Infectious disease
Abstract
BACKGROUND. HIV-1 vaccine efforts are primarily directed towards eliciting neutralizing antibodies (nAbs). However, vaccine trials and mother to child natural history cohort investigations indicate that antibody-dependent cellular cytotoxicity (ADCC), not nAbs, correlate with prevention. The ADCC characteristics associated with lack of HIV-1 acquisition remain unclear. METHODS. Here we examine ADCC and nAb properties in pre-transmission plasma from HIV-1 exposed infants and from the corresponding transmitting and non-transmitting mothers’ breast milk and plasma. Breadth and potency (BP) is assessed against a panel of heterologous, non-maternal, variants. ADCC and neutralization sensitivity is estimated for the strains present in the infected mothers. RESULTS. Infants that eventually acquire HIV-1 and those that remain uninfected have similar pre-transmission ADCC BP. The viruses circulating in the transmitting and the non-transmitting mothers also have similar ADCC susceptibility. Infants with a combination of higher pre-transmission ADCC BP and exposure to more ADCC susceptible strains are less likely to acquire HIV-1. In contrast, higher pre-existing infant neutralization BP and greater maternal virus neutralization sensitivity does not associate with transmission. Infants have higher ADCC BP closer to birth and in the presence of high plasma IgG relative to IgA levels. Mothers with potent humoral responses against their autologous viruses harbor more ADCC sensitive strains. CONCLUSION. ADCC sensitivity of the exposure variants along with preexisting ADCC BP influence mother to child HIV-1 transmission during breastfeeding. Vaccination strategies that enhance ADCC responses are likely not sufficient to prevent HIV-1 transmission because strains present in chronically infected individuals can have low ADCC susceptibility. TRIAL REGISTRATION. NCT00164736 for BAN study
Authors
Allison S. Thomas, Carolyn Coote, Yvetane Moreau, John E. Isaac, Alexander C. Ewing, Athena P. Kourtis, Manish Sagar
Abstract
BACKGROUND. SARS-CoV-2 infections are frequently milder in children than adults, suggesting that immune responses may vary with age. However, information is limited regarding SARS-CoV-2 immune responses in young children. METHODS. We compared Receptor Binding Domain binding antibody (RBDAb) titers and SARS-CoV-2 neutralizing antibody titers measured by pseudovirus neutralizing antibody assay (PsVNA) in serum specimens obtained from children aged 0-4 years, 5-17 years, and in adults aged 18-62 years at the time of enrollment in a prospective longitudinal household study of SARS-CoV-2 infection. RESULTS. Among 56 participants seropositive at enrollment, children aged 0-4 years had >10-fold higher RBDAb titers than adults (416 vs. 31, P<0.0001), and the highest RBDAb titers in 11/12 households with seropositive children and adults. Children aged 0-4 years had only 2-fold higher neutralizing Ab than adults, resulting in higher binding to neutralizing (B/N) Ab ratios compared to adults (2.36 vs. 0.35 for ID50, P=0.0002). CONCLUSIONS. These findings suggest that young children mount robust antibody responses to SARS-CoV-2 following community infections. Additionally, these results support using neutralizing Ab to measure the immunogenicity of COVID-19 vaccines in children aged 0-4 years. FUNDING. Supported by CDC Award 75D30120C08737
Authors
Ruth A. Karron, Maria Garcia Quesada, Elizabeth A. Schappell, Stephen D. Schmidt, Maria Deloria Knoll, Marissa K. Hetrich, Vic Veguilla, Nicole A. Doria-Rose, Fatimah S. Dawood
Abstract
Severe viral infections of the skin can occur in patients with inborn errors of immunity (IEI). We report an all-in-one whole-transcriptome sequencing-based method by RNA-Seq on a single skin biopsy for concomitant identification of the cutaneous virome and underlying IEI. Skin biopsies were obtained from normal and lesional skin from patients with cutaneous infections suspected to be of viral origin. RNA-Seq was utilized as the first-tier strategy for unbiased human genome-wide rare variant detection. Reads unaligned to the human genome were utilized for the exploration of 926 different viruses in a viral genome catalog. In nine families studied, the patients carried pathogenic variants in six human IEI genes, including IL2RG, WAS, CIB1, STK4, GATA2, and DOCK8. Gene expression profiling also confirmed pathogenicity of the human variants and permitted genome-wide homozygosity mapping which assisted in identification of candidate genes in consanguineous families. This automated, all-in-one computational pipeline, called VirPy, enables simultaneous detection of the viral triggers and the human genetic variants underlying skin lesions in patients with suspicion of IEI and viral dermatosis.
