 16 μmol/L was found for both porphyrins, with low toxicity to keratinocytes even in higher concentrations. Planktonic cultures of C. albicans treated by aPDT with 3-Pt achieved complete inhibition in 40 s, while 4-Pt reduced 1.3 Log10 (CFU) within 80 s. These effects were also extended to C. albicans biofilms, in which 3-Pt and 4-Pt reduced 4 and 0.8 Log10 (CFU), respectively. The mechanisms of action of 3-Pt were related to hyphae inhibition, increased ROS production, and cell wall damage. Finally, 3-Pt showed efficacy against denture stomatitis biofilms in a microcosm model and burn wounds in Galleria mellonella, indicating its potential for treating Candida-associated infections.

Less reactogenic whole-cell pertussis vaccine confers protection from Bordetella pertussis infection.

Pertussis resurged over the last decade in most countries that replaced the traditional whole-cell pertussis vaccines (wP) by the less reactogenic acellular pertussis vaccines (aP). The aP vaccines induce a Th2-polarized immune response and by a yet unknown mechanism hamper the clearance of Bordetella pertussis from infected nasopharyngeal mucosa. The aP-induced pertussis toxin-neutralizing antibodies effectively prevent the life-threatening pertussis pneumonia in infants, but aP-elicited immunity fails to prevent infection of nasopharyngeal mucosa and transmission of B. pertussis. In contrast, the more reactogenic traditional wP vaccines, alike natural infection, elicit a broad antibody response and trigger a Th1/Th17-polarized T cell immunity. We tackled here the reactogenicity of the conventional wP vaccines by genetic modification of the Fim2 and Fim3-producing B. pertussis strains used for wP vaccine manufacturing. Mutations were introduced into the genomes of vaccine strains (i) to reduce the TLR4 signaling potency of the lipid A of B. pertussis lipooligosaccharide (ΔlgmB), (ii) eliminate the enzymatic (immunosuppressive) activity of the pertussis toxin (PtxS1-R9K/E129G), and (iii) ablate the production of the dermonecrotic toxin (Δdnt). Experimental alum-adjuvanted wP vaccines prepared from such triply modified bacteria exhibited a reduced pyrogenicity in rabbits and a reduced systemic toxicity in mice, while conferring a comparable protection from B. pertussis infection as the unmodified wP vaccine.IMPORTANCEThe occasionally severe adverse reactions associated with some lots of the whole-cell pertussis vaccine (wP) led the industrialized nations to switch to the use of less reactogenic acellular pertussis vaccines that confer shorter-lasting protection. This yielded whooping cough resurgence and large whooping cough outbreaks are currently sweeping throughout European countries, calling for the replacement of the pertussis vaccine component of pediatric hexavaccines by an improved wP vaccine. We show that genetic detoxification of the Bordetella pertussis bacteria used for wP preparation yields a reduced reactogenicity wP vaccine that exhibits a reduced systemic toxicity in mice and reduced pyrogenicity in rabbits, while retaining high immunogenicity and protective potency in the mouse model of pneumonic infection by B. pertussis. This result has now been confirmed in a nonhuman primate model of B. pertussis infection of olive baboons, paving the way for the development of the next generation of pertussis vaccines.

Global phylogenomic analysis of Staphylococcus pseudintermedius reveals genomic and prophage diversity in multidrug-resistant lineages.

Staphylococcus pseudintermedius is the foremost cause of opportunistic canine skin and mucosal infections worldwide. Multidrug-resistant (MDR) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) lineages have disseminated globally in the last decade and present significant treatment challenges. However, little is known regarding the factors that contribute to the success of MDR lineages. In this study, we compared the genome sequence of 110 UK isolates of S. pseudintermedius with 2166 genomes of S. pseudintermedius populations from different continents. A novel core genome multi-locus typing scheme was generated to allow large-scale, rapid and detailed analysis of S. pseudintermedius phylogenies and was used to show that the S. pseudintermedius population structure is broadly segregated into an MDR population and a non-MDR population. MRSP lineages are predicted to encode certain resistance genes either chromosomally or on plasmids, and this is associated with their MLST sequence type. A comparison of lineages most frequently implicated in disease, ST-45 and ST-71, with the phylogenetically related ST-496 lineage that has a comparatively low disease rate, revealed that ST-45 and ST-71 genomes encode distinct combinations of phage-defence systems and concurrently encode a high number of intact prophages. In contrast, ST-496 genomes encode a wider array of phage defence systems and lack intact and complete prophages. These findings indicate that MRSP lineages have significant structural genomic differences and that prophage integration and differential antiviral systems correlate with the emergence of successful genotypes.

