HLA class I alleles confer a striking risk for T cell-mediated drug hypersensitivity, yet positive predictive values are low-typically under 10% and as low as 0.12% for some drug-HLA pairs. We propose that persistent, human-adapted pathogens-notably herpesviruses-focus postnatal immune memory on conserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). The phylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted over hundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as each individual acquires these infections and builds tissue-specific immune memory. When a drug-altered self-peptide approximates the geometry of such a target and is presented by the same risk HLA in the same niche at sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching local regulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologous immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in the same tissue where antiviral memory already resides, which helps explain why injury is tissue-restricted; and (iii) public and private TCR solutions that bridge viral and self-targets. Beginning with T cell-mediated drug hypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis and transplant rejection and conclude with proposed experimental validation strategies that may be applicable more broadly to T cell-mediated hypersensitivity and autoimmunity.
We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.
Background: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, while infections from non-tuberculous mycobacteria (NTM) represent a growing public health threat. In its 20th year of activity, the Tuberculosis Network European Trials group (TBnet; www.tbnet.eu) is one of the leading research networks in Europe. In this review, we summarize the main advances in TB and NTM that occurred in 2025. Methods: We conducted a non-systematic review of articles published in 2025, with a strong emphasis on research with current or potential impact on clinical practice. We also selected the most impactful papers regarding the management of adult TB, pediatric TB, and NTM infections. Results: Members of the TBnet Steering Committee summarize the main advances in their areas of interest, including epidemiology, pathogenesis, prevention, diagnosis, treatment, pediatric TB, and NTM infections. We also include a summary of future research priorities. Conclusions: The year 2025 presented many exciting advancements in almost all fields of mycobacterial science. This article provides an expert-based, clinically orientated summary of the main new findings in the TB and NTM fields and aims to provide an updated overview of the state of the art in those areas.
Background: To evaluate the impact of sex on acute SARS-CoV-2 infection, 668 participants from the ACTIV-2/A5401 study were followed over a 28-day period. Methods: A primary analysis was performed on 469 participants with quantifiable viral loads at baseline. Results: Male and female participants had comparable nasal SARS-CoV-2 RNA levels at study entry and throughout follow-up. However, sex-specific differences in viral shedding emerged when stratified by symptom duration. In the first 3 days after symptom onset, female participants exhibited higher nasal SARS-CoV-2 RNA levels than males, but lower viral RNA levels thereafter. The higher viral RNA levels in females during the earliest phase of acute COVID-19 were observed even after adjusting for age, race, and region of enrollment. Female participants also tended to have higher symptom scores across days since symptom onset, but no significant correlation was observed between nasal SARS-CoV-2 RNA levels and symptom score regardless of sex. Conclusion: These findings highlight the impact of sex on both viral shedding and symptom dynamics and underscore the importance of considering time since symptom onset when evaluating antiviral therapies for respiratory viruses in clinical trials.
Background: Antibodies play a critical role in the control of pathogens and tumors through their ability to recognize non-self and then direct immune-mediated destruction. Antibodies are generated by plasma cells or plasmablasts, located throughout the tissues, and are transported between blood, lymph, mucosal secretions, and tissues to survey all sites for pathogens or malignant cells. However, mounting evidence suggests antibodies that transit across compartments (from the blood to the brain, mucosal tissues, or placenta) differ from those in systemic circulation. Whether antibodies also differ as they transit from the blood into non-privileged tissues remains unclear. Thus, here we aimed to define the landscape of antibodies that exist within the blood and tissues and begin to define the properties that lead to antibody transfer across compartments. Methods: To analyze tissue antibodies, we performed antibody profiling in chyle, a fluid component of lymph collected via the thoracic duct, contrasting these profiles to matched plasma samples. Results: Equivalent levels of pathogen-specific IgG antibodies and functions were observed across the plasma and lymph in people without HIV. However, this balance in IgG transfer was disrupted in people living with HIV, with significantly lower transfer ratios across several pathogen-specific IgG subpopulations in chyle. Conclusion: Differential transfer of IgG was Fc-receptor dependent, pointing to a mechanism of transfer into tissues during inflammatory disease that may have a critical role in selecting the antibodies able to access the peripheral and lymphoid tissues.
