Cytokine Kinetics and Other Host Factors in Response to Pneumococcal Pulmonary Infection in Mice

Bergeron, Yves; Ouellet, Nathalie; Deslauriers, Anne-Marie; Simard, Marie; Olivier, Martin; Bergeron, Michel G.

doi:10.1128/iai.66.3.912-922.1998

Cited by 198 publications

(94 citation statements)

References 88 publications

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“…Nevertheless, the identification of endothelial cells as central orchestrators of early innate immune-mediated inflammation is of fundamental interest and has broad implications for treating multiple diseases. The contribution of aberrant proinflammatory cytokine and chemokine production to pathogenesis has been reported for viral and bacterial diseases, including HIV (Stacey et al, 2009), Hantavirus (Borges et al, 2006), severe acute respiratory syndrome (SARS) (Thiel and Weber, 2008), and pneumococcal bacterial pneumonia (Bergeron et al, 1998). Further, the etiology of several autoimmune conditions has been directly associated with excessive innate immune responses (Kawane et al, 2010;Link, 1998).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

Teijaro

Walsh

Cahalan

et al. 2011

Cell

617

621

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Summary Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P1 receptor, we elucidate cellular and signaling mechanisms important in initiating cytokine storm. While S1P1 receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P1 agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P1 signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases where amplification of cytokine storm is a significant pathological component could be chemically tractable.

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Section: Discussionmentioning

confidence: 99%

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

Teijaro

Walsh

Cahalan

et al. 2011

Cell

617

621

View full text Add to dashboard Cite

show abstract

“…Aberrant proinflammatory innate immune responses have been implicated in the pathogenesis of multiple viral infections (2,21), bacterial infections (22), and autoimmune conditions (23,24). A more detailed understanding of the cellular populations and signaling pathways targeted by S1P 1 R-signaling should provide insight into how to temper immune pathology and uncover novel signaling pathways that can be targeted to blunt cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection

Teijaro¹,

Walsh²,

Rice³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

204

210

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During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P 1 R) signaling provided a chemically tractable approach for the effective blunting of cytokine storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P 1 R agonist treatment suppresses global cytokine amplification. Importantly, S1P 1 R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P 1 R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge.pathology | pulmonary O verabundant innate immune responses correlate with increased morbidity and mortality during multiple pathogenic respiratory viral infections (1-5). When studying human pandemic H1N1/2009 influenza virus in mice and ferrets, we found direct evidence that cytokine storm was chemically tractable using a sphingosine-1-phosphate receptor-1 (S1P 1 R) selective agonists. S1P 1 R agonist therapy suppressed innate immune cell recruitment, cytokine-chemokine production, and improved survival without altering viral clearance, indicating that cytokine storm was causative to disease pathogenesis and that S1P therapy could suppress detrimental innate immune responses without hindering virus control (6, 7). The identification that S1P 1 R agonists suppress detrimental innate immune responses without hindering virus control indicates that S1P 1 R probes may serve as both viable drug leads to curb influenza virus morbidity and mortality, and as research tools to identify additional cellular signaling pathways that can be targeted to improve clinical outcomes during respiratory viral infection.To generate a molecular understanding how S1P 1 R agonist therapy effectively blunts pathological innate inflammatory responses, we systematically assessed the role various innate signaling pathways play in S1P 1 R-mediated suppression of inflammation following influenza virus infection. Using an S1P 1 R selective agonist synergistically with genetic and biochemical tools, we reveal that S1P 1 R signaling effectively suppressed global cytokine amplification at a point that converged downstream of multiple innate signaling pathways. We reveal that S1P 1 R signaling can suppress innate cellular recruitment and cytokine amplification downstream of both endosome and cytosolic innate sensing pathways. Moreover, we identify myeloid differentiation primary response gene 88 (MyD88) as the ...

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“…Cytokine storm is believed to play a prominent role in several other infections, such as hantavirus (30), sudden acute respiratory syndrome (31), HIV (32), pneumococcal pneumonia (33,34), and a number of immunological diseases (35)(36)(37)(38). Thus, the potential benefit of using a similar sphingosine analog therapy should be considered in these cases.…”

Section: Discussionmentioning

confidence: 99%

Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus

Walsh¹,

Teijaro²,

Wilker

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

219

211

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Human pandemic H1N1 2009 influenza virus rapidly infected millions worldwide and was associated with significant mortality. Antiviral drugs that inhibit influenza virus replication are the primary therapy used to diminish disease; however, there are two significant limitations to their effective use: ( i ) antiviral drugs exert selective pressure on the virus, resulting in the generation of more fit viral progeny that are resistant to treatment; and ( ii ) antiviral drugs do not directly inhibit immune-mediated pulmonary injury that is a significant component of disease. Here we show that dampening the host's immune response against influenza virus using an immunomodulatory drug, AAL-R, provides significant protection from mortality (82%) over that of the neuraminidase inhibitor oseltamivir alone (50%). AAL-R combined with oseltamivir provided maximum protection against a lethal challenge of influenza virus (96%). Mechanistically, AAL-R inhibits cellular and cytokine/chemokine responses to limit immunopathologic damage, while maintaining host control of virus replication. With cytokine storm playing a role in the pathogenesis of a wide assortment of viral, bacterial, and immunologic diseases, a therapeutic approach using sphingosine analogs is of particular interest.

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Cytokine Kinetics and Other Host Factors in Response to Pneumococcal Pulmonary Infection in Mice

Cited by 198 publications

References 88 publications

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection

Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus

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