Nasal delivery of secretory IgA confers enhanced neutralizing activity against Omicron variants compared to its IgG counterpart.

Nasal delivery of secretory IgA confers enhanced neutralizing activity against Omicron variants compared to its IgG counterpart.

Unveiling the Oral Lesions, Dysgeusia and Osteonecrosis Related to COVID-19: A Comprehensive Systematic Review.

Background/Objectives: The oral cavity has garnered increasing attention as a site for viral infection and related pathological manifestations in coronavirus disease-19. This article aims to provide a comprehensive overview of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-related oral manifestations, including taste disturbances, oral lesions and osteonecrosis. Methods: A search was conducted up to September 2024 according to PRISMA (Preferred Reporting Items for Systematic Reviews) guidelines using the databases PubMed and Scopus. All the observational, case-series, case-report and cross-sectional studies written in English on oral manifestations related to COVID-19 disease and long-COVID disease were included. All other types of studies and studies based on oral manifestation after COVID-19 vaccination and oral impairment due to lockdown were excluded. The risk of bias of included studies was assessed using the Joanna Briggs Appraisal checklist. Results: A total of 104 articles including 23 case-report, 15 case-series, 8 case-control, 18 cohort and 40 cross-sectional studies were selected. The results showed that patients with COVID-19 were found to have a significantly higher prevalence of xerostomia (45-74%) and dysgeusia (32-59%) compared to non-infected individuals. Regarding oral mucosal lesions, ulcers, candidiasis and herpes simplex infections were frequently observed. As for osteonecrosis, a significant number of patients with COVID-19-associated rhinomaxillary mucormycosis presented with maxillary osteonecrosis due to fungal infection, primarily mucormycosis. The methodological quality of most of the studies was moderate/high. Conclusions: COVID-19 has been associated with a range of oral manifestations. The complex interplay of viral infection, immune response, medication use and stress likely contributes to these oral complications. Early recognition and management of these oral manifestations are crucial for improving patient outcomes and developing targeted preventive and therapeutic strategies for COVID-19-related oral health issues.

Impact of the 10-valent pneumococcal conjugate vaccine (PCV10) on pneumococcal carriage in healthy children and children with acute otitis media and pneumonia: emergence of serotypes 3, 6C and 19A in Croatia.

Impact of the 10-valent pneumococcal conjugate vaccine (PCV10) on pneumococcal carriage in healthy children and children with acute otitis media and pneumonia: emergence of serotypes 3, 6C and 19A in Croatia.

Microbial players in autoimmunity: multicentric analysis of the association between Mycoplasma hominis serostatus and rheumatoid arthritis.

