scholarly journals Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nicolas Baillet ◽  
Stéphanie Reynard ◽  
Emeline Perthame ◽  
Jimmy Hortion ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
T Cell ◽  
Multiorgan Failure ◽  
Severe Disease ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Diagnostic Tools ◽  
Lassa Virus ◽  
Full Characterization ◽  
Cell Responses

AbstractLassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.

scholarly journals Identification of Common CD8+ T Cell Epitopes from Lassa Fever Survivors in Nigeria and Sierra Leone

2020 ◽  
Vol 94 (12) ◽  
Author(s):  
Saori Sakabe ◽  
Jessica N. Hartnett ◽  
Nhi Ngo ◽  
Augustine Goba ◽  
Mambu Momoh ◽  
...  
Keyword(s):  
T Cell ◽  
West Africa ◽  
Sierra Leone ◽  
T Cell Responses ◽  
Lassa Fever ◽  
Health Concern ◽  
Lassa Virus ◽  
T Cell Epitopes ◽  
Virus Surface ◽  
Cell Responses

ABSTRACT Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity. IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.

scholarly journals Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
David W. Hawman ◽  
Kimberly Meade-White ◽  
Elaine Haddock ◽  
Rumi Habib ◽  
Dana Scott ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Severe Disease ◽  
Small Animal ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Type I ◽  
Crimean Congo Hemorrhagic Fever ◽  
Cell Responses

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying. IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

scholarly journals Severe Human Lassa Fever Is Characterized by Nonspecific T-Cell Activation and Lymphocyte Homing to Inflamed Tissues

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Julia R. Port ◽  
David M. Wozniak ◽  
Lisa Oestereich ◽  
Elisa Pallasch ◽  
Beate Becker-Ziaja ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Clinical Immunology ◽  
T Cell Responses ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Effector T Cell ◽  
Cell Responses ◽  
Specific Effector

ABSTRACT Lassa fever (LF) is a zoonotic viral hemorrhagic fever caused by Lassa virus (LASV), which is endemic to West African countries. Previous studies have suggested an important role for T-cell-mediated immunopathology in LF pathogenesis, but the mechanisms by which T cells influence disease severity and outcome are not well understood. Here, we present a multiparametric analysis of clinical immunology data collected during the 2017–2018 Lassa fever outbreak in Nigeria. During the acute phase of LF, we observed robust activation of the polyclonal T-cell repertoire, which included LASV-specific and antigenically unrelated T cells. However, severe and fatal LF cases were characterized by poor LASV-specific effector T-cell responses. Severe LF was also characterized by the presence of circulating T cells with homing capacity to inflamed tissues, including the gut mucosa. These findings in LF patients were recapitulated in a mouse model of LASV infection, in which mucosal exposure resulted in remarkably high lethality compared to skin exposure. Taken together, our findings indicate that poor LASV-specific T-cell responses and activation of nonspecific T cells with homing capacity to inflamed tissues are associated with severe LF. IMPORTANCE Lassa fever may cause severe disease in humans, in particular in areas of endemicity like Sierra Leone and Nigeria. Despite its public health importance, the pathophysiology of Lassa fever in humans is poorly understood. Here, we present clinical immunology data obtained in the field during the 2018 Lassa fever outbreak in Nigeria indicating that severe Lassa fever is associated with activation of T cells antigenically unrelated to Lassa virus and poor Lassa virus-specific effector T-cell responses. Mechanistically, we show that these bystander T cells express defined tissue homing signatures that suggest their recruitment to inflamed tissues and a putative role of these T cells in immunopathology. These findings open a window of opportunity to consider T-cell targeting as a potential postexposure therapeutic strategy against severe Lassa fever, a hypothesis that could be tested in relevant animal models, such as nonhuman primates.

scholarly journals Strong HLA Class I–Restricted T Cell Responses in Dengue Hemorrhagic Fever: A Double‐Edged Sword?

