Infectious disease
Abstract
The immune mechanisms induced by the Bacillus Calmette-Guérin (BCG) vaccine, and the subset of which mediate protection against tuberculosis (TB), remain poorly understood. This is further complicated by difficulties to verify vaccine-induced protection in humans. Although research in animal models, namely mice and non-human primates (NHPs), has begun to close this knowledge gap, discrepancies in the relative importance of biological pathways across species limit the utility of animal model-derived biological insights in humans. To address these challenges, we applied a systems modeling framework, Translatable Components Regression (TransCompR), to identify human blood transcriptional variability which could predict Mtb challenge outcomes in BCG-vaccinated NHPs. These protection-associated pathways included both innate and adaptive immune activation mechanisms, along with signaling via type I interferons and anti-mycobacterial T helper cytokines. We further partially validated the associations between these mechanisms and protection in humans using publicly available microarray data collected from BCG-vaccinated infants who either developed TB or remained healthy during two years of follow-up. Overall, our work demonstrates how species translation modeling can leverage animal studies to generate hypotheses about the mechanisms that underlie human infectious disease and vaccination outcomes, which may be difficult or impossible to ascertain using human data alone.
Authors
Kate Bridges, Denis Awany, Anele Gela, Temwa-Dango Mwambene, Sherry L. Kurtz, Richard E. Baker, Karen L. Elkins, Christopher M. Sassetti, Thomas J. Scriba, Douglas A. Lauffenburger
Abstract
Sepsis contributes substantially to mortality rates worldwide, yet clinical trials that have focused on its underlying pathogenesis have failed to demonstrate benefits. Recently, enhancing self-defense has been regarded as an emerging therapeutic approach. Autophagy is a self-defense mechanism that protects septic mice, but its regulatory factor is still unknown. Moreover, the role of interferon regulatory factor 7 (IRF7) in sepsis has been debated. Here, we showed that Irf7 deficiency increased mortality during polymicrobial sepsis. Furthermore, IRF7 drove macrophages to protect against sepsis. Mechanistically, IRF7 is a transcription factor that upregulates the expression of autophagy-related genes responsible for autophagosome formation and autolysosome maturation, induces autophagic killing of bacteria, and ultimately reduces septic organ injury. Recombinant adeno-associated virus 9–Irf7–mediated IRF7 overexpression promoted the autophagic clearance of pathogens and improved sepsis outcomes, which may be the mechanism underlying the observed improvement in bacterial clearance. These findings provide evidence that IRF7 is the underlying regulatory factor that drives autophagy to eliminate pathogens in macrophages during sepsis. Collectively, IRF7 overexpression represents a potential host-directed therapeutic strategy for preclinical sepsis models, operating independently of antibiotic mechanisms.
Authors
Guiming Chen, Kangxin Li, Haihua Luo, Lianxu Zhao, Yong Jiang
Abstract
Primary exposure to influenza antigens during infancy shapes the humoral response to subsequent exposures. Development of a universal vaccine approach to protect newborns against influenza would represent a major step forward. In our previous study, we showed vaccination of newborn African green monkeys (AGMs) with an adjuvanted hemagglutinin (HA) stem nanoparticle induced robust IgG responses with broad recognition across HAs. Here, we examined the cellular responses in the lung-draining lymph node of these vaccinated newborn AGMs following challenge with a heterologous H1N1 virus. Our results show that vaccination is associated with early HA stem IgG+ B cell and antibody-secreting cell responses following infection, consistent with a rapidly recalled memory response. In addition, there was evidence of an increase in both HA stem– and head–specific plasma cells in vaccinated animals, suggesting a vaccine-engendered benefit for novel antibodies targeting HA epitopes. Finally, challenge was associated with preferential increases in antibodies that cross-react with H5 HA, suggesting improved protection against this divergent strain. Overall, these findings indicate that HA stem with AddaVax as adjuvant generates a stem-specific cross-reactive memory pool in newborn AGMs with the potential to be rapidly recalled upon infection.