Resident mucosal pathogens may induce immune tolerance breach, specific autoimmune response, and the development of rheumatoid arthritis (RA) in susceptible individuals. Despite a number of studies linking infections by Mollicutes bacteria to autoimmune disorders' onset and progression, the role of Mycoplasma hominis, a common urogenital mucosa colonizing bacterium, in inducing a specific humoral response in RA has been seldom addressed. This study reports M. hominis seroprevalence in RA patients compared to healthy controls (HC) by testing two separate cohorts sampled in two distinct geographical settings (Italy and Vietnam). The amount of circulating anti-lipid-associated membrane proteins (LAMPs) antibodies was significantly higher in RA patients than HC in both cohorts. Also, a significantly higher seroprevalence of anti-M. hominis antibodies in RA patients compared to HC in both cohorts was observed. Notably, neither ELISA OD values nor positivity of anti-LAMPs were significantly associated with RA-specific variables. Further studies are essential to elucidate the underlying mechanisms by which Mycoplasma species may contribute to the pathogenesis of RA, thereby advancing our understanding of the potential causal links between Mollicutes and autoimmune disorders.IMPORTANCEMycoplasmas may cause persistent asymptomatic mucosal infections and elicit chronic host immune responses. In this study, we evaluated the prevalence of serological response to the sexually transmitted bacterium Mycoplasma hominis in patients with rheumatoid arthritis. We show that sera of patients with rheumatoid arthritis are enriched with antibodies specifically recognizing microbial surface antigens compared with the general population. This suggests that M. hominis genital infection, with its peculiar host immunity subversion mechanisms, might play a role in predisposing to the development and progression of chronic arthritis in susceptible individuals. Thus, the range of microbes with a role as triggers of autoimmune disease (P. gingivalis, A. actinomycetemcomitans, Streptococcus spp., and F. nucleatum, among others) might have a new member in M. hominis. The potential role of the interactions taking place at the host-pathogen interface during persistent M. hominis infections in inducing autoimmunity should be further explored and characterized.

Interleukin-5 enhances human mast cell survival and interferon responses to viral infection.

Interleukin-5 enhances human mast cell survival and interferon responses to viral infection.

Retinoic acid-adjuvanted vaccine induces antigen-specific secretory IgA in the gut of newborn piglets.

Retinoic acid-adjuvanted vaccine induces antigen-specific secretory IgA in the gut of newborn piglets.

P-659. Active Surveillance of Mucosal Pneumococcal Infections to Predict the Potential Added Benefits of Extended-Spectrum PCVs in Children < 24 Months in Southern Israel

Abstract Background Although mucosal infections, such as otitis media (OM) and acute conjunctivitis (AC) are the most common manifestations of pneumococcal disease in young children, surveillances have been based mainly on invasive pneumococcal disease (IPD) due to paucity of serotype-specific data on mucosal infection rates. We present rates and serotype dynamics of OM and AC as a means for assessing potential added benefits of the new PCVs, (PCV15/PCV20) against OM and AC in children < 24m. Annual incidence rates of P-OM and P-AC episodes, children <24 months of age*, southern Israel, July 2004 through June 2023 Methods A retrospective analysis of two prospective, population-based surveillance projects on OM (Ben-Shimol CID 63:611, 2016) and AC (Dagan CID 72:1200, 2021) in southern Israel. All episodes in children < 24m with OM and/or AC with cultures in southern Israel have been included. All middle-ear fluid (MEF) and conjunctival cultures in the region are processed in a single laboratory of the hospital where ∼95% of all children are born and treated, permitting incidence calculations. The current analysis covers all pneumococcal OM and AC (P-OM, P-AC) from July 2004 through June 2023. Distribution of individual serotypes in P-AC and P-OM episodes, children <24 months of age*, southern Israel, July 2015 through June 2023 (late PCV13 period) Results A total of 2,312 and 1,039 episodes of P-OM and P-AC, respectively, were observed. The P-OM and P-AC annual rates are presented in Figure 1. The respective incidence rate ratios (95% CI) for 2017-2023 (excluding Corona year 2020-2021) vs. 2004-2008 were 0.12 (0.09-0.16) and 0.37 (0.26-0.53). During the stable PCV13 period (2015-2023), 32% and 24% of all P-OM and P-AC, respectively, were PCV20 serotypes (Figure 2). In both diseases, the PCV13 serotypes 19A, 19F, 3, and 14, and the PCV20-non-PCV13 serotypes 10A, 11A, 33F, and 15 B/C, predominated. PCV13 serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 18C, 23F (grouped) constituted only 0.6% and 1.7% of all P-OM and P-AC, respectively. Conclusion 1) PCV13 implementation resulted in a rapid and steep decline in both P-OM and P-AC rates, stabilizing within 3-4 years; 2) during the late PCV13 period, only 4 PCV13 serotypes persisted: PCV7 serotypes 19F and 14, and PCV13 non-PCV7 serotypes 3 and 19A; and 3) the non-PCV13 PCV20 serotypes constitute approximately one quarter and one third of P-AC and P-OM, respectively, in children < 24m in southern Israel. Implementation of PCV20 has the potential to add benefit against pneumococcal mucosal disease. Disclosures Ron Dagan, Professor MD, GSK: Advisor/Consultant|GSK: Honoraria|MedIMmune/AstraZeneca: Grant/Research Support|MedIMmune/AstraZeneca: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi Pasteur: Honoraria