Authors
Amir Hossein Saeidian, Leila Youssefian, Charles Y. Huang, Fahimeh Palizban, Mahtab Naji, Zahra Saffarian, Hamidreza Mahmoudi, Azadeh Goodarzi, Soheila Sotoudeh, Fatemeh Vahidnezhad, Maliheh Amani, Narjes Tavakoli, Ali Ajami, Samaneh Mozafarpoor, Mehrdad Teimoorian, Saeed Dorgaleleh, Sima Shokri, Mohammad Shenagari, Nima Abedi, Sirous Zeinali, Paolo Fortina, Vivien Béziat, Emmanuelle Jouanguy, Jean-Laurent Casanova, Jouni Uitto, Hassan Vahidnezhad
Abstract
BACKGROUND. Gut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients. METHODS. We randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI). RESULTS. The two arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at two weeks post-HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T-cell and B-cell subsets was similar between groups. Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including Staphylococcus species. CONCLUSIONS. While GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens. TRIAL REGISTRATION. ClinicalTrials.gov NCT02641236 FUNDING. NIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, Stanford MCHRI.
Authors
Christopher J. Severyn, Benjamin A. Siranosian, Sandra Tian-Jiao Kong, Angel Moreno, Michelle M. Li, Nan Chen, Christine N. Duncan, Steven P. Margossian, Leslie E. Lehmann, Shan Sun, Tessa M. Andermann, Olga Birbrayer, Sophie Silverstein, Soomin Kim, Niaz Banaei, Jerome Ritz, Anthony A. Fodor, Wendy B. London, Ami S. Bhatt, Jennifer S. Whangbo
Abstract
Sporozoite-based approaches currently represent the most effective vaccine strategies for induction of sterile protection against Plasmodium falciparum (Pf) malaria. Clinical development of sub-unit vaccines is almost exclusively centered around the Circum-sporozoite Protein (CSP) an abundantly expressed protein on the sporozoite membrane. Anti-CSP antibodies are able to block sporozoite invasion and development in human hepatocytes and subsequently prevent clinical malaria. Here we investigated whether sporozoite-induced human antibodies with specificities different from CSP can reduce Pf-liver stage development. IgG preparations were obtained from 12 volunteers inoculated with a protective immunization regime of whole-sporozoites under chloroquine prophylaxis. These IgGs were depleted for CSP-specificity by affinity chromatography. Recovered non-CSP antibodies were tested for sporozoite membrane binding and for functional inhibition of sporozoite invasion of a human hepatoma cell line and hepatocytes both in vitro and in vivo. Post-immunization IgGs depleted for CSP-specificity of 9 out of 12 donors recognized sporozoite surface antigens. Samples from 5 out of 12 donors functionally reduced parasite-liver cell invasion or development using the hepatoma cell line HC-04 and FRG-huHep mice containing human liver cells. The combined data provide clear evidence that non-CSP proteins as yet undefined do represent antibody targets for functional immunity against Plasmodium falciparum parasites responsible for malaria.
Authors
Amanda Fabra-García, Annie S.P. Yang, Marije C. Behet, Xi Zen Yap, Youri van Waardenburg, Swarnendu Kaviraj, Kjerstin Lanke, Geert-Jan van Gemert, Matthijs M. Jore, Teun Bousema, Robert W. Sauerwein
Abstract
Immune cells express an array of inhibitory checkpoint receptors that are upregulated upon activation and limit tissue damage associated with excessive response to pathogens or allergens. Mouse leukocyte immunoglobulin like receptor B4 (LILRB4), also known as glycoprotein 49B (gp49B), is an inhibitory checkpoint receptor constitutively expressed in myeloid cells and upregulated in B cells, T cells, and NK cells upon activation. Here, we report that expression of LILRB4, which binds Zika virus (ZIKV), was increased in microglia and myeloid cells infiltrating the brains of neonatal mice with ZIKV-associated meningoencephalitis. Importantly, while C57BL/6 mice developed transient neurological symptoms but survived infection, mice lacking LILRB4/gp49B (LILRB4 KO) exhibited more severe signs of neurological disease and succumbed to disease. Their brains showed increased cellular infiltration but reduced control of viral burden. The reduced viral clearance was associated with altered NK cell function in the absence of LILRB4/gp49B. In naive animals, this manifested as reduced granzyme B responses to stimulation, but in ZIKV-infected animals, NK cells showed phenotypic changes that suggested altered maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity. Together, our data reveal LILRB4/gp49B as an important regulator of NK cell function during viral infections.
