Infectious disease
Abstract
Filoviruses of the genus Ebolavirus include five species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case-fatality rates can range between 0-90%. In order to understand the molecular basis of these differences it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Non-human primates are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHP. Here we have used HLA-A2 transgenic, NOD-scid-interleukin 2γ receptor knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While significantly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, ‘humanized’ mice recapitulated the case-fatality ratios of different Ebolavirus species in humans. Our findings point out at humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and warrants further investigations on Reston virus pathogenesis in humans.
Authors
Beatriz Escudero-Pérez, Paula Ruibal, Monika Rottstegge, Anja Lüdtke, Julia R. Port, Kristin Hartmann, Sergio Gómez-Medina, Juergen Müller-Guhl, Emily V. Nelson, Susanne Krasemann, Estefanía Rodríguez, César Muñoz-Fontela
Abstract
`NK cell–mediated regulation of antigen-specific T cells can contribute to and exacerbate chronic viral infection, but the protective mechanisms against NK cell–mediated attack on T cell immunity are poorly understood. Here, we show that progranulin (PGRN) can reduce NK cell cytotoxicity through reduction of NK cell expansion, granzyme B transcription, and NK cell–mediated lysis of target cells. Following infection with the lymphocytic choriomeningitis virus (LCMV), PGRN levels increased — a phenomenon dependent on the presence of macrophages and type I IFN signaling. Absence of PGRN in mice (Grn–/–) resulted in enhanced NK cell activity, increased NK cell–mediated killing of antiviral T cells, reduced antiviral T cell immunity, and increased viral burden, culminating in increased liver immunopathology. Depletion of NK cells restored antiviral immunity and alleviated pathology during infection in Grn–/– mice. In turn, PGRN treatment improved antiviral T cell immunity. Taken together, we identified PGRN as a critical factor capable of reducing NK cell–mediated attack of antiviral T cells.
Authors
Anfei Huang, Prashant V. Shinde, Jun Huang, Tina Senff, Haifeng C. Xu, Cassandra Margotta, Dieter Häussinger, Thomas E. Willnow, Jinping Zhang, Aleksandra A. Pandyra, Jörg Timm, Sascha Weggen, Karl S. Lang, Philipp A. Lang
Abstract
Background. HIV-infected patients with poor virologic control and multi-drug resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor. Methods. Approximately 22 billion cells were collected from an elite controller by lymphaphersis and infused within 6 hours into a recipient with a pre-infusion CD4+ T cell count of 10 cells/μL (1%) and HIV plasma viral load of 114,993 copies/mL. Results. Donor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also expressed increased expression of these markers, especially in HIV-specific tetramer positive cells. Conclusions. These results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.
Authors
Stephen A. Migueles, Cheryl Chairez, Siying Lin, Noah V. Gavil, Danielle M. Rosenthal, Milad Pooran, Ven Natarajan, Adam Rupert, Robin Dewar, Tauseef Rehman, Brad T. Sherman, Joseph Adelsberger, Susan Leitman, David Stroncek, Caryn G. Morse, Mark Connors, H. Clifford Lane, Joseph A. Kovacs
Abstract
Idiopathic CD4 lymphocytopenia (ICL) is a clinically heterogeneous immunodeficiency disorder defined by low numbers of circulating CD4+ T cells and increased susceptibility to opportunistic infections. CD8+ T cells, NK, and/or B cells may also be deficient in some patients. To delineate possible pathogenic cellular mechanisms in ICL, we compared immune system development and function in NOD-RAGKO-γcKO (NRG) mice transplanted with hematopoietic stem cells from patients with ICL or healthy controls. CD34+ hematopoietic stem cells from healthy controls and patients with ICL reconstituted NRG mice equally well. In contrast, PBMC transfers into NRG mice identified 2 ICL engraftment phenotypes, reconstituting and nonreconstituting (NR), based on the absence or presence of donor lymphopenia. For patients in the NR group, the distribution of lymphocyte subsets was similar in the peripheral blood of both the patient and the corresponding humanized mice. The NR-ICL group could be further divided into individuals whose CD3+ T cells had defects in proliferation or survival. Thus, ICL cellular pathogenesis might be classified by humanized mouse models into 3 distinct subtypes: (a) T cell extrinsic, (b) T cell intrinsic affecting proliferation, and (c) T cell intrinsic affecting survival. Humanized mouse models of ICL help to delineate etiology and ultimately to guide development of individualized therapeutic strategies.
Authors
Ainhoa Perez-Diez, Xiangdong Liu, Virginia Sheikh, Gregg Roby, David F. Stroncek, Irini Sereti
Abstract
Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti–Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.
Authors
Keven M. Robinson, Krishnaveni Ramanan, Joshua M. Tobin, Kara L. Nickolich, Matthew J. Pilewski, Nicole L. Kallewaard, Bret R. Sellman, Taylor S. Cohen, John F. Alcorn
Abstract
Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes highly lethal henipavirus encephalitis in humans. Survivors develop various neurologic sequelae, including late-onset and relapsing encephalitis, several months up to several years following initial infection. However, the underlying pathology and disease mechanisms of persistent neurologic complications remain unknown. Here, we demonstrate persistent NiV infection in the brains of grivets that survived experimental exposure to NiV. Encephalitis affected the entire brains, with the majority of NiV detected in the neurons and microglia of the brainstems, cerebral cortices, and cerebella. We identified the vascular endothelium in the brain as an initial target of NiV infection during the acute phase of disease, indicating a primary path of entry for NiV into the brain. Notably, we were unable to detect NiV anywhere else except the brains in the examined survivors. Our findings indicate that late-onset and relapsing encephalitis of NiV in human survivors may be due to viral persistence in the brain and shed light on the pathogenesis of chronic henipavirus encephalitis.
