Infectious disease
Abstract
Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 6-7 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.4 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.
Authors
Shadisadat Esmaeili, Katherine Owens, Ugo Avila-Ponce de Leon, Joseph F. Standing, David M. Lowe, Shengyuan Zhang, James A. Watson, William H.K. Schilling, Jessica Wagoner, Stephen J. Polyak, Joshua T. Schiffer
Abstract
Background. Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities. Methods. We utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics “recovery factor”, trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood CyTOF protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores. Results. LC participants had lower recovery factor scores compared to recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC. Conclusion. The multi-omics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets. Trial Registration. ClinicalTrials.gov NCT04378777. Funding. This study was funded by NIH, NIAID and NSF.
Authors
Gisela Gabernet, Jessica Maciuch, Jeremy P. Gygi, John F. Moore, Annmarie Hoch, Caitlin Syphurs, Tianyi Chu, Naresh Doni Jayavelu, David B. Corry, Farrah Kheradmand, Lindsey R. Baden, Rafick-Pierre Sekaly, Grace A. McComsey, Elias K. Haddad, Charles B. Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P. Metcalf, Nelson I. Agudelo Higuita, Catherine L. Hough, William B. Messer, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Monica Kraft, Chris Bime, Elaine F. Reed, Joanna Schaenman, David J. Erle, Carolyn S. Calfee, Mark A. Atkinson, Scott C. Brakenridge, Esther Melamed, Albert C. Shaw, David A. Hafler, Alison D. Augustine, Patrice M. Becker, Al Ozonoff, Steven E. Bosinger, Walter Eckalbar, Holden T. Maecker, Seunghee Kim-Schulze, Hanno Steen, Florian Krammer, Kerstin Westendorf, IMPACC Network, Bjoern Peters, Slim Fourati, Matthew C. Altman, Ofer Levy, Kinga K. Smolen, Ruth R. Montgomery, Joann Diray-Arce, Steven H. Kleinstein, Leying Guan, Lauren I.R. Ehrlich
Abstract
The persistent challenge of sepsis-related mortality underscores the necessity for deeper insights, with our multi-center cross-age cohort study identifying insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromises macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS/IL-1β production and phagocytic capacity – defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.
Authors
Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song
Abstract
Sepsis is a life-threatening disease caused by a dysfunctional host response to infection. During sepsis, inflammation-related immunosuppression is the critical factor causing secondary infection and multiple organ dysfunction syndrome. The regulatory mechanisms underlying regulatory T-cell (Treg) differentiation and function, which significantly contribute to septic immunosuppression, require further clarification. In this study, we found that neutrophil extracellular traps (NETs) participated in the development of sepsis-induced immunosuppression by enhancing Treg differentiation and function via direct interaction with CD4+ T cells. Briefly, NETs anchored enolase 1 (ENO1) on the membrane of CD4+ T cells through its key protein myeloperoxidase (MPO) and subsequently recruited interferon-induced transmembrane protein 2 (IFITM2). IFITM2 acted as a DNA receptor that sensed NETs-DNA and activated intracellular RAS-associated protein 1B (RAP1B) and its downstream extracellular signal-regulated kinase (ERK) signaling pathway to promote Treg differentiation and function. ENO1 inhibition significantly attenuated NETs-induced Treg differentiation and alleviated sepsis in mice. Overall, we demonstrated the role of NETs in sepsis-induced immunosuppression by enhancing Treg differentiation, identified ENO1 as an anchor of NETs-MPO, and elucidated the downstream molecular mechanism by which IFITM2-RAP1B-ERK regulated Treg differentiation. These findings improve our understanding of the immunopathogenesis of sepsis and provide potential therapeutic targets for sepsis-induced immunosuppression.
Authors
Yi Jiang, Shenjia Gao, Xiya Li, Hao Sun, Xinyi Wu, Jiahui Gu, Zhaoyuan Chen, Han Wu, Xiaoqiang Zhao, Tongtong Zhang, Ronen Ben-Ami, Yuan Le, Timothy R. Billiar, Changhong Miao, Jie Zhang, Jun Wang, Wankun Chen
Abstract
Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.
Authors
Yahui Guo, Mariano A. Aufiero, Kathleen A.M. Mills, Simon A. Grassmann, Hyunu Kim, Mergim Gjonbalaj, Paul Zumbo, Audrey Billips, Katrina B. Mar, Yao Yu, Laura Echeverri Tirado, Lena Heung, Amariliz Rivera, Doron Betel, Joseph C. Sun, Tobias M. Hohl
Abstract
Antiretroviral therapy (ART) prevents HIV-1 replication but does not eliminate the latent reservoir, the source of viral rebound if treatment is stopped. Autologous neutralizing antibodies (aNAbs) can block in vitro outgrowth of a subset of reservoir viruses and therefore potentially affect viral rebound upon ART interruption. We investigated aNAbs in 31 people with HIV-1 (PWH) on ART. Participants fell into two groups based on a high or low fraction of aNAb-resistant reservoir isolates, with most isolates being aNAb-resistant (IC50 >100 μg/ml). Time on uninterrupted ART was associated with higher aNAb resistance. However, pharmacodynamic analysis predicted that many isolates would be partially inhibited at physiologic IgG concentrations, to the same degree as by single antiretroviral drugs. Steep dose-response curve slopes, an indication of cooperativity, were observed for the rare isolates that were very strongly inhibited (>5 logs) by aNAbs. Resistance to aNAbs was not fully explained by declining in aNAb titers and may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses over long time intervals, leaving only aNAb-resistant viruses which can contribute to viral rebound.