P-890. Risk Factors Associated with Carbapenem-Resistant Enterobacteria Bacteremia and Mortality in Patients with Acute Leukemia

Abstract Background The inclusion of highly cytotoxic drugs for the treatment of acute leukemia (AL) in the last decade has exposed patients to more extended periods of severe neutropenia. The study aims to describe the prevalence and risk factors for blood-stream infection (BSI) due to carbapenem-resistant enterobacteria (CRE) in patients with AL receiving chemotherapy.Table 1.Independent risk factors for blood-stream infection due to carbapenem-resistant enterobacteria FLAG-IDA chemotherapy regimen had an OR 28.8 (CI 2.9-286.68. p=0.004) for CRE-BSI Methods The study was performed at a referral center for adult patients with cancer in Mexico City. From January 2021 to December 2022, all patients with AL treated from first to fourth line chemotherapy were included. CRE and non-CRE BSI were compared for categorical variables with Pearson's chi-square. A bivariate logistic regression analysis was performed to identify risk factors associated with mortality and isolation of CRE.Table 2.Independent risk factors for mortalityPatients with AML had an OR 7 (CI 1.26-39.23 p=0.026), isolation of CRE OR 6.8 (CI 1.17-0.03 p=0.03) and being diagnosed with invasive fungal infection (IFI) OR 5.2 (CI 1.29-26.66 p=0.02) for mortality Results One hundred ten patients were included: 62 (56.3%) with acute lymphoblastic leukemia (ALL) and 48 (43.6%) with acute myeloid leukemia (AML). 119 BSI were confirmed, 41 (34%) blood isolates were antimicrobial resistant, 23 (56.1%) had extended-spectrum beta-lactamases (ESBL), and 16 (39%) had CRE. BSIs were classified as 70 (58.8%) Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infection (MBI-LCBI), 24 (20.1%) secondary, 23 (19.3%) catheter-related and 2 (1.6%) primary. Of the 23 (56.1%) isolates with ESBL and 16 (39%) CRE, all were classified as MBI-LCBI, as were two (4.9%) methicillin-resistant S. aureus. Overall, 30-day mortality was 9.2%, and at 24 weeks, 16.8%. In the bivariate analysis, receiving a FLAG-IDA had an OR 28.8 (CI 2.9-286.68. p=0.004) for CRE-BSI (Table 1). For mortality, having AML had an OR 7 (CI 1.26-39.23 p=0.026), CRE BSI isolates OR 6.8 (CI 1.17-0.03 p=0.03), and being diagnosed with invasive fungal infection (IFI) OR 5.2 (CI 1.29-26.66 p=0.02) (Table 2). Kaplan-Meier model comparing patients with and without CRE-BSI showed a mean survival of 17.8 months in CRE-BSI vs. 23.4 months without CRE-BSI, although non statistical significance (Figure 1).Figure 1.Kaplan-Meier survival analysisKaplan-Meier model comparing patients with and without CRE-BSI showed a mean survival of 17.8 months in CRE-BSI vs. 23.4 months without CRE-BSI, although without statistical significance Conclusion In this cohort, overall mortality was associated with AML, having CRE isolated in blood, and having been diagnosed with IFI. Having a CRE-BSI was associated with receiving FLAG-IDA. This highly myelosuppressive chemotherapy regime has become a niche for antimicrobial resistance development in our institution. Disclosures All Authors: No reported disclosures

