| 1. |
- Cagigi, Alberto, et al.
(author)
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Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination
- 2021
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In: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:22
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Journal article (peer-reviewed)abstract
- Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.
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| 2. |
- Scholz, Saskia, et al.
(author)
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Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways
- 2017
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In: PLoS Pathogens. - : Public library science. - 1553-7366 .- 1553-7374. ; 13:6
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Journal article (peer-reviewed)abstract
- Hantaviruses infect humans via inhalation of virus-contaminated rodent excreta. Infection can cause severe disease with up to 40% mortality depending on the viral strain. The virus primarily targets the vascular endothelium without direct cytopathic effects. Instead, exaggerated immune responses may inadvertently contribute to disease development. Mononuclear phagocytes (MNPs), including monocytes and dendritic cells (DCs), orchestrate the adaptive immune responses. Since hantaviruses are transmitted via inhalation, studying immunological events in the airways is of importance to understand the processes leading to immunopathogenesis. Here, we studied 17 patients infected with Puumala virus that causes a mild form of hemorrhagic fever with renal syndrome (HFRS). Bronchial biopsies as well as longitudinal blood draws were obtained from the patients. During the acute stage of disease, a significant influx of MNPs expressing HLA-DR, CD11c or CD123 was detected in the patients' bronchial tissue. In parallel, absolute numbers of MNPs were dramatically reduced in peripheral blood, coinciding with viremia. Expression of CCR7 on the remaining MNPs in blood suggested migration to peripheral and/or lymphoid tissues. Numbers of MNPs in blood subsequently normalized during the convalescent phase of the disease when viral RNA was no longer detectable in plasma. Finally, we exposed blood MNPs in vitro to Puumala virus, and demonstrated an induction of CCR7 expression on MNPs. In conclusion, the present study shows a marked redistribution of blood MNPs to the airways during acute hantavirus disease, a process that may underlie the local immune activation and contribute to immunopathogenesis in hantavirus-infected patients.
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| 3. |
- Sekine, Takuya, et al.
(author)
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TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells
- 2020
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In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:49
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Journal article (peer-reviewed)abstract
- CD8(+) T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8(+) T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8(+) T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8(+) T cell landscape. Here, we demonstrate that circulating TOX+ CD8(+) T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8(+) T cells generally expressed TOX, whereas naive and early-differentiated memory CD8(+) T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8(+) T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8(+) T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8(+) T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8(+) T cell subsets and not exclusively linked to exhaustion.
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| 4. |
- Sola-Riera, Caries, et al.
(author)
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Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5
- 2019
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In: Cell Reports. - : Cell Press. - 2211-1247. ; 28:8, s. 2124-2139
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Journal article (peer-reviewed)abstract
- Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.
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| 5. |
- Sun, Peifang, et al.
(author)
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Asymptomatic or symptomatic SARS-CoV-2 infection plus vaccination confers increased adaptive immunity to variants of concern
- 2022
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In: iScience. - : Elsevier BV. - 2589-0042. ; 25:10
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Journal article (peer-reviewed)abstract
- The ongoing evolution of SARS-CoV-2 requires monitoring the capability of immune responses to cross-recognize Variants of Concern (VOC). In this cross-sectional study, we examined serological and cell-mediated immune memory to SARS-CoV-2 variants, including Omicron, among a cohort of 18-21-year-old Marines with a history of either asymptomatic or mild SARS-CoV-2 infection 6 to 14 months earlier. Among the 210 participants in the study, 169 were unvaccinated while 41 received 2 doses of mRNA-based COVID-19 vaccines. Vaccination of previously infected participants strongly boosted neutralizing and binding activity and memory B and T cell responses including the recognition of Omicron, compared to infected but unvaccinated participants. Additionally, no measurable differences were observed in immune memory in healthy young adults with previous symptomatic or asymptomatic infections, for ancestral or variant strains. These results provide mechanistic immunological insights into population-based differences observed in immunity against Omicron and other variants among individuals with different clinical histories.
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| 6. |
- Vangeti, Sindhu, et al.
