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Background: We evaluated comprehension and application of the 2015 neuromyelitis optica spectrum disorder (NMOSD) criteria core elements by neurologists in Latin America (LATAM) who routinely diagnose and care for NMOSD patients by (i) identifying typical/suggestive NMOSD syndromes, (ii) detecting typical MRI NMOSD lesions and meeting MRI dissemination in space (DIS) criteria, and (iii) evaluating historical symptoms suggestive of NMOSD., Methods: We conducted an anonymous, voluntary, self-administered web- and case-based survey cross-sectional study from October 2023 to January 2024 of neurologists identified through the LACTRIMS database. Questions were presented first through iterative clinical cases or imaging, followed by questions directly evaluating comprehension of definitions. "Correct" responses were based on the 2015 criteria and adjudicated by the consensus of the experts leading the project., Results: A total of 106 neurologists (60.3% female; mean age: 46.6 ± 12.5 years) were included. Between 10.4% and 49.1% of neurologists inaccurately identified clinical or paraclinical aspects for DIS and 32.1% accurately identified the three non-cardinal (brainstem, diencephalic, and cerebral) syndromes for seronegative patients. Between 35.8% and 64.1% of neurologists identified the "optimal timing" of AQP4-IgG testing (e.g., during an attack or before receiving immunosuppressant treatments, among others); 56.6% considered live cell-based assay as the gold standard method for serological testing. Most neurologists accurately identified typical NMOSD MRI lesions, but periventricular, juxtacortical/cortical, fluffy infratentorial, corticospinal tract, and hypothalamic lesions were frequently misidentified., Conclusion: Clinical scenarios were identified where the 2015 NMOSD criteria were susceptible to misinterpretation and misapplication by expert neurologists in LATAM. Implementing collaborative educational initiatives could improve NMOSD diagnosis and raise patient care standards., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Carnero Contentti, Rojas, Alonso, Yeaman and Weinshenker.)

Introduction: Staphylococcus aureus bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant S. aureus (MRSA). In contrast to resolving MRSA bacteremia (RB), persistent MRSA bacteremia (PB) blood cultures remain positive despite appropriate antibiotic treatment. Host immune responses distinguishing PB vs. RB outcomes are poorly understood. Here, integrated transcriptomic, IL-10 cytokine levels, and genomic analyses sought to identify signatures differentiating PB vs. RB outcomes., Methods: Whole-blood transcriptomes of propensity-matched PB (n=28) versus RB (n=30) patients treated with vancomycin were compared in one independent training patient cohort. Gene expression (GE) modules were analyzed and prioritized relative to host IL-10 cytokine levels and DNA methyltransferase-3A ( DNMT3A ) genotype., Results: Differential expression of T and B lymphocyte gene expression early in MRSA bacteremia discriminated RB from PB outcomes. Significant increases in effector T and B cell signaling pathways correlated with RB, lower IL-10 cytokine levels and DNMT3A heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures., Discussion: Collectively, the present findings indicate that human PB involves dysregulated immunity characterized by impaired T and B cell responses associated with excessive IL-10 expression in context of the DNMT3A A/A genotype. These findings reveal distinct immunologic programs in PB vs. RB outcomes, enable future studies to define mechanisms by which host and/or pathogen drive differential signatures and may accelerate prediction of PB outcomes. Such prognostic assessment of host risk could significantly enhance early anti-infective interventions to avert PB and improve patient outcomes., Competing Interests: VGF reports Grant/Research Support: MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, BasileaPaid Consultant: Pfizer, Novartis Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny. Membership: Merck Co-Chair V710 Vaccine. Educational fees: Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm. Royalties: UpToDate. MRY is a founder and shareholder of NovaDigm Therapeutics, Inc., which develops vaccines and immunotherapeutics targeting multi-drug-resistant pathogens, including S. aureus. He has received research funding from the U.S. National Institutes of Health and the U.S. Department of Defense and has received honoraria for educational activities or consultation from Alexion/AstraZeneca, Genentech-Roche and Horizon/Amgen. EFR is on the board of Federation of Clinical Immunology Societies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Parmar, Pickering, Ahn, Rossetti, Gjertson, Ruffin, Chan, Fowler, Yeaman, Reed and MRSA Systems Immunology Group.)

