Background:Susceptibility to common infectious diseases is often linked to innate immune deficiencies. Patients may present normal standard immunological profiles but remain highly vulnerable to infections, complicating diagnosis. This study investigates innate and intrinsic immune deficiencies and their genetic underpinnings in Moroccan patients, emphasizing early detection and personalized care.Methods:A retrospective analysis was conducted using data from the Moroccan Inborn Errors of Immunity (IEI) registry (2008–2024). Included were patients with confirmed innate or intrinsic immunodeficiencies based on CBC, CRP, immunoglobulin levels, lymphocyte subpopulations, and whole-exome sequencing. Classification followed the 2022 IUIS criteria.Results:Among 884 patients with IEI, 79 (∼9%) had innate or intrinsic immunodeficiencies, with genetic confirmation in 46 (58%). Of these, 23 (50%) were diagnosed with Mendelian susceptibility to mycobacterial disease (MSMD), involving mutations in the IL12RB1, STAT1, IFNGR1, SPPL2A, TYK2, and TBX21 (T-bet) genes. Chronic mucocutaneous candidiasis (CMC) was found in 15 (32%) patients, linked to STAT1 and IL17RA mutations. Severe viral infection predisposition was seen in 3 patients (POLR3A, IFIH1, TLR7XL) and bacterial susceptibility in 3 others (IRF4, IFNGR1, NCSTN). Novel variants were identified, including IRAK4 c.277delT (p.F93fsX26), not previously reported, and SNORA31 (n.36T>C), previously seen in Saudi Arabia, now found in a Moroccan case of herpes simplex encephalitis.Conclusion:This study reveals the genetic complexity of innate immune disorders in Morocco, with a notable prevalence of MSMD and CMC. It underscores the value of early genetic screening to guide diagnosis and improve patient outcomes.

Background:Endophthalmitis, a severe infection of the intraocular tissues that can result in permanent loss of vision if not immediately treated, is often caused by fungi, namely Candida albicans. Treatment options are limited due to a lack of ocular penetration of antifungal drugs. Rezafungin, an echinocandin antifungal with a long half-life, which was recently approved by the US Food and Drug Administration (FDA), has shown efficacy against candidiasis.Methods:In this study, using a rabbit model, we compared rezafungin, micafungin, and voriconazole in a hematogenous C. albicans endophthalmitis rabbit model. Fungal burden was determined in the aqueous humor, vitreous humor, choroid-retina, and the kidneys of infected rabbits; eye lesions were visualized by indirect ophthalmoscopy.Results:No fungal growth was detected in the aqueous humor, vitreous humor, or choroid-retina of rabbits treated with 10 mg/kg rezafungin at the time of fungal inoculation. Additionally, rabbits given 10 mg/kg rezafungin showed the lowest kidney fungal burden (average log colony-forming units [CFUs]/g of < 0.5). In contrast, animals given either micafungin (6.2 mg/kg) or voriconazole (10 mg/kg) in the same treatment regimen were positive for fungal infection as measured by CFUs in each of these areas, demonstrating fungal burden. Additionally, significant increases in eye lesion scores were observed in rabbits given either micafungin or voriconazole, while no eye lesions were noted in rabbits that received rezafungin.Conclusion:Taken together, these results indicate that rezafungin was effective at reducing the acute fungal burden and subsequent eye lesions caused by C. albicans-induced endophthalmitis.

Technologies that provides safe and effective decontamination of surfaces and equipment between episodes of manual cleaning could be an important advance in efforts to prevent transmission of the emerging fungal pathogen Candida auris. We tested the efficacy of a novel wall-mounted far ultraviolet-C (UV-C) light technology that delivers far UV-C, when people are not detected within the field of illumination, against C. auris isolates from clades I, II, III, and IV using a quantitative disk carrier test method. In an equipment room, we examined the efficacy of the technology in reducing an isolate of C. auris from clade IV inoculated on multiple sites on portable devices. The far UV-C technology reduced isolates from all 4 clades of C. auris by >3 log10 colony-forming units (CFU) aſter an 8-hour exposure on steel disks. For the clade IV isolate, similar reductions were achieved on glass and plastic carriers. In the equipment room, the technology reduced C. auris inoculated on multiple sites on portable equipment by >2 log10 CFU in 4 hours. The far UV-C technology could be useful for decontamination of surfaces and equipment between episodes of manual cleaning. Additional studies are needed to evaluate the use of the technology in clinical settings.

Drew Weissman, MD, PhD, received the 2023 Nobel Prize in Physiology or Medicine together with Katalin Karikó, PhD. Dr. Weissman received his bachelor's and master's degrees from Brandeis University, Waltham, MA, in 1981. He received his MD and PhD in 1987 from Boston University, Boston, MA, and this was followed by a residency at Beth Israel Deaconess Medical Center, Boston, MA. He then completed a fellowship at the National Institute of Allergy and Infectious Diseases under the supervision of Anthony Fauci, MD. He joined the Faculty at the University of Pennsylvania, Philadelphia, in 1997, where, in collaboration with Dr. Katalin Karikó, he explored the use of messenger RNA (mRNA) to drive heterologous gene expression in human cells. They overcame the notorious susceptibility of RNAs to degradation by packaging the mRNA in lipid nanoparticles and learned to both optimize protein expression and attenuate the inflammatory response to the exogenous RNAs by [covalently] modifying bases in the RNA sequence. This work has revolutionized immunization technology and allowed for the production of the most effective vaccines to prevent COVID-19.