Authors
Kali F. Crofts, Beth C. Holbrook, Courtney L. Page, Maya Sangesland, Masaru Kanekiyo, Martha Alexander-Miller
Abstract
BACKGROUND Accurate prognostic assays for COVID-19 represent an unmet clinical need. We sought to identify and validate early parsimonious transcriptomic signatures that accurately predict fatal outcomes.METHODS We studied 894 patients enrolled in the prospective, multicenter Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) with peripheral blood mononuclear cells (PBMC) and nasal swabs collected within 48 hours of admission. Host gene expression was measured with RNA-Seq. We trained parsimonious prognostic classifiers incorporating host gene expression, age, and SARS-CoV-2 viral load to predict 28-day mortality in 70% of the cohort. Classifier performance was determined in the remaining 30% and externally validated in a contemporary COVID-19 cohort (n = 137) with vaccinated patients.RESULTS Fatal COVID-19 was characterized by 4,189 differentially expressed genes in the peripheral blood. A COVID-specific 3-gene peripheral blood classifier (CD83, ATP1B2, DAAM2) combined with age and SARS-CoV-2 viral load achieved an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI, 0.82–0.94). A 3-gene nasal classifier (SLC5A5, CD200R1, FCER1A), in comparison, yielded an AUC of 0.74 (95% CI, 0.64–0.83). Notably, OLAH, the most strongly upregulated gene in both PBMC and nasal swab and recently implicated in severe viral infection pathogenesis, yielded AUCs of 0.86 (0.79–0.93) and 0.78 (95% CI, 0.69–0.86), respectively. Both peripheral blood classifiers demonstrated comparable performance in an independent contemporary cohort of vaccinated patients (AUCs 0.74–0.80).CONCLUSION Our parsimonious blood- and nasal-based classifiers accurately predicted COVID-19 mortality and merit further study as accessible prognostic tools to guide triage, resource allocation, and early therapeutic interventions.FUNDING NIH: 5R01AI135803-03, R35HL140026, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, 5T32DA018926-18, and K0826161611. National Institute of Allergy and Infectious Diseases, NIH: 3U19AI1289130, U19AI128913-04S1, and R01AI122220. National Center for Advancing Translational Sciences, NIH: UM1TR004528. The National Science Foundation: DMS2310836. The Chan Zuckerberg Biohub San Francisco.
Authors
Rithwik Narendra, Emily C. Lydon, Hoang Van Phan, Natasha Spottiswoode, Lucile P. Neyton, Joann Diray-Arce, IMPACC Network, COMET Consortium, EARLI Consortium, Patrice M. Becker, Seunghee Kim-Schulze, Annmarie Hoch, Harry Pickering, Patrick van Zalm, Charles B. Cairns, Matthew C. Altman, Alison D. Augustine, Steve Bosinger, Walter Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff, Bjoern Peters, Nadine Rouphael, Ruth R. Montgomery, Elaine Reed, Joanna Schaenman, Hanno Steen, Ofer Levy, Sidney C. Haller, David Erle, Carolyn M. Hendrickson, Matthew F. Krummel, Michael A. Matthay, Prescott Woodruff, Elias K. Haddad, Carolyn S. Calfee, Charles R. Langelier
Abstract
Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent IFN responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by preexisting vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited higher immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines were more immunogenic than the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.
Authors
Bakare Awakoaiye, Shiyi Li, Sarah Sanchez, Tanushree Dangi, Nahid Irani, Laura Arroyo, Gabriel Arellano, Shadi Mohammadabadi, Malika Aid, Pablo Penaloza-MacMaster
Abstract
Elite controllers (ECs) maintain undetectable levels of plasma viremia in the absence of treatment, but small reservoirs of replication-competent proviruses persist in the vast majority of these persons. We longitudinally studied paired blood and inguinal lymph node samples (LNMC) from two ECs to better characterize distinguishing features of viral reservoir cell dynamics in ECs. In both participants, we observed a 7- to 10-fold lower frequency of intact proviruses in LNMC samples relative to reservoir cells circulating in blood. The landscape of intact proviruses in both tissue compartments was dominated by shared large clones that were frequently integrated in non-coding DNA regions, but the frequency and diversity of intact proviruses was more limited in LNMCs. Of note, over 9-10 years of longitudinal follow-up, a 3- to 18-fold reduction of intact proviruses was observed. Together, these data support the hypothesis that viral reservoirs in ECs’ blood and lymphoid tissues are under strong, likely immune-mediated selection pressure.