2001 ◽  
Vol 184 (11) ◽  
pp. 1369-1373 ◽  
Author(s):  
Hsin Loke ◽  
Delia B. Bethell ◽  
C. X. T. Phuong ◽  
Minh Dung ◽  
Joerg Schneider ◽  
...  
Keyword(s):  
T Cell ◽  
Dengue Hemorrhagic Fever ◽  
T Cell Responses ◽  
Hla Class I ◽  
Hemorrhagic Fever ◽  
Class I ◽  
Cell Responses

scholarly journals Human Dendritic Cells Infected with the Nonpathogenic Mopeia Virus Induce Stronger T-Cell Responses than Those Infected with Lassa Virus

2011 ◽  
Vol 85 (16) ◽  
pp. 8293-8306 ◽  
Author(s):  
D. Pannetier ◽  
S. Reynard ◽  
M. Russier ◽  
A. Journeaux ◽  
N. Tordo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Lassa Virus ◽  
Cell Responses ◽  
Human Dendritic Cells

scholarly journals Dengue Virus and Vaccines: How Can DNA Immunization Contribute to This Challenge?

2021 ◽  
Vol 3 ◽  
Author(s):  
Ada Maria Barcelos Alves ◽  
Simone Morais Costa ◽  
Paolla Beatriz Almeida Pinto
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dengue Virus ◽  
Antibody Production ◽  
Dna Vaccines ◽  
Yellow Fever Virus ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Severe Dengue ◽  
Cell Responses

Dengue infections still have a tremendous impact on public health systems in most countries in tropical and subtropical regions. The disease is systemic and dynamic with broad range of manifestations, varying from mild symptoms to severe dengue (Dengue Hemorrhagic Fever and Dengue Shock Syndrome). The only licensed tetravalent dengue vaccine, Dengvaxia, is a chimeric yellow fever virus with prM and E genes from the different dengue serotypes. However, recent results indicated that seronegative individuals became more susceptible to develop severe dengue when infected after vaccination, and now WHO recommends vaccination only to dengue seropositive people. One possibility to explain these data is the lack of robust T-cell responses and antibody-dependent enhancement of virus replication in vaccinated people. On the other hand, DNA vaccines are excellent inducers of T-cell responses in experimental animals and it can also elicit antibody production. Clinical trials with DNA vaccines have improved and shown promising results regarding the use of this approach for human vaccination. Therefore, in this paper we review preclinical and clinical tests with DNA vaccines against the dengue virus. Most of the studies are based on the E protein since this antigen is the main target for neutralizing antibody production. Yet, there are other reports with DNA vaccines based on non-structural dengue proteins with protective results, as well. Combining structural and non-structural genes may be a solution for inducing immune responses aging in different infection moments. Furthermore, DNA immunizations are also a very good approach in combining strategies for vaccines against dengue, in heterologous prime/boost regimen or even administering different vaccines at the same time, in order to induce efficient humoral and cellular immune responses.

scholarly journals Cross-Reactive T-Cell Responses to the Nonstructural Regions of Dengue Viruses among Dengue Fever and Dengue Hemorrhagic Fever Patients in Malaysia

2007 ◽  
Vol 14 (8) ◽  
pp. 969-977 ◽  
Author(s):  
Ramapraba Appanna ◽  
Tan Lian Huat ◽  
Lucy Lum Chai See ◽  
Phoay Lay Tan ◽  
Jamuna Vadivelu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dengue Virus ◽  
Dengue Fever ◽  
Dengue Hemorrhagic Fever ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
T Cell Response ◽  
Cell Responses ◽  
Number Of Patients