Introduction: SARS-CoV-2 is the etiologic agent of coronavirus disease 2019 (COVID-19). Questions remain regarding correlates of risk and immune protection against COVID-19., Methods: We prospectively enrolled 200 participants with a high risk of SARS-CoV-2 occupational exposure at a U.S. medical center between December 2020 and April 2022. Participant exposure risks, vaccination/infection status, and symptoms were followed longitudinally at 3, 6, and 12 months, with blood and saliva collection. Serological response to the SARS-CoV-2 spike holoprotein (S), receptor binding domain (RBD) and nucleocapsid proteins (NP) were quantified by ELISA assay., Results: Based on serology, 40 of 200 (20%) participants were infected. Healthcare and non-healthcare occupations had equivalent infection incidence. Only 79.5% of infected participants seroconverted for NP following infection, and 11.5% were unaware they had been infected. The antibody response to S was greater than to RBD. Hispanic ethnicity was associated with 2-fold greater incidence of infection despite vaccination in this cohort., Discussion: Overall, our findings demonstrate: 1) variability in the antibody response to SARS-CoV-2 infection despite similar exposure risk; 2) the concentration of binding antibody to the SARS-CoV-2 S or RBD proteins is not directly correlated with protection against infection in vaccinated individuals; and 3) determinants of infection risk include Hispanic ethnicity despite vaccination and similar occupational exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jenkins, Phan Tran, Flores, Kupferwasser, Pickering, Zheng, Gjertson, Ross, Schaenman, Miller, Yeaman and Reed.)

Background: Evidence suggests the renin-angiotensin system (RAS) plays key immunomodulatory roles. In particular, angiotensin-converting enzyme (ACE) has been shown to play a role in antimicrobial host defense. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are some of the most commonly prescribed medications, especially in patients undergoing invasive surgery. Thus, the current study assessed the immunomodulatory effect of RAS-modulation in a preclinical model of implant infection. Methods: In vitro antimicrobial effects of ACEi and ARBs were first assessed. C57BL/6J mice subsequently received either an ACEi (lisinopril; 16 mg/kg/day), an ARB (losartan; 30 mg/kg/day), or no treatment. Conditioned mice blood was then utilized to quantify respiratory burst function as well as Staphylococcus aureus Xen36 burden ex vivo in each treatment group. S. aureus infectious burden for each treatment group was then assessed in vivo using a validated mouse model of implant infection. Real-time quantitation of infectious burden via bioluminescent imaging over the course of 28 days post-procedure was assessed. Host response via monocyte and neutrophil infiltration within paraspinal and spleen tissue was quantified by immunohistochemistry for F4/80 and myeloperoxidase, respectively. Results: Blood from mice treated with an ACEi demonstrated a decreased ability to eradicate bacteria when mixed with Xen36 as significantly higher levels of colony forming units (CFU) and biofilm formation was appreciated ex vivo ( p < 0.05). Mice treated with an ACEi showed a higher infection burden in vivo at all times ( p < 0.05) and significantly higher CFUs of bacteria on both implant and paraspinal tissue at the time of sacrifice ( p < 0.05 for each comparison). There was also significantly decreased infiltration and respiratory burst function of immune effector cells in the ACEi group ( p < 0.05). Conclusion: ACEi, but not ARB, treatment resulted in increased S. aureus burden and impaired immune response in a preclinical model of implant infection. These results suggest that perioperative ACEi use may represent a previously unappreciated risk factor for surgical site infection. Given the relative interchangeability of ACEi and ARB from a cardiovascular standpoint, this risk factor may be modifiable., (Copyright © 2020 Trikha, Greig, Kelley, Mamouei, Sekimura, Cevallos, Olson, Chaudry, Magyar, Leisman, Stavrakis, Yeaman and Bernthal.)

Antimicrobial compounds first arose in prokaryotes by necessity for competitive self-defense. In this light, prokaryotes invented the first host defense peptides. Among the most well-characterized of these peptides are class II bacteriocins, ribosomally-synthesized polypeptides produced chiefly by Gram-positive bacteria. In the current study, a tensor search protocol-the BACIIα algorithm-was created to identify and classify bacteriocin sequences with high fidelity. The BACIIα algorithm integrates a consensus signature sequence, physicochemical and genomic pattern elements within a high-dimensional query tool to select for bacteriocin-like peptides. It accurately retrieved and distinguished virtually all families of known class II bacteriocins, with an 86% specificity. Further, the algorithm retrieved a large set of unforeseen, putative bacteriocin peptide sequences. A recently-developed machine-learning classifier predicted the vast majority of retrieved sequences to induce negative Gaussian curvature in target membranes, a hallmark of antimicrobial activity. Prototypic bacteriocin candidate sequences were synthesized and demonstrated potent antimicrobial efficacy in vitro against a broad spectrum of human pathogens. Therefore, the BACIIα algorithm expands the scope of prokaryotic host defense bacteriocins and enables an innovative bioinformatics discovery strategy. Understanding how prokaryotes have protected themselves against microbial threats over eons of time holds promise to discover novel anti-infective strategies to meet the challenge of modern antibiotic resistance., (Copyright © 2020 Yount, Weaver, de Anda, Lee, Lee, Wong and Yeaman.)