(author)
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Human Blood and Tonsil Plasmacytoid Dendritic Cells Display Similar Gene Expression Profiles but Exhibit Differential Type I IFN Responses to Influenza A Virus Infection
- 2019
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In: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 202:7, s. 2069-2081
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Journal article (peer-reviewed)abstract
- Influenza A virus (IAV) infection constitutes an annual health burden across the globe. Plasmacytoid dendritic cells (PDCs) are central in antiviral defense because of their superior capacity to produce type I IFNs in response to viruses. Dendritic cells (DCs) differ depending on their anatomical location. However, only limited host-pathogen data are available from the initial site of infection in humans. In this study, we investigated how human tonsil PDCs, likely exposed to virus because of their location, responded to IAV infection compared with peripheral blood PDCs. In tonsils, unlike in blood, PDCs are the most frequent DC subset. Both tonsil and blood PDCs expressed several genes necessary for pathogen recognition and immune response, generally in a similar pattern. MxA, a protein that renders cells resistant to IAV infection, was detected in both tonsil and blood PDCs. However, despite steady-state MxA expression and contrary to previous reports, at high IAV concentrations (typically cytopathic to other immune cells), both tonsil and blood PDCs supported IAV infection. IAV exposure resulted in PDC maturation by upregulation of CD86 expression and IFN-alpha secretion. Interestingly, blood PDCs secreted 10-fold more IFN-alpha in response to IAV compared with tonsil PDCs. Tonsil PDCs also had a dampened cytokine response to purified TLR ligands compared with blood PDCs. Our findings suggest that tonsil PDCs may be less responsive to IAV than blood PDCs, highlighting the importance of studying immune cells at their proposed site of function.
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| 7. |
- Vangeti, Sindhu
(author)
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Monocytes and dendritic cells : roles during human influenza and hantavirus infections
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Viruses infect a vast majority of the other species on the planet and rarely leave the host undamaged. Most human viruses need to infect an individual to replicate and disseminate, and must contend with the full force of the human immune system. On the host side, immune cells must withstand virus infection, impairment of function and possible death, to recruit other immune cells, train them against the specific weaknesses of the adversary, muster a host, eliminate the threat, and leave behind a legacy of sentinels who maintain immune memory. Host-pathogen interactions are, in many ways, like warfare. In this thesis, we describe an important early aspect of the human immune response to two re-emerging viruses of global importance– influenza viruses and hantaviruses. Both influenza viruses and hantaviruses are pathogens which enter through the respiratory route but cause vastly different diseases. A strong, proinflammatory innate response is mounted against influenza viruses, but clearance of virus is carried out by antigen-specific adaptive responses. On the other hand, hantavirus disease is only recognizable once the host immune response has injured the vasculature and starting the cascade of hemorrhagic events associated with the disease. In both instances, the adaptive responses rely on efficient programming and specification by innate immune cells including monocytes and dendritic cells (DCs). In this thesis, we investigated the different roles played by monocytes and DCs during human influenza A virus (IAV) and Puumala orthohantavirus infections. We first investigated the functional differences between human plasmacytoid DCs (PDCs) from different tissues in the context of IAV infection. We found that PDCs in blood are more potent producers of the antiviral mediator, IFNα, than tonsil-resident PDCs. Next, we studied the distribution and function of monocytes and DCs in circulation and in the upper respiratory tract during acute influenza disease. We observed that IAV infection resulted in expansion of specialized inflammatory monocytes in circulation which cause inflammation via TNFα. Additionally, monocytes and DCs were recruited to the nasopharynx, where the virus is typically located and we found significant evidence of local TNFα and inflammation. To assess whether monocyte and DC redistribution is also provoked by hantavirus infections, we studied patients suffering from hemorrhagic fever with renal syndrome (HFRS) due to Puumala orthohantavirus. We report a dramatic loss of monocytes and DCs in peripheral circulation during acute HFRS and indications of migratory chemokine signaling. And finally, we assessed the influence of disease severity on monocyte redistribution in acute HFRS. We found that severe HFRS is characterized by depletion of nonclassical monocytes from circulation and impairment of myeloid cell ability to respond to additional TLR stimuli. The findings in this thesis indicate tissue- and pathogen-specific differences in inflammatory behavior of human monocytes and DCs.
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| 8. |
- Vangeti, Sindhu, 1989-, et al.
(author)
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Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection
- 2022
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In: Microbiology Spectrum. - : American Society for Microbiology. - 2165-0497. ; 10:6
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Journal article (peer-reviewed)abstract
- We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels.
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