423. Mirror Mirror on the Wall Who is Driving all the Invasive GAS After All - The Utah Experience

Abstract Background Streptococcus pyogenes (GAS) is a common cause of non-invasive mucosal infections as well as rare life-threatening invasive disease. At the onset of the COVID-19 pandemic there was a decline in invasive GAS (iGAS) disease, followed by an increase in the fall of 2022 with the rise of emm12. Data on the association of circulating non-invasive and invasive emm-types are limited. We sought to characterize and compare emm-types of pharyngeal GAS to iGAS before and after the emergence of COVID-19.Figure 1:Positive GAS pharyngeal culture, PCH ED and iGAS cases by Quarter, Utah Q1 2018 - Q1 2023 Methods We retrospectively identified both pharyngeal and invasive GAS isolates obtained at Primary Children’s Hospital (Salt Lake City, Utah) from 2018-2023 using our GAS isolate database. Pharyngeal isolates were obtained primarily from our emergency department, while iGAS isolates were from hospitalized patients. Isolates underwent whole genome sequencing for emm typing, virulence factor identification, and phylogenetic analysis. We compared pharyngeal and invasive isolates for emm-type distribution over time and the presence of known virulence genes.Figure 2:Invasive and Pharyngeal emm-type Percentages, by Year, Utah 2018-2023 Results From 1/2018 to 4/2023, we identified ∼650 pharyngeal GAS isolates, of which a random subsample of 306 were sequenced; 286 yielded sequences suitable for analysis. We identified 145 iGAS cases; all were sequenced. We observed a marked decrease in pharyngeal GAS from Q2 2020 through Q3 2022, followed by a steep increase which paralleled iGAS (Figure 1). The distribution of emm-types causing iGAS mirrored that of non-invasive pharyngeal isolates over time (Figure 2). Post-pandemic, emm12 and emm1 dominated both pharyngeal and invasive isolates. Comparing virulence genes between pharyngeal and iGAS isolates showed sfbl/prtF1 were strongly associated with invasive disease in emm12 and emm59 (OR: 5.0, 95% CI [2.2-11]) while the presence of sic was strongly associated with invasive disease in emm1 (OR: 16.2, 95% CI [5.6-45.9]). Conclusion After a marked decrease in GAS infections in children during the COVID-19 pandemic in Utah, there was a rebound of disease. Molecular analysis revealed invasive emm-types mirrored trends in pharyngeal isolates. Virulence genes sfbl/prtF1 and sic were associated with invasive disease in emm12 and emm1 respectively. Further analysis of evolutionary relatedness and virulence determinants is ongoing. Disclosures Krow Ampofo, MBChB, Merck: Grant/Research Support Andrew T. Pavia, MD, GSK/Haleon: Advisor/Consultant|Sanofi: Advisor/Consultant Anne J. Blaschke, MD, PhD, BioFire Diagnostics/Biomerieux: I have IP owned by the U. of Utah licensed to BioFire and receive royalties.|Merck & Co: Advisor/Consultant

The stress-protectant molecule trehalose mediates fluconazole tolerance in Candida glabrata.

The incidence of non-albicans Candida infections has witnessed a substantial rise in recent decades. Candida glabrata (Nakaseomyces glabratus), an opportunistic human fungal pathogen, is accountable for both superficial mucosal and life-threatening bloodstream infections, particularly in immunocompromised individuals. Distinguished by its remarkable resilience to environmental stressors, C. glabrata exhibits intrinsic tolerance to azoles and a high propensity to swiftly develop azole resistance during treatment. The molecular mechanism for the high tolerance is not fully understood. In this work, we investigated the possible role of trehalose in this tolerance. We generated mutants in the C. glabrata TPS1, TPS2, and NTH1 genes, encoding trehalose 6-phosphate synthase (Tps1), trehalose 6-phosphate phosphatase (Tps2), and neutral trehalase (Nth1), respectively. As expected, the tps1∆ strain cannot grow on glucose. The tps2∆ strain demonstrated diminished trehalose accumulation and very high levels of trehalose 6-phosphate (T6P), the biosynthetic intermediate, in comparison to the wild-type (WT) strain. Whereas these higher T6P levels did not affect growth, the lower trehalose levels clearly resulted in lower environmental stress tolerance and a lower susceptibility to fluconazole. More interestingly, the tps2∆ strain completely lost tolerance to fluconazole, characterized by the absence of slow growth at supra-MIC concentrations of this drug. All these phenotypes are reversed in the nth1∆ strain, which accumulates high levels of trehalose. Our findings underscore the role of trehalose in enabling tolerance toward fluconazole in C. glabrata. We further show that the change in tolerance is a result of the effect that trehalose has on the sterol pattern in the cell.

