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Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice
Open accessAbstract
Pneumococcal infection of the respiratory tract is often secondary to recent influenza virus infection and accounts for much of the morbidity and mortality during seasonal and pandemic influenza. Here, we show that coinfection of the upper respiratory tract of mice with influenza virus and pneumococcus leads to synergistic stimulation of type I IFNs and that this impairs the recruitment of macrophages, which are required for pneumococcal clearance, due to decreased production of the chemokine CCL2. Type I IFN expression was induced by pneumococcal colonization alone. Colonization followed by influenza coinfection led to a synergistic type I IFN response, resulting in increased density of colonizing bacteria and susceptibility to invasive infection. This enhanced type I IFN response inhibited production of the chemokine CCL2, which promotes the recruitment of macrophages and bacterial clearance. Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin. Indeed, the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin. We therefore propose that the synergistic stimulation of type I IFN production during concurrent influenza virus and pneumococcal infection leads to increased bacterial colonization and suggest that this may contribute to the higher rates of disease associated with coinfection in humans.
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TL;DR
In a mouse upper respiratory tract coinfection model, influenza virus and pneumococcus synergistically induced type I IFNs, which suppressed CCL2-dependent macrophage recruitment and increased pneumococcal colonization. This type I IFN–dependent effect required Nod2 and pneumolysin pore formation and was associated with higher rates of invasive disease.
Key findings
- Pneumococcal colonization alone induced a moderate type I IFN response, but additional type I IFN stimulation with intranasal poly-ICLC increased mean pneumococcal colonization density by greater than 20-fold at day 7; this effect was absent in *Ifnar*−/− mice.
- Concurrent influenza PR8 infection after pneumococcal colonization caused synergistic IFN-β expression, inhibited macrophage but not neutrophil recruitment, decreased *Ccl2* but not KC expression, and increased pneumococcal load; none of these increases occurred in *Ifnar*−/− mice.
- The increased colonization during coinfection required Nod2 and pneumolysin: *Nod2*−/− mice and mice challenged with pneumolysin mutants (*ply*− or *plyW433F*) did not show synergistic IFN-β induction or increased colonization density.
- Coinfection with an invasive serotype 6A pneumococcal strain led to a higher rate of late-onset sepsis compared with pneumococcal challenge alone.
Methods
- Mice were colonized intranasally with *S. pneumoniae* strain P1121 (type 23F; ~10^7 CFU) and then infected intranasally with influenza A virus PR8 (1,000 TCID50) one day later; some experiments used poly-ICLC, invasive serotype 6A strain P1547, or pneumolysin mutants.
- Wild-type C57BL/6 and congenic *Nod2*−/−, *Tlr2*−/−, *Ccr2*−/−, and *Ifnar*−/− mice were used, with additional *Irf3*−/− and *Irf5*−/− bone marrow–derived macrophages; outcomes included URT lavage quantitative culture, qRT-PCR for IFN-α/β, *Ccl2*, KC, and IL-17A, flow cytometry for macrophages/neutrophils, ELISA for CCL2, and luciferase NF-κB reporter assays.
- Statistical comparisons used ANOVA with Dunn’s post-tests, with survival compared by Fisher’s exact test; P < 0.05 was considered significant.
Limitations
- Stated: the components downstream of Nod2 affected by the type I IFN response to *S. pneumoniae* were not yet defined, and how the Nod2-dependent pathway synergizes with the influenza-stimulated pathway remains to be understood.
- Stated: the effect of influenza virus on pneumococcal colonization may be most relevant to concurrent infection; when P1121 was given on day 6 after PR8, there was no synergistic type I IFN stimulation or significant effect on colonization density at day 7.
- Evident: the study is a mouse model of URT coinfection, and the authors note that their model avoided direct LRT inoculation and showed minimal lung viral/bacterial titers and pathology, so the findings may not fully represent secondary pneumococcal pneumonia or human coinfection.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that coinfection of the upper respiratory tract of mice with influenza virus and pneumococcus leads to synergistic stimulation of type I IFNs”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“Coinfected mice showed a synergistic increase in IFN-β mRNA expression compared with mice infected with either S. pneumoniae or influenza virus alone (Figure 3F).”