ABSTRACT Dengue virus infections are a major cause of morbidity and mortality in tropical and subtropical areas in the world. Attempts to develop effective vaccines have been hampered by the lack of understanding of the pathogenesis of the disease and the absence of suitable experimental models for dengue viral infection. The magnitude of T-cell responses has been reported to correlate with dengue disease severity. Sixty Malaysian adults with dengue viral infections were investigated for their dengue virus-specific T-cell responses to 32 peptides antigens from the structural and nonstructural regions from a dengue virus isolate. Seventeen different peptides from the C, E, NS2B, NS3, NS4A, NS4B, and NS5 regions were found to evoke significant responses in a gamma interferon enzyme-linked immunospot (ELISPOT) assay of samples from 13 selected patients with dengue fever (DF) and dengue hemorrhagic fever (DHF). NS3 and predominantly NS3422-431 were found to be important T-cell targets. The highest peaks of T-cell responses observed were in responses to NS3422-431 and NS5563-571 in DHF patients. We also found almost a sevenfold increase in T-cell response in three DHF patients compared to three DF patient responses to peptide NS3422-431. A large number of patients' T cells also responded to the NS2B97-106 region. The ELISPOT analyses also revealed high frequencies of T cells that recognize both serotype-specific and cross-reactive dengue virus antigens in patients with DHF.

scholarly journals From Genome-Based In Silico Predictions to Ex Vivo Verification of Leprosy Diagnosis

2009 ◽  
Vol 16 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Annemieke Geluk ◽  
John S. Spencer ◽  
Kidist Bobosha ◽  
Maria C. V. Pessolani ◽  
Geraldo M. B. Pereira ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Immunoglobulin M ◽  
Diagnostic Tools ◽  
Cell Responses ◽  
Household Contacts ◽  
Diagnostic Potential ◽  
Human T Cell ◽  
Leprosy Patients

ABSTRACT The detection of hundreds of thousands of new cases of leprosy every year suggests that transmission of Mycobacterium leprae infection still continues. Unfortunately, tools for identification of asymptomatic disease and/or early-stage M. leprae infection (likely sources of transmission) are lacking. The recent identification of M. leprae-unique genes has allowed the analysis of human T-cell responses to novel M. leprae antigens. Antigens with the most-promising diagnostic potential were tested for their ability to induce cytokine secretion by using peripheral blood mononuclear cells from leprosy patients and controls in five different areas where leprosy is endemic; 246 individuals from Brazil, Nepal, Bangladesh, Pakistan, and Ethiopia were analyzed for gamma interferon responses to five recombinant proteins (ML1989, ML1990, ML2283, ML2346, and ML2567) and 22 synthetic peptides. Of these, the M. leprae-unique protein ML1989 was the most frequently recognized and ML2283 the most specific for M. leprae infection/exposure, as only a limited number of tuberculosis patients responded to this antigen. However, all proteins were recognized by a significant number of controls in areas of endemicity. T-cell responses correlated with in vitro response to M. leprae, suggesting that healthy controls in areas where leprosy is endemic are exposed to M. leprae. Importantly, 50% of the healthy household contacts and 59% of the controls in areas of endemicity had no detectable immunoglobulin M antibodies to M. leprae-specific PGL-I but responded in T-cell assays to ≥1 M. leprae protein. T-cell responses specific for leprosy patients and healthy household contacts were observed for ML2283- and ML0126-derived peptides, indicating that M. leprae peptides hold potential as diagnostic tools. Future work should concentrate on the development of a sensitive and field-friendly assay and identification of additional peptides and proteins that can induce M. leprae-specific T-cell responses.

scholarly journals Long-Term Elevated Inflammatory Protein Levels in Asymptomatic SARS-CoV-2 Infected Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Liina Tserel ◽  
Piia Jõgi ◽  
Paul Naaber ◽  
Julia Maslovskaja ◽  
Annika Häling ◽  
...  
Keyword(s):  
T Cell ◽  
Severe Disease ◽  
T Cell Responses ◽  
Viral Neutralization ◽  
Neutralization Capacity ◽  
N Protein ◽  
Cell Responses ◽  
Wide Range ◽  
Asymptomatic Individuals

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.

scholarly journals CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent

2021 ◽  
Author(s):  
Iulia Popescu ◽  
Mark E. Snyder ◽  
Carlo J. Iasella ◽  
Stefanie J. Hannan ◽  
Ritchie Koshy ◽  
...  
Keyword(s):  
T Cell ◽  
Severe Disease ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Infliximab Treatment ◽  
Mild Disease ◽  
Cell Responses ◽  
Activation Induced Cell Death ◽  
Tnf Α

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.

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