Structural insights into mechanisms of zinc scavenging by the Candida albicans zincophore Pra1.

Candida albicans causes more than 400,000 life-threatening, and half a billion mucosal infections annually. In response to infection, the host limits availability of essential micronutrients, including zinc, to restrict growth of the invading pathogen. As assimilation of zinc is essential for C. albicans pathogenicity, its limitation induces the secretion of the zincophore protein Pra1 to scavenge zinc from the host. Pra1 also plays a number of important roles in host-pathogen interactions and is conserved in most fungi. However, the structure of fungal zincophores is not known. Here, we present the first cryogenic electron microscopy structures of C. albicans Pra1 in its apo- and zinc-bound states, at 2.8 and 2.5 Å resolution respectively. Our work reveals a hexameric ring-like assembly with multiple zinc binding sites. Through genetic studies, we show that one of these zinc binding sites is essential for C. albicans growth under zinc restriction but does not affect the inflammatory properties of Pra1. These data provide a foundation for future work to explore the structural basis of Pra1-mediated host-pathogen interactions, C. albicans zinc uptake, as well therapeutics development.

Activity of Antiseptics Against Pseudomonas aeruginosa and Its Adaptation Potential.

Pseudomonas aeruginosa rapidly acquires antibiotic resistance and demonstrates increasing tolerance to antiseptics. This study evaluated the activity of eight antiseptics against P. aeruginosa, assessed its ability to develop adaptation to these antiseptics, and, for the first time, determined the Karpinski Adaptation Index (KAI) for this bacterium. The minimal inhibitory concentration (MIC), susceptibility to antibiotics, bactericidal time according to EN 1040:2005, adaptation potential, and KAI of P. aeruginosa strains were evaluated. The most effective antiseptics against P. aeruginosa, based on MIC activity, were octenidine dihydrochloride (OCT; mean MIC 11.3 ± 4.5 µg/mL), polyhexamethylene biguanide (PHMB; MIC 22.6 ± 8.0 µg/mL), and chlorhexidine digluconate (CHX; MIC 26.6 ± 14.4 µg/mL). Sodium hypochlorite (NaOCl) and ethacridine lactate (ET) showed moderate activity, while boric acid (BA), povidone-iodine (PVI), and potassium permanganate (KMnO4) exhibited the weakest MIC activity. MIC values for NaOCl (95 ± 15.4 µg/mL) and KMnO4 (>10 mg/mL) were close to or exceeded the clinical concentrations used in commercial products. OCT, CHX, and PVI exhibited the fastest bactericidal effect within 1 min. Bactericidal times were up to 15 min for PHMB, up to 60 min for ET, and more than 60 min for BA, NaOCl, and KMnO4. The lowest KAI values, indicating a low resistance risk, were observed for OCT (0.12), PHMB (0.19), and BA (0.19). Moderate resistance risk was noted for PVI (0.21), CHX (0.29), and ET (0.47). The highest KAI values, signifying a very high resistance risk, were found for NaOCl (1.0) and KMnO4 (≥1.0). Antiseptics like OCT, CHX, and partially PVI can be critical in quick antibacterial action on infected wounds, while agents such as PHMB might be reserved for cases where prolonged contact times are possible. Given the rapid adaptation of P. aeruginosa to the clinical concentrations of NaOCl and KMnO4 currently in use, reconsideration of their effectiveness in treating skin and mucous membrane infections is recommended.

The vicious spiral in Sudden Infant Death Syndrome.