- Also stated in: § Discussion · boosted
“Moreover, this synergistic increase in type I IFNs was seen during coinfection with influenza virus and was necessary and sufficient to promote bacterial colonization.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This requirement for Nod2 for the stimulation of IFN-β was also observed in peritoneal macrophages treated ex vivo with P1121.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin.”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“In the absence of the synergistic increase in IFN-β there was no increased pneumococcal colonization in the presence of influenza virus in Nod2 -/-mice (Figure 5F).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An effect of poly-ICLC on colonization was not seen with dosing every third day rather than daily.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the expression of IFN-β mRNA was no longer stimulated in Nod2 -/-colonized mice (Figure 5C).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 5B, there was no difference between Tlr2 +/+ and Tlr2 -/-mice in the type I IFN mRNA expression in URT lavages at 3 days after infection with strain P1121.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“resulting in increased density of colonizing bacteria”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“As shown in Figure 3E, intranasal inoculation of PR8 resulted in increased pneumococcal load at day 7 of bacterial infection.”
- Also stated in: § Discussion · boosted
“Our results demonstrated that concurrent influenza infection increased the density of colonizing pneumococci.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin.”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“In contrast, in Ifnar -/-mice there was no increase in the density of colonizing P1121 during coinfection with PR8 (Figure 4A).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and susceptibility to invasive infection”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“The rate of late-onset sepsis was higher in coinfected mice compared with mice receiving pneumococcal challenge alone (Figure 3I).”
- Also stated in: § Discussion · boosted
“The consequence of increased bacterial load was also demonstrated in our study when an invasive strain was analyzed and, in the setting of coinfection, led to a higher rate of sepsis.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An effect of poly-ICLC was not observed in Ifnar -/-mice, with a targeted deletion of the common type I IFN receptor, demonstrating that additional stimulation of type I IFNs was required for the poly-ICLC-mediated increase in colonization density.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Poly-ICLC treatment was sufficient to increase the mean pneumococcal colonization density by greater than 20-fold at day 7 after inoculation (Figure 2B).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As expected, poly-ICLC treatment induced higher levels of type I IFN mRNA in URT lavages of colonized mice (Figure 2A).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Type I IFN expression was induced by pneumococcal colonization alone.”
- Also stated in: § Pneumococcal nasopharyngeal colonization induces type I IFNs. · plain
“There was a moderate increase in mRNA for Ifna and Ifnb in the URT, with a maximal response at day 1 after inoculation and decline that paralleled the loss of colonization (Figure 1D).”
- Also stated in: § Discussion · plain
“We noted that pneumococcal infection alone was associated with a moderate increase in expression of IFN-α and IFN-β.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Pneumococcal nasopharyngeal colonization induces type I IFNs. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin.”
- Also stated in: § Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin. · boosted
“In vivo, neither mutant showed synergistic induction of IFN-β or increased colonization density during coinfection with influenza virus (Figure 7, B and C).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin. · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, Nod2 -/-mice no longer showed a synergistic increase in IFN-β or suppression of Ccl2 mRNA levels in URT lavages during coinfection (Figure 5, D and E).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the inhibitory effect of poly-ICLC and IFN-β was not seen in macrophages from Ifnar -/-mice.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN-β transcription in P1121-stimulated bone marrow-derived macrophages was reduced in Irf3 -/-and Irf5 -/-macrophages (Figure 5G).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The decreased macrophage recruitment correlated with lower expression of Ccl2 in poly-ICLC-treated mice (Figure 2E).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Poly-ICLC treatment was associated with an IFNdependent decrease in macrophage recruitment to the URT lumen at day 7, the time point when the numbers of luminal macrophages per animal peaks (Figure 2C).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This enhanced type I IFN response inhibited production of the chemokine CCL2”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“The stimulation of CCL2 protein and Ccl2 mRNA expression by P1121 was inhibited by both poly-ICLC and IFN-β (Figure 6, A and B).”
