Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody–dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.
Eleanor C. Semmes, Itzayana G. Miller, Nicole Rodgers, Caroline T. Phan, Jillian H. Hurst, Kyle M. Walsh, Richard J. Stanton, Justin Pollara, Sallie R. Permar
The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared to other vaccine platforms. Here, we recruited 88 healthy individuals that received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the 2nd and 3rd dose of vaccination induced robust spike-specific neutralizing antibodies, with a 3rd vaccine further increased the overall magnitude of antibody response, and neutralization against Omicron sub-lineages B.1.1.529, BA.2, BA.4/BA.5 and BA.2.75.2. Spike-specific CD4+ T cell and circulating T follicular helper (cTFH) cells were markedly increased by the 2nd and 3rd dose of CoronaVac vaccine, accompanied with altered composition of functional cTFH cell subsets with distinct effector and memory potential. Additionally, cTFH cells are positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.
Pengcheng Zhou, Cheng Cao, Tuo Ji, Ting Zheng, Yaping Dai, Min Liu, Junfeng Jiang, Daoqi Sun, Zhonghu Bai, Xiaojie Lu, Fang Gong
Influenza A virus (IAV) infection is commonly complicated by secondary bacterial infections, leading to increased morbidity and mortality. Our recent work demonstrates that IAV disrupts airway homeostasis, leading to airway pathophysiology resembling cystic fibrosis disease through diminished cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we use human airway organotypic cultures to investigate how IAV alters the airway microenvironment to increase susceptibility to secondary infection with Streptococcus pneumoniae (Spn). We observed that IAV-induced CFTR dysfunction and airway surface liquid acidification is central to increasing susceptibility to Spn. Additionally, we observed that IAV induced profound transcriptional changes in the airway epithelium and proteomic changes in the airway surface liquid in both CFTR dependent and independent manners. These changes correspond to multiple diminished host defense pathways and altered airway epithelial function. Collectively, these findings highlight both the importance of CFTR function during infectious challenge and demonstrate a central role for the lung epithelium in secondary bacterial infections following IAV.
Erin Y. Earnhardt, Jennifer L. Tipper, Adonis D'Mello, Ming-Yuan Jian, Elijah S. Conway, James A. Mobley, Carlos J. Orihuela, Hervé Tettelin, Kevin S. Harrod
The virulence of intracellular pathogens relies largely on the ability to survive and replicate within phagocytes, but also on the release and transfer into new host cells. Such cell-to-cell transfer could represent a target for counteracting microbial pathogenesis. However, our understanding of the underlying cellular and molecular processes remains woefully insufficient. Using intravital 2-photon microscopy of caspase-3 activation in the Leishmania major (L. major)-infected live skin, we show increased apoptosis in cells infected by the parasite. Also, transfer of the parasite to new host cells occurred directly without a detectable extracellular state, and was associated with concomitant uptake of cellular material from the original host cell. These in vivo findings were fully recapitulated in infections of isolated human phagocytes. Furthermore, we observed that high pathogen proliferation increased cell death in infected cells, and long-term residency within an infected host cell was only possible for slowly proliferating parasites. Our results therefore suggest that L. major drives its own dissemination to new phagocytes by inducing host cell death in a proliferation-dependent manner.
Iris Baars, Moritz Jaedtka, Leon-Alexander Dewitz, Yan Fu, Tobias Franz, Juliane Mohr, Patricia Gintschel, Hannes Berlin, Angelina Degen, Sandra Freier, Stefan M. Rygol, Burkhart Schraven, Sascha Kahlfuss, Ger van Zandbergen, Andreas J. Müller
BACKGROUND. Antibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalised with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A. METHODS. To probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalised with influenza A or B viruses (IAV or IBV) were analysed for antibody isotype/subclass and Fc-gamma receptor (FcgR) binding by ELISA, bead-based multiplex and NK cell activation assays. RESULTS. Influenza-specific FcgR binding antibodies were elevated in Flu-IVIG infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcgR binding were associated with more favourable outcomes. Flu-IVIG therapy also improved the odds of a more favourable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcgR binding antibody was associated with less favourable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favourable outcome in participants with low levels of anti-IAV Fc-functional antibody. CONCLUSION. These detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT02287467 FUNDING SOURCES. Funding for this research was provided by Subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.
Hillary A. Vanderven, Deborah N. Wentworth, Win Min Han, Heidi Peck, Ian G. Barr, Richard T. Davey, Jr., John H. Beigel, Dominic E. Dwyer, Mamta K. Jain, Brian Angus, Christian T. Brandt, Analia Mykietiuk, Matthew G. Law, James D. Neaton, Stephen J. Kent
Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2–infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.
Jennifer R. Habel, Brendon Y. Chua, Lukasz Kedzierski, Kevin J. Selva, Timon Damelang, Ebene R. Haycroft, Thi H.O. Nguyen, Hui-Fern Koay, Suellen Nicholson, Hayley A. McQuilten, Xiaoxiao Jia, Lilith F. Allen, Luca Hensen, Wuji Zhang, Carolien E. van de Sandt, Jessica A. Neil, Katherine Pragastis, Jillian S.Y. Lau, Jaycee Jumarang, E. Kaitlynn Allen, Fatima Amanant, Florian Krammer, Kathleen M. Wragg, Jennifer A. Juno, Adam K. Wheatley, Hyon-Xhi Tan, Gabrielle Pell, Susan Walker, Jennifer Audsley, Arnold Reynaldi, Irani Thevarajan, Justin T. Denholm, Kanta Subbarao, Miles P. Davenport, P. Mark Hogarth, Dale I. Godfrey, Allen C. Cheng, Steven Y.C. Tong, Katherine Bond, Deborah A. Williamson, James H. McMahon, Paul G. Thomas, Pia S. Pannaraj, Fiona James, Natasha E. Holmes, Olivia C. Smibert, Jason A. Trubiano, Claire L. Gordon, Amy W. Chung, Clare L. Whitehead, Stephen J. Kent, Martha Lappas, Louise C. Rowntree, Katherine Kedzierska
Emerging data indicates an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single cell RNA-sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with S. pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory post-translational modification of peroxisome proliferator-activated receptor ɣ (PPARɣ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARɣ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, subjects residing in areas of high air cadmium levels had increased cadmium concentration in their BAL fluid, increased barrier dysfunction, and showed PPARɣ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARɣ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.
