Infectious disease
Abstract
The increase in antimicrobial resistant infections has fueled a resurgent interest in bacteriophage (phage) therapy. We conducted a literature review of personalized phage therapy cases in the peer-reviewed, English-language literature reported between 1/1/2005, to 8/31/2025 for which individual patient data were available, identifying and synthesizing data from a total of 323 patients described in 83 studies. Most patients (68%, 221/323) were treated with ≥ 2 phages (a phage cocktail). The median concentration of phages was 108 PFU/mL (IQR 107–109). Most patients (76%, 246/323) received antibiotics concurrent with phage therapy. The median duration of therapy was 10 days (IQR 5–21). The most common indications for phage therapy were skin/soft tissue, pulmonary, orthopedic, osteoarticular, and genitourinary infections. 144 patients received fixed (off-the-shelf) phage preparations whereas 179 received bespoke phage preparations (i.e., personalized therapy). For cases where outcomes data were available, 78% (253/323), experienced clinical improvement while the targeted pathogen was eradicated in 61% (177/290) of cases. Nine patients had treatment withdrawn due to tolerability concerns. These data indicate that there is substantial heterogeneity in current personalized phage therapy clinical practices but that this approach can be successful.
Authors
Patrick M. Blankenberg, Robert Targ, Grace D. Cullen, Gina A. Suh, Krystyna Dąbrowska, Aarav Singh, Tiffany Luong, Daisuke Furukawa, Paul L. Bollyky
Abstract
Ebola virus disease is a severe viral hemorrhagic illness with high maternal and perinatal mortality. Although the replication-competent vesicular stomatitis virus–based Ebola vaccine (VSV-EBOV) has been deployed successfully in outbreak settings, pregnant women were excluded from clinical trials, leaving critical safety gaps. To address this, we developed a murine model to assess pregnancy outcomes following VSV-EBOV exposure at different gestational stages. Pregnant C57BL/6 mice vaccinated at embryonic day 7 (E7), E10, or E15 mounted robust anti–Ebola virus (anti-EBOV) antibody responses comparable to those of non-pregnant controls and efficiently cleared the vaccine virus without evidence of vertical transmission. However, peri-implantation vaccination modestly increased fetal resorption and early postnatal mortality, accompanied by placental pathology characterized by vascular remodeling defects and inflammation. Later gestational vaccination had minimal impact on survival or offspring development. Mechanistic studies revealed that these adverse effects were mediated by type I interferon signaling rather than direct viral infection, as IFN-β–deficient mice exhibited normal pregnancy outcomes and blocking interferon receptor activity ameliorated placental pathology despite higher viral loads. To our knowledge, these findings represent the first comprehensive preclinical safety evaluation of VSV-EBOV vaccination during pregnancy and identify a critical window of vulnerability early in gestation. More broadly, this work underscores the central role of interferons in shaping placental immune responses and provides an experimental framework to guide evaluation of live-virus vaccines in pregnancy.
Authors
Aaron P. Lewkowicz, Yiru Wang, Mirian I. Mendoza, Kaliroi Engel, Logan Kelley-Baker, Iara Rattner, Amber Lopez, Ian L. McWilliams, Derek D.C. Ireland, Mohanraj Manangeeswaran, Ha-Na Lee, Daniela Verthelyi, Sandra M. Blois
Abstract
BACKGROUND. Despite the availability of effective vaccines, pneumococcal disease remains a major global health concern. Pneumococcal conjugate vaccines (PCVs) have progressively increased in valency, a change associated with reduced antibody titers against individual polysaccharide antigens. Whether increasing vaccine valency affects B cell responses through antigenic competition remains incompletely understood. We investigated pneumococcal polysaccharide-specific B cell responses in peripheral blood and vaccine draining lymph nodes following vaccination with PCV13. METHODS. Healthy adults (n = 5) received PCV13. Peripheral blood and lymph node fine needle aspirations (FNA) were collected longitudinally at baseline and after vaccination. Pneumococcal polysaccharide-specific B cell responses, polysaccharide-specific antibody responses and opsonophagocytic activity were analyzed in peripheral blood and draining lymph nodes. RESULTS. Antigen-specific memory B cells in peripheral blood expanded rapidly and peaked 2 weeks after vaccination. In contrast, germinal center formation in lymph nodes was delayed, peaking at 4 weeks. Germinal center B cell responses were dominated by a limited number of polysaccharide specificities, whereas the expansion of memory B cells in peripheral blood was more evenly distributed across specificities. Polysaccharide-specific antibodies followed similar dynamics in plasma and FNA supernatant. CONCLUSION. Adult immune responses to PCV are characterized by robust extrafollicular memory B cell expansion and delayed germinal center responses. The restricted specificity of germinal center B cells provides evidence for antigenic competition during germinal center formation, with potential implications for the design and immunogenicity of multivalent vaccines. TRIAL REGISTRATION. EU CT number 2022-501519-15-00. FUNDING. LUMC PhD Fellowship, ZonMW Vidi and ZonMW Clinical Fellowship.