Recent years have seen an unprecedented rise in the incidence of multidrug-resistant (MDR) Gram-negative bacteria (GNBs) such as Acinetobacter and Klebsiella species. In view of the shortage of novel drugs in the pipeline, alternative strategies to prevent, and treat infections by GNBs are urgently needed. Previously, we have reported that the Candida albicans hypha-regulated protein Hyr1 shares striking three-dimensional structural homology with cell surface proteins of Acinetobacter baumannii . Moreover, active vaccination with rHyr1p-N or passive immunization with anti-Hyr1p polyclonal antibody protects mice from Acinetobacter infection. In the present study, we use molecular modeling to guide design of monoclonal antibodies (mAbs) generated against Hyr1p and show them to bind to priority surface antigens of Acinetobacter and Klebsiella pneumoniae . The anti-Hyr1 mAbs block damage to primary endothelial cells induced by the bacteria and protect mice from lethal pulmonary infections mediated by A. baumannii or K. pneumoniae . Our current studies emphasize the potential of harnessing Hyr1p mAbs as a cross-kingdom immunotherapeutic strategy against MDR GNBs., (Copyright © 2020 Youssef, Zhang, Alkhazraji, Gebremariam, Singh, Yount, Yeaman, Uppuluri and Ibrahim.)

A Phase 1b/2a clinical trial of NDV-3A vaccine containing a Candida albicans recombinant Als3 protein formulated with alum protected women <40 years old from recurrent vulvovaginal candidiasis (RVVC). We investigated the potential use of anti-Als3p sera as surrogate marker of NDV-3A efficacy. Pre- and post-vaccination sera from subjects who experienced recurrence of vulvovaginal candidiasis (R) vs. those who were recurrence-free [non-recurrent (NR)] were evaluated. Anti-Als3p antisera obtained were evaluated for (1) titer and subclass profile and (2) their ability to influence C. albicans virulence traits including hyphal elongation, adherence to plastic, invasion of vaginal epithelial cells, biofilm formation on plastic and catheter material, and susceptibility to neutrophil killing in vitro . Serum IgG titers in NR patients were consistently higher than in R patients, particularly for anti-Als3 subclass IgG2. Sera from vaccinated NR patients reduced hyphal elongation, adhesion to plastic, invasion of vaginal epithelial cells, and biofilm formation significantly more than pre-immune sera, or sera from R- or placebo-group subjects. Pre-adsorption of sera with C. albicans germ tubes eliminated these effects, while heat inactivation did not. Finally, sera from NR subjects enhanced neutrophil-mediated killing of C. albicans relative to pre-immune sera or sera from R patients. Our results suggest that higher Als3p antibody titers are associated with protection from RVVC, attenuate C. albicans virulence, and augment immune clearance of the fungus in vitro . Thus, Als3p serum IgG antibodies are likely useful markers of efficacy in RVVC patients vaccinated with NDV-3A.

Recent perspectives forecast a new paradigm for future "third generation" vaccines based on commonalities found in diverse pathogens or convergent immune defenses to such pathogens. For Staphylococcus aureus, recurring infections and a limited success of vaccines containing S. aureus antigens imply that native antigens induce immune responses insufficient for optimal efficacy. These perspectives exemplify the need to apply novel vaccine strategies to high-priority pathogens. One such approach can be termed convergent immunity, where antigens from non-target organisms that contain epitope homologs found in the target organism are applied in vaccines. This approach aims to evoke atypical immune defenses via synergistic processes that (1) afford protective efficacy; (2) target an epitope from one organism that contributes to protective immunity against another; (3) cross-protect against multiple pathogens occupying a common anatomic or immunological niche; and/or (4) overcome immune subversion or avoidance strategies of target pathogens. Thus, convergent immunity has a potential to promote protective efficacy not usually elicited by native antigens from a target pathogen. Variations of this concept have been mainstays in the history of viral and bacterial vaccine development. A more far-reaching example is the pre-clinical evidence that specific fungal antigens can induce cross-kingdom protection against bacterial pathogens. This trans-kingdom protection has been demonstrated in pre-clinical studies of the recombinant Candida albicans agglutinin-like sequence 3 protein (rAls3) where it was shown that a vaccine containing rAls3 provides homologous protection against C. albicans, heterologous protection against several other Candida species, and convergent protection against several strains of S. aureus. Convergent immunity reflects an intriguing new approach to designing and developing vaccine antigens and is considered here in the context of vaccines to target S. aureus.