Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti–spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV–induced MCP1 and IL-8 production by human monocyte–derived wound-healing macrophages, whereas blockade of FcγR reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury.
Li Liu, Qiang Wei, Qingqing Lin, Jun Fang, Haibo Wang, Hauyee Kwok, Hangying Tang, Kenji Nishiura, Jie Peng, Zhiwu Tan, Tongjin Wu, Ka-Wai Cheung, Kwok-Hung Chan, Xavier Alvarez, Chuan Qin, Andrew Lackner, Stanley Perlman, Kwok-Yung Yuen, Zhiwei Chen
Spine implant infections portend disastrous outcomes, as diagnosis is challenging and surgical eradication is at odds with mechanical spinal stability. Current imaging modalities can detect anatomical alterations and anomalies but cannot differentiate between infection and aseptic loosening, diagnose specific pathogens, or delineate the extent of an infection. Herein, a fully human monoclonal antibody 1D9, recognizing the immunodominant staphylococcal antigen A on the surface of Staphylococcus aureus, was assessed as a nuclear and fluorescent imaging probe in a preclinical model of S. aureus spinal implant infection, utilizing bioluminescently labeled bacteria to confirm the specificity and sensitivity of this targeting. Postoperative mice were administered 1D9 probe dual labeled with 89-zirconium (89Zr) and a bars represent SEM dye (NIR680) (89Zr-NIR680-1D9), and PET-CT and in vivo fluorescence and bioluminescence imaging were performed. The 89Zr-NIR680-1D9 probe accurately diagnosed both acute and subacute implant infection and permitted fluorescent image-guided surgery for selective debridement of infected tissue. Therefore, a single probe could noninvasively diagnose an infection and facilitate image-guided surgery to improve the clinical management of implant infections.
Stephen D. Zoller, Howard Y. Park, Tove Olafsen, Charles Zamilpa, Zachary D.C. Burke, Gideon Blumstein, William L. Sheppard, Christopher D. Hamad, Kellyn R. Hori, Jen-Chieh Tseng, Julie Czupryna, Craig McMannus, Jason T. Lee, Mafalda Bispo, Francisco Romero Pastrana, Elisa J.M. Raineri, Jeffery F. Miller, Lloyd S. Miller, Jan Maarten van Dijl, Kevin P. Francis, Nicholas M. Bernthal
The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ T helper (Th) cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells, but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we employed a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphocytes (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity prior to lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.
Paulette A. Krishack, Tyler J. Louviere, Trevor S. Decker, Timothy G. Kuzel, Jared A. Greenberg, Daniel F. Camacho, Cara L. Hrusch, Anne I. Sperling, Philip A. Verhoef
BACKGROUND. The West African Ebola virus epidemic from 2014–2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. METHODS. Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. RESULTS. We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a “chemokine storm.” The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. CONCLUSION. The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. FUNDING. French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.
Stéphanie Reynard, Alexandra Journeaux, Emilie Gloaguen, Justine Schaeffer, Hugo Varet, Natalia Pietrosemoli, Mathieu Mateo, Nicolas Baillet, Cédric Laouenan, Hervé Raoul, Jimmy Mullaert, Sylvain Baize
Matrix metalloproteinase-9 (MMP-9) cleaves various proteins to regulate inflammatory and injury responses. However, MMP-9’s activities during influenza A viral (IAV) infections are incompletely understood. Herein, plasma MMP-9 levels were increased in patients with pandemic H1N1 and seasonal IAV infections. MMP-9 lung levels were increased and localized to airway epithelial cells and leukocytes in H1N1-infected WT murine lungs. H1N1-infected Mmp-9–/– mice had lower mortality rates, reduced weight loss, lower lung viral titers, and reduced lung injury, along with lower E-cadherin shedding in bronchoalveolar lavage fluid (BALF) samples than WT mice. H1N1-infected Mmp-9–/– mice had an altered immune response to IAV with lower BALF PMN and macrophage counts, higher Th1-like CD4+ and CD8+ T cell subsets, lower T regulatory cell counts, reduced lung type I interferon levels, and higher lung interferon-γ levels. Mmp-9 bone marrow–chimera studies revealed that Mmp-9 deficiency in lung parenchymal cells protected mice from IAV-induced mortality. H1N1-infected Mmp-9–/– lung epithelial cells had lower viral titers than H1N1-infected WT cells in vitro. Thus, H1N1-infected Mmp-9–/– mice are protected from IAV-induced lung disease due to a more effective adaptive immune response to IAV and reduced epithelial barrier injury due partly to reduced E-cadherin shedding. Thus, we believe that MMP-9 is a novel therapeutic target for IAV infections.