Sudden Infant Death Syndrome (SIDS) is the sudden and unexpected death of an otherwise healthy infant less than 1 year of age where the cause of death remains unexplained after a thorough post-mortem investigation and evaluation of the circumstances. Epidemiological, clinical, biochemical, immunological and pathological evidence indicates that three factors must coincide for SIDS to occur: a vulnerable developmental stage of the immune system and central nervous system in the infant, predisposing factors, and external trigger events. This model is referred to as the fatal triangle or triple risk hypothesis. The concept of a vicious spiral in SIDS, starting with the fatal triangle and ending in death, is proposed as a model to understand the death mechanism. The vicious spiral is initiated by a mucosal infection and immune activation in the upper respiratory and digestive tracts, increased production of cytokines, and an overstimulation of the immature and rapidly developing immune system. A second trigger is the prone sleeping position, which may lead to rebreathing and hypercapnia, in addition to intensify the immune stimulation. In susceptible infants, this induces an aberrant cytokine production that affects sleep regulation, induces hyperthermia, and disrupts arousal mechanisms. In turn, this initiates downregulation of respiration and hypoxemia, which is worsened by nicotine. Inefficient autoresuscitation results in severe hypoxia and accumulation of hypoxic markers which, if not prevented by a normally functioning serotonergic network, contribute to a self-amplifying vicious spiral that eventually leads to coma and death. The purpose of this review is to summarize the research that underpins the concept of the vicious spiral.

Detection of Some Virulence Factors from Candida spp. Isolated from Vaginal and Oral Candidiasis in Iraqi Patients.

Candidiasis can be present as a cutaneous, mucosal, or deep-seated organ infection, which is caused by more than 20 types of Candida spp., with C. albicans being the most common. Hence, this work aimed to estimate some virulence factors, including phospholipase and biofilm formation, in some Candida spp. A total of eighty-six specimens were collected from patients with oral and vaginal candidiasis and subjected into different examinations, including cultural characteristic (on Sabouraud Dextrose Agar SDA and chromogenic Candida agar) and microscopic examination and germ tube formation (GT)to isolate Candida spp. In addition, the egg-yolk agar plate method was used to determine the extracellular phospholipase production, and the microtiter plate method was used to determine biofilm formation of Candida spp. Vitek Compact equipment was used to identify the highest phospholipase and biofilm-producers of Candida spp. As a result of all examinations, 58.1% (n = 50/86) of isolates of Candida spp. were obtained, including 26.7% (n = 23/86) isolates of Candida spp. from oral cavity and 31.3% (n = 27/86) isolates of Candida spp. from vaginal cavity. These isolates included 58% (n = 29/50) C. albicans, 10% (n = 5/50) C. glabrata, 6% (n = 3/50) C. parasilosis, 6% (n = 3/50) C. krusei, 6% (n = 3/50) C. lusitaniae, 6% (n = 3/50) C. kefyr, 6% (n = 3/50) C. tropicalis, and 2% (n = 1/50) C. ciferrii. To quantify extracellular phospholipase production, the egg-yolk agar plate method was utilized. The results indicated that the majority of isolates (n = 33; 66%) were phospholipase-strong producers, 18% (n = 9) of isolates were phospholipase-moderate producers, 5% (n = 10) were phospholipase-weak producers, and 6% (n = 3) were non-phospholipase producers. Microtiter plate method was utilized to estimate formation of biofilm by Candida spp. obtained from vaginal and oral cavities. The majority of Candida spp. isolates (n = 32; 64%) were biofilm-strong producers, followed by 30% (n=15) moderate-biofilm producers and 6% (n = 3) weak-biofilm producers. The results of VITEK 2 system indicated that the probability of C. albicans, C. krusei, C. kefyr, C. tropicalis, C. lusitaniae, C. glabrata, and C. ciferrii was 98, 95, 94, 91, 85, 93, and 85 %, respectively. Candida albicans was the most frequent isolate among all isolates.

Design, Synthesis, and Anti-Infective Effect Against Candida Albicans of a New Urolithin Derivative.