Authors
Natalie F. McMyn, Joseph Varriale, Hanna W. S. Wu, Vivek Hariharan, Milica Moskovljevic, Toong Seng Tan, Jun Lai, Anushka Singhal, Kenneth Lynn, Karam Mounzer, Pablo Tebas, Luis J. Montaner, Rebecca Hoh, Xu G. Yu, Mathias Lichterfeld, Francesco R. Simonetti, Colin Kovacs, Steven G. Deeks, Janet M. Siliciano, Robert F. Siliciano
Abstract
Background: Anti-TNF biologics are widely used to treat patients with immune-mediated inflammatory diseases. In mouse models, the complete absence of TNF impairs germinal center (GC) responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. Widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on responses to specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF biologics exhibit decreased Spike-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. Methods: Here we analyzed humoral responses to SARS-CoV-2 immunization using single-cell RNA-Sequencing and flow cytometry of Spike-specific memory B cells (MBC), as well as avidity measurements of plasma antibodies from IBD patients treated with anti-TNF or anti-IL-12/23 or from healthy controls. Results: We observed decreased somatic hypermutation in the B cell receptors of Spike-specific MBCs and decreased antigen-specific MBC accumulation following SARS-CoV-2 mRNA vaccination in anti-TNF treated IBD patients, compared to IBD patients treated with anti-IL-12/23 or healthy controls. This decreased somatic hypermutation in Spike-specific MBCs in anti-TNF treated patients correlated with decreased and delayed antibody affinity maturation and reduced neutralization activity. Conclusion: These data provide in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity and quality of antigen-specific GC outputs in humans. Funding: Juan and Stefania Speck (donation) and by Canadian Institutes of Health Research (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711, VS1-175545, GA2-177716, GA1-177703 and CIHR FDN 143301 &143350.
Authors
Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya Dayam, Ying Liu, Jenny Choi, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Abstract
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA’s role in biofilm formation. Collectively, these data reveal a critical mechanism—epigenetic regulation of staphylococcal gene expression—by which phage can regulate virulence to drive adaptive leaps by S. aureus.
Authors
Robert J. Ulrich, Magdalena Podkowik, Rebecca Tierce, Irnov Irnov, Gregory Putzel, Nora M. Samhadaneh, Keenan A. Lacey, Daiane Boff, Sabrina M. Morales, Sohei Makita, Theodora K. Karagounis, Erin E Zwack, Chunyi Zhou, Randie H. Kim, Karl Drlica, Alejandro Pironti, Harm van Bakel, Victor J. Torres, Bo Shopsin
Abstract
HIV infection accelerates biological aging, but the contribution of the host’s age to this process is unknown. We investigated the influence of SIV infection in macaques (SIVmac) on the risk of comorbidities and aging in young and old rhesus macaques (RMs) by assessing pathogenesis markers, DNA methylation–based epigenetic age (EA), and EA acceleration (EAA) in blood and tissues. Initially, upon SIV infection, the young RMs showed greater resilience to CD4+ T cell depletion, better control of T cell activation, hypercoagulation, and excessive inflammation, yet this resilience was progressively lost in the advanced stages of infection. During the late stages of infection, the young RMs, but not the aged ones, showed an increase in EA in PBMCs; also, EAA in the cerebellum and heart of young RMs was higher compared with old RMs. SIV infection was more pathogenic in aged animals in early stages, leading to a more rapid disease progression; however, accelerated aging mostly affected young animals, so that the levels of multiple key pathogenesis markers in the young RMs converged toward those specific to aged ones in the late stages of infection. We conclude that SIV infection–driven age acceleration is tissue specific, and that host age influences the susceptibility of different tissues to enhanced aging.
Authors
Anna J. Jasinska, Ranjit Sivanandham, Sindhuja Sivanandham, Cuiling Xu, Juozas Gordevicius, Milda Milčiūtė, Robert T. Brooke, Paola Sette, Tianyu He, Egidio Brocca-Cofano, Benjamin B. Policicchio, Krishna Nayak, Saharsh Talwar, Haritha Annapureddy, Dongzhu Ma, Ruy M. Ribeiro, Cristian Apetrei, Ivona Pandrea
Abstract
Although virus-like particle (VLPs) vaccines were shown to be effective against several viruses, their advantage over vaccines which include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding for the Marburg virus (MARV) full-length GP delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 co-expressed. We vaccinated guinea pigs with a two-component mRNA vaccine encoding for GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than the GP-only group. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP exhibited only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cells responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole blood RNA-seq revealed that the VLP vaccine down-regulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated interferon signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection by as little as one µg dose in guinea pigs.
Authors
Chandru Subramani, Michelle N. Meyer, Matthew A. Hyde, Margaret E. Comeaux, Haiping Hao, James E. Crowe Jr., Vsevolod L. Popov, Harshwardhan Thaker, Sunny Himansu, Andrea Carfi, Alexander Bukreyev
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ISSN: 0021-9738 (print), 1558-8238 (online)