Joselyn Rojas-Quintero, Xiaoyun Wang, Jennifer Tipper, Patrick R. Burkett, Joaquin Zuñiga, Amit R. Ashtekar, Francesca Polverino, Amit Rout, Ilyas Yambayev, Carmen Hernández, Luis Jimenez, Gustavo Ramírez, Kevin S. Harrod, Caroline A. Owen
Anemia is a major complication of malaria, driven largely by loss of uninfected RBCs during infection. RBC clearance through loss of complement regulatory proteins (CRPs) is a significant contributor to anemia in Plasmodium falciparum infection, but its role in Plasmodium vivax infection is unknown. CRP loss increases RBC susceptibility to macrophage clearance, a process that is also regulated by CD47. We compared CRPs and CD47 expression on infected and uninfected RBCs in adult patients with vivax and falciparum malaria and different anemia severities from Papua, Indonesia. Complement activation and parasite-specific complement-fixing antibodies were measured by ELISA. Levels of CR1 and CD55 were reduced in severe anemia in both falciparum and vivax malaria. Loss of CRPs and CD47 was restricted to uninfected RBCs, with infected RBCs having higher expression. There was no association among complement-fixing antibodies, complement activation, and CRP loss. Our findings demonstrate that CRP loss is a pan-species, age-independent mechanism of malarial anemia. Higher levels of CRP and CD47 expression on infected RBCs suggest that parasites are protected from complement-mediated destruction and macrophage clearance. Lack of associations between protective antibodies and CRP loss highlight that complement pathogenic and protective pathways are distinct mechanisms during infection.
Damian A. Oyong, Enny Kenangalem, Jeanne R. Poespoprodjo, James G. Beeson, Nicholas M. Anstey, Ric N. Price, Michelle J. Boyle
BACKGROUND. An intricate fetal-maternal immune crosstalk during pregnancy is essential for a healthy birth. Hence, the infection-induced alterations of maternal immunity often lead to adverse outcomes for mother and/or child. The emergence of Zika virus (ZIKV) infection in pregnant women has been associated with more than 3,000 cases of microcephaly and nervous system malformations. METHODS. To explore the potential correlation of ZIKV-induced alteration of maternal immunity with fetal abnormalities, we performed extensive sera immunoprofiling of 74 pregnant women: 30 symptomatic ZIKV+ pregnant patients and 30 healthy pregnant controls in ZIKV-endemic Rio de Janeiro, along with 14 healthy pregnant controls in non-endemic Los Angeles. RESULTS. Extensive multiplexing analysis of 69 cytokines revealed that CXCL10, CCL2, and CCL8 chemokines were specifically associated with symptomatic ZIKV+ infection during pregnancy, and distinct immunoprofiles were detected at different trimesters in ZIKV-infected pregnant women. Intriguingly, the high CCL2 level and its inverse correlation with CD163, TNFRSF1A, and CCL22 levels was apparently associated with ZIKV-induced abnormal birth. CONCLUSION. Our findings provide insights into the alteration of ZIKV-elicited maternal immunity, serving as a potential clinical biomarker platform. FUNDING. NIH (CA200422, CA180779, DE023926, AI073099, AI116585, AI129496, AI140705, AI069120, AI056154, AI078389, AI28697, AI40718 and AI129534-01), Hastings Foundation, Fletcher Jones Foundation, Departamento de Ciência e Tecnologia (DECIT/25000.072811/2016-17) do Ministério da Saúde do Brasil, and Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior CAPES/88887.116627/2016-01.