Authors
Ha-Na Lee, Mohanraj Manangeeswaran, Aaron P. Lewkowicz, Kaliroi Engel, Monica Chowdhury, Mamatha Garige, Michael A. Eckhaus, Carole Sourbier, Derek D.C. Ireland, Daniela Verthelyi
Abstract
SARS-CoV-2 provokes a robust T cell response. Peptide-based studies exclude antigen processing and presentation biology and may influence T cell detection studies. To focus on responses to whole virus and complex antigens, we used intact SARS-CoV-2 and full-length proteins with dendritic cells (DC) to activate CD8 and CD4 T cells from convalescent persons. T cell receptor (TCR) sequencing showed partial repertoire preservation after expansion. Resultant CD8 T cells recognize SARS-CoV-2-infected respiratory tract cells, and CD4 T cells detect inactivated whole viral antigen. Specificity scans with proteome-covering protein/peptide arrays show that CD8 T cells are oligospecific per subject and that CD4 T cell breadth is higher. Some CD4 T cell lines enriched using SARS-CoV-2 cross-recognize whole seasonal coronavirus (sCoV) antigens, with protein, peptide, and HLA restriction validation. Conversely, recognition of some epitopes is eliminated for SARS-CoV-2 variants, including spike (S) epitopes in the alpha, beta, gamma, and delta variant lineages.
Authors
Lichen Jing, Xia Wu, Maxwell P. Krist, Tien-Ying Hsiang, Victoria L. Campbell, Christopher L. McClurkan, Sydney M. Favors, Lawrence Hemingway, Charmie Godornes, Denise Q. Tong, Stacy Selke, Angela C. LeClair, Chul-Woo Pyo, Daniel E. Geraghty, Kerry J. Laing, Anna Wald, Michael Gale, Jr., David M. Koelle
Abstract
Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: Healthy control participants weeks (early) or months (late) following vaccination in comparison to symptomatic SARS-CoV-2 infections after partial or full mRNA vaccination. During the study time, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the healthy controls were sustained over time against the vaccine parent virus, but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time in healthy controls. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against parent virus than the healthy controls, similar IgG antibody titers and similar virus-specific T cell responses measured by IFN-γ. Compared to healthy controls, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended toward lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.
Authors
Han-Sol Park, Janna R. Shapiro, Ioannis Sitaras, Bezawit A. Woldemeskel, Caroline Garliss, Amanda Dziedzic, Jaiprasath Sachithanandham, Anne E. Jedlicka, Christopher A. Caputo, Kimberly E. Rousseau, Manjusha Thakar, San Suwanmanee, Pricila Hauk, Lateef Aliyu, Natalia I. Majewska, Sushmita Koley, Bela Patel, Patrick Broderick, Giselle Mosnaim, Sonya L. Heath, Emily S. Spivak, Aarthi Shenoy, Evan M. Bloch, Thomas J. Gniadek, Shmuel Shoham, Arturo Casadevall, Daniel Hanley, Andrea L. Cox, Oliver Laeyendecker, Michael Betenbaugh, Steven M. Cramer, Heba H. Mostafa, Andrew Pekosz, Joel N. Blankson, Sabra L. Klein, Aaron A.R. Tobian, David Sullivan, Kelly A. Gebo
Abstract
Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45– populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.
Authors
Forrest Jessop, Benjamin Schwarz, Dana Scott, Lydia M. Roberts, Eric Bohrnsen, John R. Hoidal, Catharine M. Bosio
Abstract
Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells causing their death and TBI induces the state of immunodeficiency combined with intestinal dysbiosis and non-productive immune responses. We found enhanced Pseudomonas aeruginosa (PA) colonization of the gut leading to the host cell death and strikingly decreased survival of irradiated mice. PA-driven pathogenic mechanism includes theft-ferroptosis is realized via: i) curbing host anti-ferroptotic system GSH/GPx4 and ii) employing bacterial 15-lipoxygenase (pLoxA) to generate pro-ferroptotic signal - 15-hyderoperoxy-arachidonyl-PE (15-HpETE-PE) - in the intestines of irradiated/infected mice. Global redox phospholipidomics of the ileum revealed that lyso-phospholipids and oxidized phospholipids (particularly PEox) represented the major factors which contributed to the TBI+PA induced pathogenic changes. A lipoxygenase inhibitor, baicalein, significantly attenuated animal lethality, PA colonization, as well as intestinal epithelial cell death and generation of ferroptotic PEox signals. Opportunistic PA mechanisms included stimulation of the anti-inflammatory lipoxin A4 (LXA4) production and suppression of the pro-inflammatory hepoxilin A3 (HxA3) and leukotriene B4 (LTB4). Unearthing complex PA pathogenic/virulence mechanisms including effects on the host anti-/pro-inflammatory responses, lipid metabolism and ferroptotic cell death points to new therapeutic and radiomitigative targets.
Authors
Haider H. Dar, Michael W. Epperly, Vladimir A. Tyurin, Andrew A. Amoscato, Tamil S. Anthonymuthu, Austin B. Souryavong, Alexander A. Kapralov, Galina V. Shurin, Svetlana N. Samovich, Claudette M. St. Croix, Simon C. Watkins, Sally E. Wenzel, Rama K. Mallampalli, Joel S. Greenberger, Hulya Bayir, Valerian E. Kagan, Yulia Y. Tyurina
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