Authors
Jun Liu, Kayla M. Coffin, Sara C. Johnston, April M. Babka, Todd M. Bell, Simon Y. Long, Anna N. Honko, Jens H. Kuhn, Xiankun Zeng
Abstract
Influenza-associated mortality continues to occur annually despite available antiviral therapies. New therapies that improve host immunity could reduce influenza virus disease burden. Targeting macrophage migration inhibitory factor (MIF) has improved the outcomes of certain inflammatory diseases, but its role in influenza viral infection is unclear. Here, we showed that, during influenza viral infection, Mif-deficient mice have less inflammation, viral load, and mortality compared with WT control mice; conversely, Tg mice, overexpressing Mif in alveolar epithelial cells, had higher inflammation, viral load, and mortality. Antibody-mediated blockade of MIF in WT mice during influenza viral infection improved their survival. Mif-deficient murine lungs showed reduced levels of parkin, a mitophagy protein that negatively regulates antiviral signaling, prior to infection and augmented antiviral type I/III IFN levels in the airspaces after infection as compared with WT lungs. Additionally, in vitro assays with human lung epithelial cells showed that treatment with recombinant human MIF increased the percentage of influenza virus–infected cells. In conclusion, our study reveals that MIF impairs antiviral host immunity and increases inflammation during influenza infection and suggests that targeting MIF could be therapeutically beneficial during influenza viral infection.
Authors
Candice A. Smith, Daniel J. Tyrell, Upasana A. Kulkarni, Sherri Wood, Lin Leng, Rachel L. Zemans, Richard Bucala, Daniel R. Goldstein
Abstract
Tuberculosis patients and mice infected with live Mycobacterium tuberculosis (Mtb) accumulate high numbers of myeloid-derived suppressor cells (MDSCs). Here, we hypothesized that also dead Mtb vaccines may induce MDSCs that could impair the efficacy of vaccination. We found that repeated injections of Mtb vaccines (heat-killed Mtb in Incomplete Freund's Adjuvant, like Montanide) but not single or control vaccines without Mtb strongly expanded CD11b+ myeloid cells in the spleen, that suppressed T cell proliferation and killing ex vivo. Dead Mtb vaccination induced the generation of CD11b+ Ly-6Chigh CD115+ iNOS/Nos2+ monocytic MDSCs (M-MDSCs) upon application of inflammatory or microbial activation signals. In vivo these M-MDSCs positioned strategically in the spleen by infiltrating the splenic bridging channels and white pulp areas. Notably, within 6 to 24 hours in a Nos2-dependent fashion they produced NO to rapidly kill conventional and plasmacytoid dendritic cells (cDCs, pDCs) while, surprisingly, sparing T cells in vivo. Thus, we demonstrate that Mtb vaccine induced M-MDSCs to not directly suppress T cell in vivo but, instead, M-MDSCs directly target DC subpopulations thereby indirectly suppressing effector T cell responses. Collectively, we demonstrate that Mtb booster vaccines induce M-MDSCs in the spleen that can be activated to kill DCs cautioning to thoroughly investigate MDSC formation in individuals after Mtb vaccination in clinical trials.
Authors
Eliana Ribechini, Ina Eckert, Andreas Beilhack, Nelita Du Plessis, Gerhard Walzl, Ulrike Schleicher, Uwe Ritter, Manfred B. Lutz
Abstract
Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.
Authors
Anna Zychlinsky Scharff, Matthieu Rousseau, Livia Lacerda Mariano, Tracy Canton, Camila Rosat Consiglio, Matthew L. Albert, Magnus Fontes, Darragh Duffy, Molly A. Ingersoll
Abstract
Virulent protozoans named Leishmania in tropical and subtropical areas produce devastating diseases by exploiting host immune responses. Amastigotes of Leishmania amazonensis stimulate macrophages to express CD200, an immunomodulatory ligand, which binds to its cognate receptor (CD200R) and inhibits the inducible nitric oxide synthase and nitric oxide (iNOS/NO) signaling pathways, thereby promoting intracellular survival. However, the mechanisms underlying CD200 induction in macrophages remain largely unknown. Here, we show that phagocytosis-mediated internalization of L. amazonensis amastigotes following activation of endosomal TLR9/MyD88/TRIF signaling is critical for inducing CD200 in infected macrophages. We also demonstrate that Leishmania microvesicles containing DNA fragments activate TLR9-dependent CD200 expression, which inhibits the iNOS/NO pathway and modulates the course of L. amazonensis infection in vivo. These findings demonstrate that Leishmania exploits TLR-signaling pathways not only to inhibit macrophage microbicidal function, but also to evade host systemic immune responses, which has many implications in the severity of the disease.
Authors
Ismael P. Sauter, Katerine G. Madrid, Josiane B. de Assis, Anderson Sá-Nunes, Ana C. Torrecilhas, Daniela I. Staquicini, Renata Pasqualini, Wadih Arap, Mauro Cortez
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