Increased Susceptibility for Superinfection with Streptococcus pneumoniae during Influenza Virus Infection Is Not Caused by TLR7-Mediated Lymphopenia

Stegemann, Sabine; Dahlberg, Sofia; Kröger, Andrea; Gereke, Marcus; Bruder, Dunja; Henriques‐Normark, Birgitta; Gunzer, Matthias

doi:10.1371/journal.pone.0004840

Cited by 41 publications

(56 citation statements)

References 44 publications

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“…Furthermore, neutrophil entry into sinuses was blocked (supplemental Video 5). In contrast to the depleting anti-Gr-1 antibody RB6-8C5, 23 the Cxcr2 antiserum did not deplete neutrophils from the BM (supplemental Figure 3). Thus, the induced release of Cxcr2-binding chemokines by G-CSF provides a selective trigger for enhanced motility of neutrophils in the BM, which is a prerequisite for their mobilization into local sinuses and the circulation.…”

Section: G-csf-triggered Release Of Cxcr2 Ligands Mediates Mobilizationmentioning

confidence: 84%

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Köhler

Filippo²,

Hasenberg

et al. 2011

Blood

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184

174

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Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker. IntroductionNeutrophils are the most abundant and, arguably, the most important leukocyte in the vertebrate immune system. Under normal conditions, human bone marrow (BM) produces ϳ 10 11 neutrophils per day. 1 In "danger situations" such as peripheral infections, the constant release of neutrophils can be dramatically increased within hours, a process termed danger or stress mobilization. 2 The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) is central to the danger mobilization of neutrophils in both humans and mice. 3 However, although recombinant G-CSF has been used in clinical hematology for 20 years, the molecular mechanisms by which it mobilizes neutrophils are still not well understood.Neutrophils are restrained in the BM by the binding of their chemokine receptor Cxcr4 to the chemokine Cxcl12, which is expressed in a membrane-associated fashion by BM stromal cells. 4 There is evidence that G-CSF breaks the Cxcr4-Cxcl12 bond by activating neutrophil proteases, 5 thereby releasing neutrophils from the BM into the bloodstream. 3,6 However, several findings cannot be explained by the Cxcr4-Cxcl12 breakage concept alone. First, G-CSF can mobilize neutrophils in protease-deficient mice, arguing against the need for protease activation for this process. 7,8 Second, because neutrophil-specific deletion of Cxcr4 in mice results in much higher numbers of circulating neutrophils compared with wild-type animals, factors other than Cxcr4 must be involved in steering neutrophils into the BM blood sinuses (unless the process is passive). Finally, the specific Cxcr4-antagonist AMD3100 a...

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Section: G-csf-triggered Release Of Cxcr2 Ligands Mediates Mobilizationmentioning

confidence: 84%

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Köhler

Filippo²,

Hasenberg

et al. 2011

Blood

Self Cite

184

174

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“…First, we characterized the infection with these strains alone as a reference for coinfection. We used the highly invasive strain TIGR4 (T4) of serotype 4 (27), an invasive strain of serotype 7F, and a carrier strain of serotype 19F (29). According to previous reports, serotype 4 and serotype 7F harbor a high invasive disease potential while serotype 19F is less invasive (30)(31)(32).…”

Section: Resultsmentioning

confidence: 99%

“…At KI, the blood agar plates and THY medium were produced by the Karolinska Microbiology Laboratory (Solna, Sweden). For viral challenges, influenza A/PR/8/34 virus (H1N1; PR8) was produced in Madin-Darby canine kidney (MDCK) cells as described previously (27). The 50% tissue culture infectious dose (TCID 50 ) of the viral stock was determined by incubating 10-fold dilutions of virus stock solution on MDCK cells cultured in Dulbecco's modified Eagle medium (DMEM; Life Technologies, Germany) supplemented with 0.0002% trypsin (Sigma-Aldrich, Germany) and 1% penicillin-streptomycin (ThermoFisher, USA).…”

Section: Methodsmentioning

confidence: 99%

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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e Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks. Infection with secondary bacterial pathogens is attributed to be the major cause of excessive mortality during influenza A virus (IAV) outbreaks. This lethal synergism has been recognized as early as during the 1918-1919 IAV pandemic with an estimated global death toll of 50 to 100 million (1, 2). Retrospective studies disclosed that 71% of the fatal cases during this pandemic were positive for Streptococcus pneumoniae (also called pneumococcus), providing the first epidemiological evidence for viral-bacterial coinfections (2). A clear predisposition to bacterial disease was also evident in all of the succeeding influenza pandemics, including the more recent 2009 H1N1 outbreak, which had a 10 to 55% higher incidence of hospitalizations and mortality due to bacterial pneumonia (3). Pneumococcal colonization is transient and asymptomatic in immunocompetent individuals and most commonly occurs in early childhood (4). At the same time, however, pneumococci are able to cause a variety of diseases ranging from mild sinusitis and otitis media to more-severe infections like sepsis and meningitis. Even though the introduction of the polyvalent pneumococcal conjugate vaccines...

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“…One theory proposes that the respiratory epithelial surface is damaged during influenza virus infection and that the exposure of new binding partners, such as platelet-activating factor receptor, enhanced bacterial adherence and growth in the respiratory tract (2,22,34,50). Another theory suggested that the production of a variety of different cellular mediators during influenza virus infection affected the recruitment and function of effector leukocytes, such as neutrophils, in response to a secondary bacterial infection (20,23,39,(41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Induction during Influenza Virus Infection Increases Susceptibility to Secondary Streptococcus pneumoniae Infection by Negative Regulation of γδ T Cells

Moltedo

Moran

2012

J Virol

176

181

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The majority of deaths following influenza virus infection result from secondary bacterial superinfection, most commonly caused by Streptococcus pneumoniae. Several models have been proposed to explain how primary respiratory viral infections exacerbate secondary bacterial disease, but the mechanistic explanations have been contradictory. In this study, mice were infected with S. pneumoniae at different days after primary influenza A (X31) virus infection. Our findings show that the induction of type I interferons (IFNs) during a primary nonlethal influenza virus infection is sufficient to promote a deadly S. pneumoniae secondary infection. Moreover, mice deficient in type I interferon receptor (IFNAR knockout [KO] mice) effectively cleared the secondary bacterial infection from their lungs, increased the recruitment of neutrophils, and demonstrated an enhanced innate expression of interleukin-17 (IL-17) relative to wild-type (WT) mice. Lung ␥␦ T cells were responsible for almost all IL-17 production, and their function is compromised during secondary S. pneumoniae infection of WT but not IFNAR KO mice. Adoptive transfer of ␥␦ T cells from IFNAR KO mice reduced the susceptibility to secondary S. pneumoniae infection in the lung of WT mice. Altogether, our study highlights the importance of type I interferon as a key master regulator that is exploited by opportunistic pathogens such as S. pneumoniae. Our findings may be utilized to design effective preventive and therapeutic strategies that may be beneficial for coinfected patients during influenza epidemics.

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Increased Susceptibility for Superinfection with Streptococcus pneumoniae during Influenza Virus Infection Is Not Caused by TLR7-Mediated Lymphopenia

Cited by 41 publications

References 44 publications

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

Type I Interferon Induction during Influenza Virus Infection Increases Susceptibility to Secondary Streptococcus pneumoniae Infection by Negative Regulation of γδ T Cells

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