[This corrects the article DOI: 10.20411/pai.v8i2.665.].

Increased antifungal resistance is exacerbating the burden of invasive fungal infections, as well as potentially contributing to the increase in resistant dermatomycoses. In this commentary, we focus on antifungal drug resistance, in contrast to antibacterial resistance. We provide a brief historical perspective on the emergence of antifungal resistance and propose measures for combating this growing health concern. The increase in the incidence of invasive and cutaneous fungal infections parallels advancements in medical interventions, such as immunosuppressive drugs, to manage cancer and reduce organ rejection following transplant. A disturbing relatively new trend in antifungal resistance is the observation of several fungal species that now exhibit multidrug resistance (eg, Candida auris, Trichophyton indotineae). Increasing awareness of these multidrug-resistant species is paramount. Therefore, increased education regarding potential fungus-associated infections is needed to address awareness in the general healthcare setting, which may result in a more realistic picture of the prevalence of antifungal-resistant infections. In addition to education, increased use of diagnostic tests (eg, micro and macro conventional assays or molecular testing) should be routine for healthcare providers facing an unknown fungal infection. Two critical barriers that affect the low rates for Antifungal Susceptibility Testing (AST) are low (or a lack of) sufficient insurance reimbursement rates and the low number of qualified laboratories with the capacity to perform AST. The ultimate aim is to improve the quality of patient care through fungal identification, diagnosis, and, where appropriate, susceptibility testing. Here we propose an all-encompassing call to action to address this emerging challenge.

Background:Throughout HIV infection, productively infected cells generate billions of viral particles and are thus responsible for body-wide HIV dissemination, but their phenotype during AIDS is unknown. As AIDS is associated with immunological changes, analyzing the phenotype of productively infected cells can help understand HIV production during this terminal stage.Methods:Blood samples from 15 untreated viremic participants (recent infection, n=5; long-term infection, n=5; active opportunistic AIDS-defining disease, n=5) and 5 participants virologically controlled on antiretroviral therapy (ART) enrolled in the Analysis of the Persistence, Reservoir and HIV Latency (APRIL) study (NCT05752318) were analyzed. Cells expressing the capsid protein p24 (p24+ cells) after 18 hours of resting or 24 hours of stimulation (HIV-Flow) revealed productively infected cells from viremic participants or translation-competent reservoir cells from treated participants, respectively.Results:The frequency of productively infected cells tended to be higher during AIDS in comparison with recent and long-term infections (median, 340, 72, and 32/million CD4+ T cells, respectively) and correlated with the plasma viral load at all stages of infection. Altogether, these cells were more frequently CD4low, HLA-ABClow, CD45RA-, Ki67+, PD-1+, with a non-negligible contribution from pTfh (CXCR5+PD-1+) cells, and were not significantly enriched in HIV coreceptors CCR5 nor CXCR4 expression. The comparison markers expression between stages showed that productively infected cells during AIDS were enriched in memory and exhausted cells. In contrast, the frequencies of infected pTfh were lower during AIDS compared to non-AIDS stages. A UMAP analysis revealed that total CD4+ T cells were grouped in 7 clusters and that productive p24+ cells were skewed to given clusters throughout the course of infection. Overall, the preferential targets of HIV during the latest stages seemed to be more frequently highly differentiated (memory, TTD-like) and exhausted cells and less frequently pTfh-like cells. In contrast, translation-competent reservoir cells were less frequent (5/million CD4+ T cells) and expressed more frequently HLA-ABC and less frequently PD-1.Conclusions:In long-term infection and AIDS, productively infected cells were differentiated and exhausted. This could indicate that cells with these given features are responsible for HIV production and dissemination in an immune dysfunction environment occurring during the last stages of infection.

Splinter “Do what you need to,” I said. As though this was extractingan arrowhead buried in flesh, not a sliver of wood from a pinky. She my officemate, colleague,friend. But not – it occurred to me as she started to probe – a surgeon. Probably hadn’t fingered a forceps in years. What I warn my patients against every day – not wise to compromisewith convenience. I had no fear of pain.A dozen tours in the OR, years of drawing blood – we learn to distance, numb ourselves. Numb ourselves, that is, to the pain of another – my pinky should have taken itself to Urgent Care. Maybe there was hurt,but I never noticed. All I recall is a flood of sweetness, a drowsy warmth, as when the world is about to go dark. Sometimes as we’re fallingwe hear a voice calling in the distance. “Oh, shit – going vagal,” this one said. It sounded like mine.