Authors
David W. de Vos, Marina Johnson, Dennis Hoving, Giovanni E. Loe-Sack-Sioe, Catherina Kienhuis, Els L. van Persijn van Meerten, David Goldblatt, Leo G. Visser, Anna H.E. Roukens, Simon P. Jochems
Abstract
Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors, often including an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed baseline NK-cytopenia and CTL activation resembling MAS-susceptible patients. NK transcriptomes reflected IL-18/IFNg-axis activation and cell cycle upregulation. LCMV infection of Il18tg mice causes HLH/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox, Il18tg NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected Il18tg mice then developed signs of HLH/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice partially rescued virus-specific CTL responses, viral control, and survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.
Authors
Jemy A. Varghese, Leonardo Huang, Stephen D. Carro, Emily E. Landy, Anastasia Frank-Kamenetskii, Hannah Klinghoffer, Jeremy A. Morrissette, Vinh Dang, Laurence C. Eisenlohr, Scott W. Canna
Abstract
The role of CD8+ T cells in filarial infections remains poorly understood. Given the chronic nature of these infections, individuals living in endemic regions are frequently exposed to other pathogens including viruses. Because CD8 cells are essential for antiviral immunity, understanding how filarial infections shape the cytotoxic compartment is essential to elucidate their impact on bystander immunity. We evaluated the phenotype and function of CD8+ T cells from Loa loa-infected (Fil+) and -uninfected (Fil–) individuals at baseline and following cytomegalovirus (CMV) re-stimulation. Filarial infection was associated with increased activation and proliferation of CD8+ T cells, characterized by elevated expression of Ki-67, CD107a, and production of type 1 and 17 cytokines. Upon CMV re-stimulation, Fil+ individuals showed markedly reduced expansion of antigen-experienced (CD137+) and polyfunctional (CD137+IFN-γ+TNF-α+, CD137+IFN-γ+TNF-α+IL-2+) CD8+ T cells, along with decreased cytotoxic activity. Unbiased clustering analysis revealed markedly reduced frequency of the CD8+CD45RA+CD57+ subset in Fil+ individuals- a population further defined through transcriptomic profiling that showed enrichment for cytolytic gene signatures (GZMB, GNLY, GZMH, CD244, CX3CR1). These results demonstrated that filarial infection is associated with an altered CD8+ T cell profile that is associated with failure to mount effective viral-specific effector responses, including impaired cytokine production and cytotoxic activity.
Authors
Camila Queiroz-Glauss, Justin Lack, Daniel E. Sturdevant, Thomas B. Nutman
Abstract
Pneumocystis jirovecii pneumonia (PCP) remains a major cause of life-threatening respiratory failure in people with advanced HIV, yet the biological factors associated with mortality are incompletely understood. We performed integrated transcriptomic, proteomic, and metabolomic profiling of bronchoalveolar lavage fluid from 42 adults with HIV-associated PCP, relating molecular signatures to mortality. We found that fungal burden, measured by sputum immunofluorescence, Pneumocystis qPCR, and 1,3-β-D-glucan, did not differ between survivors and non-survivors or correlate with baseline gas exchange. Instead, non-survivors exhibited a bronchoalveolar immunometabolic failure signature characterised by marked depletion of immunoglobulins and complement, reduced pattern recognition receptors and fibroblast growth factor family proteins, and broad disruption of extracellular matrix organisation. Metabolomic profiling revealed enrichment of arginine-urea cycle and tricarboxylic acid pathways, with coordinated accumulation of arginine, citrulline, and TCA cycle intermediates consistent with nitrosative and mitochondrial stress. An integrated proteo-metabolomic score summarising this state was significantly higher in non-survivors and did not correlate with fungal burden or cytomegalovirus co-infection. In an immunodeficient precision-cut lung slice model, antigen-screened intravenous immunoglobulin restored macrophage-mediated Pneumocystis clearance, providing proof-of-concept for opsonic augmentation. Our findings indicate that mortality in HIV-PCP is defined by profound immunometabolic failure, highlighting humoral depletion and impaired alveolar repair as potential targets for host-directed adjunctive therapy.
Authors
Peter Rossi-Smith, Ayanda Trevor Mnguni, Dora Pungan, Robert J. Samuels, Vaishnavi R. Kumaran, Leena Syed, Trevor Ferris, Kamil Skirlo, Joseph N. Jarvis, Nelesh P. Govender, Graeme Meintjes, Sean Wasserman, Jay K. Kolls, Rachel P.J. Lai
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death globally. Despite wide use of antiretroviral therapy (ART) by people living with HIV, the risk of TB remains increased. To understand immune interactions within lung granulomas, we compared spatial transcriptomics of Mtb and simian immunodeficiency virus (SIV) in co-infected macaques with or without ART as a model for HIV/Mtb co-infection. Spatially differentiated transcriptional profiles were observed in Mtb-only granulomas, with myeloid cells enriched in metabolic/antimicrobial pathways within the inner ring and T cell co-stimulatory/activation pathways enriched in the outer ring. These spatially distinct patterns were lost in SIV/Mtb granulomas with higher enrichment in type I IFN pathways compared to Mtb-only granulomas. SIV/ART/Mtb granulomas had an intermediate transcriptional pattern without restoration to Mtb-only granulomas, despite a lack of viral replication. Cell-cell communication was reduced among SIV/Mtb co-infected groups. These data suggest that HIV disrupts spatially organized immune functions of granulomas, which are not fully restored by ART.
