Treatment With Anti-C5a Antibody Improves the Outcome of H7N9 Virus Infection in African Green Monkeys

Sun, Shihui; Zhao, Guangyu; Chenfeng, Liu; Fan, Wei; Zhou, Xiaojun; Zeng, Lin; Guo, Yan; Kou, Zheng; Yu, Hong; Li, Junfeng; Wang, Renxi; Li, Yan; Schneider, Conny; Habel, Maria; Riedemann, Niels C.; Du, Lanying; Jiang, Shibo; Guo, Renfeng; Zhou, Yusen

doi:10.1093/cid/ciu887

Cited by 71 publications

(78 citation statements)

References 32 publications

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“…In addition, severe inflammatory responses and their associated organ damage during avian H5N1 and H1N1 viral infections have also been linked to complement activation, especially the overproduction of C5a 46,47 . Along these lines, a monoclonal antibody raised against human C5a greatly attenuated H7N9-induced lung damage in non-human primates, reducing the viral load and the levels of several different cytokines in this setting 48 . The same antibody is currently being tested in patients with early abdominal or pulmonary septic organ dysfunction 49 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Sepsis and septic shock

Hotchkiss

Moldawer

Opal

et al. 2016

Nat Rev Dis Primers

1,018

884

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For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15–25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30–50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Sepsis and septic shock

Hotchkiss

Moldawer

Opal

et al. 2016

Nat Rev Dis Primers

1,018

884

View full text Add to dashboard Cite

show abstract

“…Substantial studies have shown that ALI occurring after HPAIV H5N1 virus infection is closely related to an abnormal host innate immune response [26][27][28][29]. Since the complement system plays a key role in the innate immunity and aberrant complement activation contributes to ALI caused by influenza virus [30][31][32], we then determined whether change in PA-X expression could affect the expression of complement-derived peptides C3a and C5a that are the central effectors of the complement system [30][31][32][33][34][35][36][37] (Fig. 4).…”

Section: Reduced Pa-x Expression Results In the Excessive C3a And C5amentioning

confidence: 99%

PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice

Zhao

et al. 2016

Med Microbiol Immunol

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PA-X is a novel discovered accessory protein encoded by the PA mRNA. Our previous study demonstrated that PA-X decreases the virulence of a highly pathogenic H5N1 strain A/Chicken/Jiangsu/k0402/2010 in mice. However, the underlying mechanism of virulence attenuation associated with PA-X is still unknown. In this study, we compared two PA-X-deficient mutant viruses and the parental virus in terms of induction of pathology and manipulation of host response in the mouse lung, stimulation of cell death and PA nuclear accumulation. We first found that down-regulated PA-X expression markedly aggravated the acute lung injury of the infected mice early on day 1 post-infection (p.i.). We then determined that loss of PA-X expression induced higher levels of cytokines, chemokines and complement-derived peptides (C3a and C5a) in the lung, especially at early time point's p.i. In addition, in vitro assays showed that the PA-X-deficient viruses enhanced cell death and increased expression of reactive oxygen species (ROS) in mammalian cells. Moreover, we also found that PA nuclear accumulation of the PA-X-null viruses accelerated in MDCK cells. These results demonstrate that PA-X decreases the level of complement components, ROS, cell death and inflammatory response, which may together contribute to the alleviated lung injury and the attenuation of the virulence of H5N1 virus in mice.

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“…Of note, a serial of pathotypings including higher virus load, excess chemokine/cytokine response and functional impairments of B and T cells have been observed in H7N9 infection cases, particularly in fatal cases [33,34]. The aberrant inflammatory response in H7N9-infected animals could be reversed partially by anti-C5a, indicating a hyperactivated complement mediated [35]. Therefore, the strong MBL-H7N9 virus interaction whereas limited effects on viral HA-receptor binding or NA-mediated releasing, might amplify immune dysfunctions in vivo and confer clinical severity of H7N9 infection via activating complement pathway and further investigates are needed.…”

Section: Discussionmentioning

confidence: 99%

Limited effect of recombinant human mannose-binding lectin on the infection of novel influenza A (H7N9) virus in vitro

Guo

Cao

Qin

et al. 2015

Biochemical and Biophysical Research Communications

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Mannose-binding lectin (MBL), a pattern-recognition molecule in serum, recognizes specific hexose sugars rich in mannose and N-acetylglucosamine on bacterium, yeasts, viruses as well as apoptotic cells. It has been well-identified that MBL has antiviral effects via binding to seasonal influenza H1 and H3 subtype viruses. Influenza A (H7N9) virus, a novel reassortant virus to human population, possesses the surface hemagglutinin (HA) and neuraminidase (NA) genes from duck and wild-bird influenza viruses and internal genes from poultry H9N2 viruses. As of Dec 7th, 2014, a total of 467 human infections and 183 fatal cases have been identified. Here, recombinant human (rh) MBL was tested for its binding and effects on hemagglutination inhibition (HI) and NA activity inhibition (NAI) of avian H7N9, H9N2 and human H3N2 viruses. We discovered that rhMBL exhibited a strong binding to H7N9 virus as human H3N2 did at high virus titers. However, it performed a significantly weaker HI activity effect on H7N9 comparing to those of H3N2 and H9N2, even at a much higher concentration (3.67 ± 0.33 vs. 0.026 ± 0.001 and 0.083 ± 0.02 μg/mL, respectively). Similarly, minor NAI effect of rhMBL, even at up to 10 μg/mL, was found on H7N9 virus while it displayed significant effects on both H3N2 and H9N2 at a lowest concentration of 0.0807 ± 0.009 and 0.0625 μg/mL, respectively. The HI and NAI effects of rhMBL were calcium-dependent and mediated by lectin domain. Our findings suggest that MBL, the host innate molecule, has differential interference effects with human and avian influenza virus and limited antiviral effect against H7N9 virus.

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Treatment With Anti-C5a Antibody Improves the Outcome of H7N9 Virus Infection in African Green Monkeys

Abstract: Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia.

Cited by 71 publications

References 32 publications

Sepsis and septic shock

Sepsis and septic shock

PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice

Limited effect of recombinant human mannose-binding lectin on the infection of novel influenza A (H7N9) virus in vitro

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