Jennifer L. Larson-Casey, Shanrun Liu, Jennifer M. Pyles, Suzanne E. Lapi, Komal Saleem, Veena B. Antony, Manuel Lora Gonzalez, David K. Crossman, A. Brent Carter
Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with non-severe sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients while the plasminogen activator inhibitor-1 (PAI-1) correlated positively with IL-6. Plg deficiency render mice susceptible to non-severe sepsis induced by cecal ligation and puncture (CLP), showing higher numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis and increased IL-6 and neutrophil extracellular traps (NETs) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen) and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Altogether, Plg/Pla are important host protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.
Juliana P. Vago, Isabella Zaidan, Luiza O. Perucci, Larissa F. Brito, Lívia C.R. Teixeira, Camila M.S. Silva, Thaís C. Miranda, Eliza M. Melo, Alexandre S. Bruno, Celso M. Queiroz-Junior, Michelle A. Sugimoto, Luciana P. Tavares, Laís C. Grossi, Isabela N. Borges, Nagyung Baik, André Talvani, Raphael G. Ferreira, José C. Alves-Filho, Vandack Nobre, Mauro M. Teixeira, Robert J. Parmer, Lindsey A. Miles, Lirlândia P. Sousa
BACKGROUND. After its introduction as standard-of-care for severe COVID-19, dexamethasone has been administered to a large number of patients globally. Detailed knowledge of its impact on the cellular and humoral immune response to SARS-CoV-2 remains scarce. METHODS. We included immunocompetent individuals with 1) mild COVID-19, 2) severe COVID-19 before introduction of dexamethasone treatment, and 3) severe COVID-19 infection treated with dexamethasone from prospective observational cohort studies at Charité-Universitätsmedizin Berlin, Germany. We analyzed SARS-CoV-2 spike-reactive T cells, spike-specific IgG titers as well as serum neutralizing activity against B.1.1.7, B.1.617.2 in samples ranging from two weeks to six months post infection. We also analyzed BA.2 neutralization in sera after booster immunization. RESULTS. Patients with severe COVID-19 and dexamethasone treatment had lower T cell and antibody responses to SARS-CoV-2 compared to patients without dexamethasone treatment in the early phase of disease, which converged in both groups before six months post infection and also post-immunization. Patients with mild COVID-19 had a comparatively lower T cell and antibody response than patients with severe disease, including a lower response to booster-immunization during convalescence. CONCLUSION. Dexamethasone treatment is associated with short-term reduction of T cell and antibody response in severe COVID-19 when compared to the non-treated group, but this difference evens out six months after infection. We confirm higher cellular and humoral immune responses in patients after severe versus mild COVID-19 infection and the concept of improved hybrid immunity upon immunization. TRIAL REGISTRATION.: n/aFunding: Berlin Institute of Health, German Federal Ministry of Education and German Federal Institute for Drugs and Medical Devices
Charlotte Thibeault, Lara Bardtke, Kanika Vanshylla, Veronica Cristianzano, Kirsten A. Eberhardt, Paula Stubbemann, David Hillus, Pinkus Tober-Lau, Parnika Mukherjee, Friederike Münn, Lena J Lippert, Elisa T. Helbig, Tilman Lingscheid, Fridolin Steinbeis, Mirja Mittermaier, Martin Witzenrath, Thomas Zoller, Florian Klein, Leif E. Sander, Florian Kurth
Sosuga virus (SOSV) is a recently discovered paramyxovirus with a single known human case of disease. There has been little laboratory research on SOSV pathogenesis or immunity, and no approved therapeutics or vaccines are available. Here, we report the discovery of human monoclonal antibodies (mAbs) from the circulating memory B cells of the only known human case and survivor of SOSV infection. We isolated six mAbs recognizing the functional attachment protein hemagglutinin-neuraminidase (HN) and 18 mAbs against the fusion (F) protein. The anti-HN mAbs all target the globular head of the HN protein and can be organized into 4 competition-binding groups that exhibit epitope diversity. The anti-F mAbs can be divided into pre- or postfusion conformation-specific categories and further into 8 competition-binding groups. The only antibody in the panel that did not display neutralization activity was the single, postfusion-specific anti-F mAb. Most of the anti-HN mAbs were more potently neutralizing than the anti-F mAbs, with mAbs in one of the HN competition-binding groups possessing ultra-potent (<1 ng/mL) half maximal inhibitory (IC50) virus neutralization values. These findings provide insight into the molecular basis for human antibody recognition of paramyxovirus surface proteins and the mechanisms of SOSV neutralization.
Helen M. Parrington, Nurgun Kose, Erica Armstrong, Laura S. Handal, Summer Diaz, Joseph Reidy, Jinhui Dong, Guillaume B.E. Stewart-Jones, Punya Shrivastava-Ranjan, Shilpi Jain, César G. Albariño, Robert H. Carnahan, James E. Crowe
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