Suan-Sin Foo, Weiqiang Chen, Yen Chan, Wai-Suet Lee, Shin-Ae Lee, Genhong Cheng, Karin Nielsen-Saines, Patrícia Brasil, Jae U. Jung
Innate immune responses that control early Mtb infection are poorly understood, but understanding these responses may inform vaccination and immunotherapy strategies. Innate T cells that respond to conserved bacterial ligands such as mucosal-associated invariant T (MAIT) and γδ T cells are prime candidates to mediate these early innate responses but have not been examined in subjects who have been recently exposed to Mtb. We recruited a cohort living in the same household with an active tuberculosis (TB) case and examined the abundance and functional phenotypes of 3 innate T cell populations reactive to M. tuberculosis: γδ T, invariant NK T (iNKT), and MAIT cells. Both MAIT and γδ T cells from subjects with Mtb exposure display ex vivo phenotypes consistent with recent activation. However, both MAIT and γδ T cell subsets have distinct response profiles, with CD4+ MAIT and γδ T cells accumulating after infection. Examination of exposed but uninfected contacts demonstrates that resistance to initial infection is accompanied by robust MAIT cell CD25 expression and granzyme B production coupled with a depressed CD69 and IFNγ response. Finally, we demonstrate that MAIT cell abundance and function correlate with the abundance of specific gut microbes, suggesting that responses to initial infection may be modulated by the intestinal microbiome.
Charles Kyriakos Vorkas, Matthew F. Wipperman, Kelin Li, James Bean, Shakti K. Bhattarai, Matthew Adamow, Phillip Wong, Jeffrey Aubé, Marc Antoine Jean Juste, Vanni Bucci, Daniel W. Fitzgerald, Michael S. Glickman
Otits media (OM) is the most frequent indication for antimicrobial prescription to US children. Streptococcus pneumoniae (S. pneumoniae) remains one of the most common pathogens causing OM. Successful eradication of S. pneumoniae in the middle ear can be achieved by adhering to a 7–10 day regimen of oral antibiotics. However, oral drug administration is challenging for parents. Lack of adherence has been associated with treatment failure or early relapse. To overcome this challenge, we used a noninvasive formulation to achieve high transtympanic antibiotic flux and cured S. pneumoniae OM in chinchillas. The formulation consists of a thermosensitive in situ gelling hydrogel, chemical permeation enhancers, and an antibiotic. The direct transport of drugs into the middle ear produced high concentrations of ciprofloxacin (in the range of hundreds of micrograms per milliliter) within the first 24 hours of administration. Drug concentrations above the minimum inhibitory concentration (MIC) for S. pneumoniae were sustained throughout the 7-day treatment. S. pneumoniae OM in a chinchilla model was successfully eradicated, without causing tissue toxicity. Transtympanic delivery minimized systemic drug exposure, as evidenced by undetectable levels in blood, measured by high-performance liquid chromatography.
Rong Yang, Vishakha Sabharwal, Nadya Shlykova, Obiajulu S. Okonkwo, Stephen I. Pelton, Daniel S. Kohane
The robust regenerative potential of skeletal muscle is imperative for the maintenance of tissue function across a host of potential insults including exercise, infection, and trauma. The highly coordinated action of multiple immune populations, especially macrophages, plays an indispensable role in guiding this reparative program. However, it remains unclear how skeletal muscle repair proceeds in a chronically inflamed setting, such as infection, where an active immune response is already engaged. To address this question, we used a cardiotoxin injury model to challenge the reparative potential of chronically infected muscle. Compared with regenerating naive skeletal muscle, infected skeletal muscle exhibited multiple indicators of delayed muscle repair including a divergent morphologic response to injury and dysregulated expression of myogenic regulatory factors. Further, using both flow cytometric and single-cell RNA sequencing approaches, we show that reduced macrophage heterogeneity due to delayed emergence of restorative subsets underlies dysfunctional tissue repair during chronic infection. Our findings highlight how the preexisting inflammatory environment within tissue alters reparative immunity and ultimately the quality of tissue regeneration.
Richard M. Jin, Jordan Warunek, Elizabeth A. Wohlfert
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