Authors
Samantha K. Marzi, Chloé M. Naasz, Leah Carrere, Carmen Gasca-Capote, Isabelle C. Roseto, Ce Gao, Matthias Cavassini, Andrea Mastrangelo, Mathias Lichterfeld, Matthieu Perreau, Xu G. Yu
Abstract
High-affinity antibody production depends on CD4+ T-follicular helper (Tfh) cells. In humans, peripheral blood Tfh cells are heterogenous, as evidenced by differential expression of the chemokine receptors, CXCR3 and CCR6, which to date have served to classify three subsets, pTfh1, pTfh2 and pTfh17. Although pTfh1 responses dominate during blood-stage Plasmodium infections, a clear association with protective antibody responses remains to be described. We hypothesise that pTfh cells exhibit greater phenotypic and functional heterogeneity than that described by CXCR3/CCR6 alone, and that these more nuanced pTfh subsets play distinct roles during Plasmodium infection. We map pTfh cell heterogeneity in healthy individuals prior to and during controlled human malaria infection (CHMI) using parallel scRNA-seq and VDJ-seq. We uncover two pTfh1 subsets or differential phenotypic states, distinguishable by CCR7 expression. Prior to infection, Tfh1-CCR7neg cells exhibit higher baseline expression of inflammatory cytokines and genes associated with cytotoxicity. While Tfh1-CCR7pos cells have higher GC signatures. Indeed, during CHMI, Tfh1-CCR7pos, Tfh1-CCR7neg, and Tfh2 cells, all clonally expand and become activated. However, only Tfh1-CCR7pos and Tfh2 cells positively associate with protective antibody production. Hence, our data reveal further complexity amongst human Tfh cells, and highlight two distinct subsets associated with antibody-mediated immunity to malaria.
Authors
Megan S.F. Soon, Damian A. Oyong, Nicholas L. Dooley, Reena Mukhiya, Zuleima Pava, Dean Andrew, Jessica R. Loughland, James S. McCarthy, Jo-Anne Chan, James G. Beeson, Christian Engwerda, Ashraful Haque, Michelle J. Boyle
Abstract
Acute lower respiratory infections are the primary cause of global mortality in post-neonatal children. Most respiratory viruses primarily involve upper airway infection and inflammation, yet nasal responses are poorly characterized. Using a mouse model of human metapneumovirus (HMPV), we found viral burden was higher in nasal airways and exhibited delayed clearance. Despite high burden, there was low nasal expression of type I and III interferon (IFN). Single-cell RNA-sequencing (scRNA-seq) from HMPV-infected mice showed lower nasal interferon-stimulated gene (ISG) expression and nasal enrichment of genes negatively regulating IFN. scRNA-seq of COVID-19 patients confirmed lower ISG expression in upper airways. HMPV infection downregulated nasal expression of interferon regulatory factor-3, suggesting a mechanism for limited response. To rescue the quiescent environment, we administered type I or III IFN to upper airways early post-infection, leading to lower nasal HMPV titer and virus-specific CD8+ T-cell upregulation. Intranasal immunization adjuvanted with type I or III IFN improved immune response, reduced clinical disease, and enhanced viral clearance in HMPV and influenza infection. IFN adjuvant increased recruitment of dendritic cells, resident-memory T-cells, and neutralizing antibodies. These findings reveal locally suppressed IFN production contributes to a quiescent nasal immune landscape that delays viral clearance and impairs mucosal vaccine responses.
