Pathogens and Immunity最新文献

Background: Human immunodeficiency virus (HIV) and Plasmodium spp., which causes malaria, are co-endemic. Previously, we showed that during antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)/Plasmodium fragile co-infection, peripheral markers of neutrophil extracellular trap (NET) formation positively correlated with peripheral markers of disease and gastrointestinal (GI) dysfunction. However, the impact of co-infection directly in the GI mucosa is unclear. We hypothesized that ART-treated SIV/P. fragile co-infection would result in peripheral and GI immune disruption associated with exacerbated clinical manifestations of SIV and P. fragile.

Methods: Adult male rhesus macaques (RMs; n=6) were inoculated with SIVmac239, initiated ART at week 8 post-SIV infection (p.i.), were inoculated with P. fragile at week 12 p.i., and were followed until week 20 p.i. Plasma viral loads, peripheral parasitemia, and peripheral and GI immune cell frequencies and function were assessed longitudinally.

Results: We observed significant CCR5+ CD4+ T cell decline in the periphery, colon, and duodenum following SIV infection. Neutrophil frequencies were unchanged throughout ART-treated SIV/P. fragile co-infection. Notably, duodenum NET-forming granulocyte frequencies were significantly positively associated with peripheral SIV burden following P. fragile co-infection but were unassociated with peripheral parasitemia and CD4+ T cell frequencies. Finally, although P. fragile was present in the duodenum, GI parasite burden was not associated with NET-forming granulocyte frequencies, peripheral viral loads, or CD4+ T cell frequencies.

Conclusions: P. fragile co-infection during ART-treated SIV could cause mucosal disruptions that contribute to peripheral SIV replication despite ART. These data may have implications for HIV and malaria disease progression and treatment strategies.

Background: Coronary artery disease (CAD), tuberculosis (TB), and HIV are major global health concerns. Individuals affected by one or more of these conditions often exhibit chronic inflammation and immune dysregulation, with monocytes playing a central role. Monocyte subsets are known to expand in individuals with HIV, TB, or CAD, but the mechanisms by which these cells contribute to inflammation and immune responses remain poorly understood.

Methods: We employed high-dimensional mass cytometry to characterize monocyte heterogeneity in 61 Ugandan adults with varying combinations of HIV, TB, and subclinical or overt CAD. An integrative approach was used, combining manual gating, unsupervised clustering, and machine learning to identify distinct monocyte phenotypes associated with CAD and TB. Monocyte activation markers soluble CD14 (sCD14) and sCD163 were measured in plasma. CAD was diagnosed by coronary computed tomography angiography. TB was determined by a questionnaire and interferon-gamma release assay (IGRA) testing.

Results: Participants' demographics and clinical characteristics were similar by CAD or HIV/TB status. Median age was 61 years; 37.7% were female. People living with HIV and latent TB or prior active TB had higher sCD14 plasma levels compared with HIV/TB-negative individuals. Individuals with CAD showed reduced surface expression of the scavenger receptor CD163 on non-classical monocytes. Unsupervised clustering further revealed 2 distinct non-classical monocyte subsets associated with disease states: A CD86dim CX3CR1dim CD45RA+ GPR56+ CXCR3+ subset significantly depleted in individuals with CAD, and a CD86+ CX3CR1++ CD45RA++ GPR56- CD38- CXCR3- subset enriched in individuals with latent TB.

Conclusions: These findings underscore the complexity of the monocyte landscape in CAD progression, particularly in regions where HIV and TB are co-endemic. Our study reveals distinct alterations within 2 non-classical monocyte subpopulations associated with CAD and with HIV/TB, offering mechanistic insights that may support the development of precision biomarkers and immune-targeted therapies across these disease contexts.

Background: Fecal microbiota transplantation (FMT) is a standard therapy for recurrent Clostridioides difficile infection (CDI). Limited information is available on the durability of response after FMT via freeze-dried oral capsules and on whether patients who fail an initial FMT can be successfully managed with repeated FMT.

Methods: We conducted a retrospective cohort study of all patients undergoing initial FMT for recurrent CDI via freeze-dried capsules from March 2015 through June 2022 at 2 acute-care hospitals. Information on response to FMT during the initial management period (ie, 3 months after the initial FMT) and long-term durability of response was collected through direct communication with patients and medical record review. Episodes occurring within 90 days of the initial FMT were defined as recurrences, whereas those occurring more than 90 days after the initial FMT were defined as additional CDI episodes.

Results: Of 129 patients with recurrent CDI treated with FMT via freeze-dried capsules, 114 (89%) had experienced 3 or more prior episodes of CDI. At 3 months after the initial FMT, 103 (80%) patients had no recurrence, 26 (20%) patients had 1 or more recurrences managed with 1 (n=21) or 2 (n=2) additional FMTs, and 3 (12%) were transitioned to CDI suppressive therapy. During subsequent long-term follow-up (median 182 weeks), 21 of the 126 patients (17%) who did not transition to suppressive therapy had additional episodes managed with CDI therapy only (n=9), CDI therapy and additional FMT (n=10), or suppressive CDI therapy (n=2).