Deep mucosal and organ infections caused by the infestation of Candida albicans in immunocompromised patients represent a significant cause of mortality in hospitalized patients. The rise in fungal resistance is a consequence of the overuse of antibiotics. Therefore, innovative immunostimulants must be developed to combat pathogenic fungal infections. We used urolithin A (UA), an intestinal metabolite rich in the naturally occurring polyphenolic antioxidants ellagic acid (EA) or ellagitannin (ET), as a lead compound for structural modification. Through liquid screening of 17 synthesized compounds, we discovered compound 1e effectively inhibited C. albicans biofilm formation, thereby reducing its virulence. Furthermore, it protects animals from severe infections by enhancing tolerance to infection by intestinal pathogens and reducing oxidative stress. Moreover, our findings indicate that compound 1e exerts its effects through the p38 mitogen-activated protein kinase (MAPK) innate immune pathway, which is evolutionarily conserved. These observations not only enhance our comprehension of immune mechanisms but also provide a crucial foundation for the development of immune activators with the potential to resist pathogenic bacterial infections.

Mechanisms of sterilizing immunity provided by an HIV-1 neutralizing antibody against mucosal infection.

Broadly neutralizing antibodies (bnAbs) against HIV-1 have been shown to protect from systemic infection. When employing a novel challenge virus that uses HIV-1 Env for entry into target cells during the first replication cycle, but then switches to SIV Env usage, we demonstrated that bnAbs also prevented mucosal infection of the first cells. However, it remained unclear whether antibody Fc-effector functions contribute to this sterilizing immunity. Therefore, additional challenge viruses were produced that contain SIV Env and graded doses of a fusion-defective trimer of HIV-1 Env, to which the bnAb, PGT121 can bind without interfering with the SIV Env-based cell entry. After administration of either PGT121 or its mutant deficient in Fc-effector functions, rhesus macaques were intrarectally exposed to these challenge viruses and to those using either HIV-1 Env or SIV Env for entry into the first cells. Both antibodies similarly reduced infection events with the challenge virus using HIV-1 Env by a factor close to 200. Incorporating fusion-defective HIV-1 Env trimers into the particles of the challenge viruses at densities observed in primary virus isolates did not reduce SIV Env-mediated infection events. The results indicate that the sparsity of bnAb binding-sites on HIV-1 virions limits the contribution of Fc-effector functions to provide sterilizing immunity against mucosal viral infection. Hence, harnessing Fc-effector functions for sterilizing immunity against mucosal HIV-1 infection may require strategies to increase the degree of antibody opsonization.

Proportions of IgA antibodies targeting glycosylated epitopes of secreted Escherichia coli mucinase YghJ in initial plasmablast response differ from salivary and intestinally secreted IgA

Mucosal infections normally cause an immune response including activation of antigen-specific B cells in regional mucosa-associated lymphoid tissue. After recirculation of plasmablasts, and maturation at mucosal surfaces or bone marrow, plasma cells produce secretory or systemic IgA. It remains uncertain to what extent secretory and systemic IgA share the same target specificities. For vaccine candidate optimization, it is important to know whether IgA targeting of glycosylated epitopes of a protein antigen vary between mucosal and systemic sites. We evaluated glycosylated epitope specificity of systemic and mucosally secreted IgA against YghJ, a potential vaccine candidate antigen secreted by most pathogenic Escherichia coli. IgA from intestinal lavage, saliva, serum, and blood-derived antibody in lymphocyte supernatants (ALS) were collected from 21 volunteers following experimental infection with enterotoxigenic E. coli. Methods for preparing IgA from saliva and ALS were developed, and multiplex bead flow cytometric immunoassays were used to determine levels of IgA targeting natively glycosylated YghJ and estimating what proportion of these antibodies specifically targeted glycosylated epitopes. Following infection, anti-YghJ IgA levels increased substantially for most volunteers across all four specimen types. Target specificity of ALS IgA correlated well with serum IgA, but not with mucosally secreted IgA. Furthermore, glycosylation-specific proportion of salivary IgA was higher than, and did not correlate with, intestinally secreted IgA. These results indicate a new degree of complexity to our understanding of epitope-targeting and tissue specificity of mucosal antibody responses. Our findings also suggest that all features of an intestinal IgA response may not be well reflected in serum, saliva, or ALS, which are commonly used proxy specimens for evaluating intestinal immune responses.