This editorial provides a brief background on over a century of research on bacteriophages, which led to the inaugural 2025 Conference on Bacteriophages: Biology, Dynamics, and Therapeutics, supported by the IAS–USA. A summary of this meeting is included in this issue of Pathogens and Immunity and emphasizes the promise of phage therapy.
The 2025 Conference on Bacteriophages: Biology, Dynamics, and Therapeutics, supported by the International Antiviral Society–USA, brought over 250 researchers, clinicians, and industry innovators from 17 countries to Washington, DC, from October 12 – 14, 2025. The meeting emphasized collaboration across the full spectrum of phage science—from molecular biology to clinical translation—reflecting a field rapidly translating novel biological insights from the laboratory into clinical applications. This summary provides highlights of the 43 oral and 97 poster presentations made during this 2.5-day conference.
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: 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: 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: 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.
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.
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 persistence of viral reservoirs which drive recrudescence once ART is stopped. This necessitates curative interventions which can achieve either eradication or durable remission off ART. Advances in technology have fostered development of multi-omic techniques encompassing Polymerase Chain Reaction (PCR) and sequencing, spatial transcriptomic and proteomic analysis, immunofluorescent imaging, and Artificial intelligence (AI)-driven multi-modal data analysis, to understand the HIV reservoir biology and mechanisms of persistence. These have informed the investigation of therapeutic interventions including broadly neutralizing antibodies, latency reversal, immune cell argumentation, antiviral compounds, and gene therapy. Between 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.
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.
Background: Circulating degranulated platelets have been described during acute SARS-CoV-2 infection and associated with COVID-19 complications. This study investigated the relationship between the presence of plasma SARS-CoV-2 RNA (ie, SARS-CoV-2 RNAemia), systemic inflammation, and platelet dysfunction in a group of patients with COVID-19. Unlike our previous publication, which focused on platelet characterization, this work explores potential determinants of platelet activation, based on a distinct subset of patients with available stored samples. Methods: Patients with COVID-19 were stratified by platelet δ-granule content using the luciferin/luciferase assay into 2 groups: normal (COVδ-norm) and low (COVδ-low). Plasma SARS-CoV-2 RNAemia (RT-qPCR), cytokines, and chemokines (Cytometric Bead Array) were quantified on plasma samples. Markers of platelet activation were measured by flow cytometry in whole blood. Results: A total of 75 patients with COVID-19 were enrolled; 57 presented normal levels of platelet δ-granule content (COVδ-norm) and 18 had low levels of platelet δ-granules (COVδ-low). Groups were comparable in terms of age, sex, comorbidities, and SARS-CoV-2 RNAemia levels. Patients in the COVδ-low group showed significantly higher chemokine and cytokine levels compared to those in the COVδ-norm group, with strong correlations between IL-6, as well as granulocyte-macrophage colony-stimulating factor (GM-CSF), with platelet degranulation parameters. A similar trend, albeit less pronounced, was observed when patients were stratified based on their platelet activation phenotype. Conclusions: These findings suggest that peripheral inflammation, rather than SARS-CoV-2 RNAemia, is associated with platelet dysfunction during acute SARS-CoV-2 infection.
The recent study by van Schuijlenburg et al [1] suggests that the lungs may serve as an active and previously underappreciated site of T-cell priming following late-arresting genetically attenuated parasites (LA-GAP) malaria vaccination. Their findings channel traditional liver-focused models and open important avenues for understanding the immunological dynamics of whole-sporozoite vaccines.
Background: Despite the control of Bordetella pertussis with vaccine introduction, the incidence of pertussis has increased in the United States and globally. New vaccine strategies are clearly needed to regain control of this vaccine-preventable infection. Methods: Experimental pertussis infection of baboons induces an acute respiratory illness with clinical and laboratory features similar to whooping cough in man. In a previous study, acellular pertussis-vaccinated (aP) baboons were protected from clinical illness but not from prolonged airway colonization. In contrast, convalescent baboons are protected from both clinical illness and colonization. These studies suggest that current aP vaccines may be ineffective at preventing airway colonization, contributing to resurgence of pertussis. Results: In studies conducted at the University of Massachusetts Chan Medical School in Worcester, Massachusetts, mucosal IgG antibody responses in nasopharyngeal washes are similar in convalescent and vaccinated baboons. However, significantly higher mucosal anti-pertussis immunoglobulin A (IgA) responses are observed in convalescent animals. Conclusions: These studies suggest that mucosal IgA responses to some pertussis antigens will result in bacterial clearance.