Conclusions: In a real-world setting with long-term follow-up, FMT via freeze-dried capsules was effective for the management of recurrent CDI. Repeated FMT procedures were effective for the management of patients with early failure after initial FMT and with additional episodes during long-term follow-up.

Background: HIV infection leads to profound alterations of gut structure, immunity, and microbiome, resulting in immune activation and inflammation, which drive the development of non-infectious comorbidities. The introduction of combination antiretroviral therapy (cART) in the chronic stages of disease does not correct such abnormalities; however, the effect of viro-suppressive treatment in the gastrointestinal tract during primary HIV infection (PHI) is largely unknown. We studied the effects of 12-week cART on gastrointestinal (GI) structure, immunity, and mucosal microbiome in people living with HIV (PLWH) with PHI.

Methods: Eleven participants with PHI enrolled in the INACTION trial underwent colonoscopy with ileum and colon biopsies, as well as peripheral blood mononuclear cell (PBMC) and plasma collection, prior to and at 12 weeks of cART. Gut biopsies were stained with CD14, CD68, CD163, and E-cadherin antibodies and Masson trichrome. Flow cytometry was performed on lamina propria and PBMCs to characterize CD4, γδ T, Treg, and Th17 cells. Gut tissue-associated microbiome analysis was conducted on colon and ileum biopsies. Ten untreated individuals with chronic HIV infection (CHI) were also studied for comparative analysis.

Results: Despite treatment of PHI, gut barrier damage (E-cadherin loss, collagen deposition) progressed, with a partially preserved distribution of intestinal macrophages. Treated PHI showed stable CD4+ and γδ T-cell frequencies and decreased activation of these subsets in the colon, with no effect on intestinal Th17 and Treg cells. No major changes in peripheral inflammation and intestinal barrier integrity markers were observed. Gut tissue-associated microbiome composition evolved during cART treatment in PHI.

Conclusion: Despite early initiation, 12-week cART is unable to correct the HIV-mediated gut damage. Since gut injury drives systemic inflammation, which in turn fosters the pathogenesis of non-communicable comorbidities, our findings provide pathogenetic evidence of limited efficacy of early cART in reverting the HIV-associated pro-inflammatory signature and clinical risk.

Dr. David Baltimore's contributions to modern biology span more than six decades and continue to shape the fields of virology, immunology, biochemistry, and molecular biology. Beyond his landmark discoveries-such as reverse transcriptase and NF-κB, as well as the Baltimore classification of viruses-his influence endures through his mentorship, leadership, and the generations of scientists he trained and inspired. In this essay, I recount my journey as his postdoctoral trainee at the California Institute of Technology, offering a personal glimpse into the mind, character, and legacy of a scientist whose approach to thinking, teaching, and living science remains timeless.

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.

Antiretroviral therapy (ART) can effectively control human immunodeficiency virus (HIV) replication; however, lifelong treatment is required due to viral reservoirs, which fuel viral rebound. This necessitates curative interventions that can achieve either eradication of the reservoir or durable remission off ART. Advances in technology have fostered development of multi-omic techniques encompassing molecular tools, proteomic analyses, imaging, and artificial intelligence (AI)-driven data analysis to understand HIV reservoir biology and persistence. These have informed the investigation of therapeutic interventions such as broadly neutralizing antibodies, latency reversal, immune cell augmentation, antivirals, and gene therapy. From April 7-10, 2025, experts in the field convened at the Keystone Symposia conference, HIV Cure: Antiretroviral Therapy (ART)-Free Control of HIV Infection in Durban, South Africa, to discuss novel strategies for eradication and/or durable ART-free control of HIV.

Stanley Plotkin, M.D., reflects on his professional journey, describing how formative educational experiences influenced his career. He discusses his contributions to vaccine development, notably for rubella and rotavirus, and shares insight on advancements in vaccine technology, including strengths and limitations of mRNA and DNA platforms. Dr. Plotkin emphasizes the importance of adapting public health recommendations as scientific understanding evolves, discusses the challenges of establishing mucosal immunity, and highlights the benefits of combining vaccines. He also offers thoughtful perspectives on natural versus vaccine-induced immunity, drawing upon his extensive expertise. Finally, he touches on his personal interest in learning to fly.

In this engaging interview, Dr. John Perfect reflects on his distinguished career in infectious diseases, focusing on his early scientific interests, his pivotal experiences during the emergence of HIV/AIDS, and his extensive research on fungal pathogens, particularly Cryptococcus. Dr. Perfect discusses the evolution of antifungal therapies, the challenges of drug resistance, the promise of molecular diagnostics and immunotherapies, and the complexities faced in clinical research. He emphasizes the importance of mentorship and optimism for future generations of scientists, concluding with a message of hope and encouragement for ongoing innovation and resilience in medical science.