Authors
Jorna Sojati, Olivia B. Parks, Taylor Eddens, Jie Lan, Monika Johnson, John V. Williams
Abstract
Background. The SARS-CoV-2 virus has evolved subvariants since the emergence of the omicron variant in 2021. Whether these changes impact viral shedding and transmissibility is not known. Methods. POSITIVES is a prospective longitudinal cohort of individuals with mild SARS-CoV-2 infection. Ambulatory, immunocompetent participants who did not receive antivirals self-administered 6 anterior nasal swabs over 15 days. Samples were analyzed by qPCR to quantify viral RNA, semi-quantitative viral culture to detect shedding of replication-competent virus, and whole genome sequencing to classify subvariants. Our predictor of interest was omicron subvariant: BA.1x, BA.2x, BA.4/5x, XBB.x and JN.x. Outcomes included RNA levels and duration of shedding replication-competent virus. We additionally explored whether the duration and severity of symptom correlated with duration of viral shedding and whether symptoms are a valid marker for ending isolation. Results. The median peak nasal SARS-CoV-2 RNA (6.0-6.3 log10 RNA copies/mL), median days to peak RNA (4-5 days), median days to undetectable viral RNA (10-12 days) and median days to negative viral culture (3.5-6 days) was similar across omicron subvariants. Number and severity of symptoms were also similar. For all subvariants, a sizeable percentage (range 28.2-52.0%) shed replication-competent virus after fever resolution and improvement of symptoms. Conclusion. Despite ongoing viral evolution, key aspects of viral dynamics of SARS-CoV-2 infection, including the duration of shedding replication-competent virus, have not substantially changed across omicron subvariants. Replication-competent shedding of these subvariants is detected for a large proportion of people who meet criteria for ending isolation. Funding. This work was supported by the National Institutes of Health (NIH), the Massachusetts Consortium on Pathogen Readiness, and the Massachusetts General Hospital Department of Medicine.
Authors
Julie Boucau, Owen T. Glover, Caitlin Marino, Gregory E. Edelstein, Manish C. Choudhary, Yijia Li, Brooke M. Leeman, Zahra Reynolds, Karry Su, Dessie Tien, Chase B. Mandell, Eliza Passell, Andrew Alexandrescu, Emory Abar, Mamadou Barry, Dibya Ghimire, Tammy D. Vyas, Jatin M. Vyas, Jacob E. Lemieux, Jonathan Z. Li, Mark J. Siedner, Amy K. Barczak
Bcl6 reactivity is associated with a distinct immune landscape and spatial transcriptome in COVID-19
Abstract
The regulation of follicular (F) and germinal center (GC) immune reactivity in human lymph nodes (LNs), particularly during the acute stages of viral infection, remains poorly understood: We have analyzed lung-draining lymph nodes (LD-LNs) from COVID-19 autopsies using multiplex imaging and spatial transcriptomics to examine the immune landscape with respect to follicular immune reactivity. We identified three groups of donors based on the Bcl6 prevalence of their Reactive Follicles (RFs): RF-Bcl6no/low, RF-Bcl6int, and RF-Bcl6high. A distinct B/TFH immune landscape, associated with increased prevalence of proliferating B-cell and TFH-cell subsets, was found in RF-Bcl6high LD-LNs. The comparison between LD-LNs and subdiaphragmatic (SD) LNs from the same donor revealed a divergent Bcl6 expression between the two anatomical sites. LD-LN Bcl6 expression was also associated with a distinct spatial transcriptomic profile. TH1-associated genes/pathways (e.g., CXCR3, STAT5, TNF-signaling) were significantly up-regulated in RF-Bcl6no/low tissues, while the RF-Bcl6high tissues exhibited significant up-regulation of GC-promoting genes/pathways (e.g., CXCL13, B-cell receptor signaling). Our findings reveal a heterogeneous F/GC landscape in COVID-19 LD-LNs, highlighting specific molecular targets and pathways that could regulate human F/GC immune dynamics during acute viral infections.
Authors
Cloé Brenna, Bernat Bramon Mora, Kalliopi Ioannidou, Julien Bodelet, Mia L. Siebmanns, Simon Burgermeister, Spiros Georgakis, Michail Orfanakis, Yannick D. Muller, Nazanin Sédille, Matthew J. Feinstein, Jon W. Lomasney, Oliver Y. Chén, Giuseppe Pantaleo, Sabina Berezowska, Laurence de Leval, Raphael Gottardo, Constantinos Petrovas
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