Authors
Jessica M. Medrano, Persis Sunny, Collin R. Diedrich, Pauline Maiello, Christopher Kline, Tara Rutledge, Edwin Klein, Joshua T. Mattila, Jishnu Das, Zandrea Ambrose, Philana Ling Lin
Abstract
Patients who survive sepsis are predisposed to new hospitalizations for respiratory failure, but the underlying mechanisms are unknown. Using a murine model in which prior sepsis predisposes to enhanced lung injury, we previously discovered that classical monocytes persist in the lungs after long-term recovery from sepsis and exhibit enhanced cytokine expression after secondary challenge with intra-nasal lipopolysaccharide. Here, we hypothesized that immune reprogramming of post-sepsis monocytes and altered ontogeny predispose to enhanced lung injury. Monocyte depletion and/or adoptive transfer was performed three weeks and three months after sepsis. Monocytes from post-sepsis mice were necessary and sufficient for enhanced LPS-induced lung injury and promoted neutrophil degranulation. Prior sepsis enhanced JAK-STAT signaling and AP-1 accessibility in monocytes and shifted monocytes toward the neutrophil-like monocyte lineage. Neutrophil-like monocytes demonstrated a pro-inflammatory phenotype with enhanced IL-1β expression and reduced phagocytic capacity. In human sepsis and/or pneumonia survivors, monocytes were predictive of 90-day mortality and exhibit transcriptional and proteomic neutrophil-like signatures. We conclude that sepsis reprograms monocytes into a pro-inflammatory phenotype and skews bone marrow progenitors and monocytes toward the neutrophil-like lineage, predisposing them to induce neutrophil degranulation and lung injury.
Authors
Scott J. Denstaedt, Breanna McBean, Alan P. Boyle, Brett C. Arenberg, Matthias Mack, Bethany B. Moore, Michael W. Newstead, Yamei Deng, Alexey I. Nesvizhskii, Benjamin H. Singer, Jennifer Cano, Hallie C. Prescott, Helen S. Goodridge, Rachel L. Zemans
Abstract
Early antiretroviral therapy (ART) limits viral reservoir establishment in infants but also constrains viral-specific immunity required to clear reactivated cells. In the early ART context, we evaluated whether combining adeno-associated virus serotype 9 (AAV9)–vectored eCD4-IgG1 with pharmacologic latency reversal using the second mitochondria-derived activator of caspases (SMAC) mimetic AZD5582 could promote reservoir reduction and control in simian immunodeficiency virus (SIV)–infected infant macaques. AAV9 delivery achieved sustained eCD4-IgG1 expression and AZD5582 induced on-ART viremia, but the combination did not reduce intact SIV proviral DNA relative to controls. Partial post-intervention control of viremia during Analytical Treatment Interruption (ATI) occurred in 2/6 infants receiving AAV9-eCD4-IgG1 + AZD5582 with restricted reservoir expansion during recrudescence at week 13. Intact reservoir size during ATI correlated inversely with on-ART viremia during AZD5582 treatment. Controllers did not show increased eCD4-IgG1 expression nor increased on-ART viremia during AZD5582 treatment, but harbored less pre-ART intact SIV DNA in PBMCs than non-controllers. Controllers also exhibited higher frequencies and greater polyfunctionality of virus-specific CD8+ T-cells prior to ATI. These findings implicate immune control of reservoir size and post-ART viral dynamics in early-treated infants and suggest that AAV9-eCD4-IgG1 + AZD5582 increases the likelihood of post-ART viral control.
Authors
Jairo A. Fonseca, Alexis C. King, Kaleaha S. Davis, Daniel O'Hagan, Adrian Khoei, Lucas Alves Britto Da Costa, Camryn Cockerham, Mackenzie Cottrell, Stephanie Ehnert, Jennifer S. Wood, Michael D. Alpert, Matthew R. Gardner, Jeffrey D. Lifson, Maud Mavigner, Mauricio A. Martins, Ann Chahroudi
Abstract
Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.
Authors
Venkata-Viswanadh Edara, Sienna Freeman, Maureen Sampson, Kathryn M. Moore, Rebecca Richardson, Nils Schoof, Divine Burgess, Michelle J. Lee, Gregory K. Tharp, Roza Vlasova, Shane Taylor, Ariana Hodjatzadeh, Yihana P. Melendez-Alejandro, Samia M. Abdallah, Esther W. Ndungu, Ava K. Mascarenhas, Chao-Hsiung Hsu, Tsang-Wei Tu, Martin Styner, Mehul S. Suthar, Mar M. Sanchez, Steven E. Bosinger, Mark W. Burke, Steven A. Sloan, Jessica Raper, Ann Chahroudi
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