- Also stated in: § Discussion · plain
“Our in vivo observations that synergistic stimulation of type I IFNs inhibits expression of CCL2 correlated with the effects of IFN-β and poly-ICLC on the transcription and production of CCL2 by ex vivo macrophages.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The stimulation of CCL2 protein and Ccl2 mRNA expression by P1121 was inhibited by both poly-ICLC and IFN-β (Figure 6, A and B).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stimulation of type I IFNs increased pneumococcal nasopharyngeal colonization.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Poly-ICLC is a synthetic analog of viral dsRNA.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Pretreatment of mice for 7 days with broad-spectrum oral antibiotics did not affect levels of URT type I IFNs, suggesting that the effect of the pneumococcus could not be explained by changes in the normal mouse flora (data not shown).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN-β inhibits production of CCL2 in peritoneal macrophage stimulated with heat-killed S. pneumoniae.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Macrophages and Nod2 contribute to production of type I IFN by S. pneumoniae.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, this response did not seem to be sufficient to impact colonization, since pneumococcal colonization alone was unaltered in Ifnar -/-mice.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effect of coinfection of influenza strain PR8 on colonization by pneumococcal strain P1121 is dependent on type I IFNs.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Coinfection with influenza virus induces synergistic IFN-β expression and enhances pneumococcal nasopharyngeal colonization.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Pore formation by Ply contributes to type I IFN expression.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, Il17a transcription in response to P1121 was similar with and without PR8 (data not shown).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Macrophages and Nod2 contribute to production of type I IFN by S. pneumoniae.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Coinfection with influenza virus induces synergistic IFN-β expression and enhances pneumococcal nasopharyngeal colonization.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Type I IFNs are expressed during pneumococcal carriage.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Statistics.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“which are required for pneumococcal clearance”
- Also stated in: § Introduction · plain
“The decline in the bacterial load requires the influx of monocytes/macrophages into the airway lumen (15).”
- Also stated in: § Discussion · plain
“loss of URT macrophages inhibits the clearance of pneumococcal colonization (15).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
What the sources say
- Not checked yetcites [15] Zhang, 2009, J Clin Invest.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Introduction · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CCL2-CCR2-dependent recruitment of monocytes/macrophages contributed to the sustained production of type I IFNs.”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“At day 7 after inoculation, Ccr2 -/-mice showed lower levels of IFN-β transcription (Figure 5A).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
In the paper
“Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin.”
- Also stated in: § Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin. · plain
“An additional factor in Nod2-mediated responses to S. pneumoniae is the expression of the pneumococcal pore-forming toxin pneumolysin (17).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
What the sources say
- Not checked yetcites [17] Davis, 2011, J Clin Invest. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin. · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicated that the higher density of bacterial colonization induced by influenza virus may predispose to invasive disease and mortality.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin.”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“We had previously shown that the CCL2 response to S. pneumoniae was NF-κB-dependent and required sensing of peptidoglycan by Nod2 (17).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
What the sources say
- Not checked yetcites [17] Davis, 2011, J Clin Invest. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
None of the sources cited for this claim have been checked yet.
In the paper
“and suggest that this may contribute to the higher rates of disease associated with coinfection in humans.”
- Also stated in: § Discussion · hedged
“Since the IFN response is common to many viruses, our report offers a mechanistic explanation for the association of acute viral infections and the increased rates of pneumococcal disease and its markedly seasonal pattern (5,20).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The mouse model of upper respiratory tract coinfection is representative of human coinfection.
- Rests on an assumption: The type I IFN response is common to many viruses.
- Also stated in: § Discussion · hedged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the effect of influenza virus on pneumococcal colonization may be most relevant to concurrent infection.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We therefore propose that the synergistic stimulation of type I IFN production during concurrent influenza virus and pneumococcal infection leads to increased bacterial colonization”
- Also stated in: § Discussion · boosted
“Moreover, this synergistic increase in type I IFNs was seen during coinfection with influenza virus and was necessary and sufficient to promote bacterial colonization.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · boosted
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Pretreatment of mice for 7 days with broad-spectrum oral antibiotics did not affect levels of URT type I IFNs, suggesting that the effect of the pneumococcus could not be explained by changes in the normal mouse flora (data not shown).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesWhat the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No cytotoxicity was observed following stimulation with strain P1121 or poly-ICLC or IFN-β treatment, as measured using the Cytotoxicity Detection Kit (LDH) (Roche) according to the manufacturer's protocol.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Influenza virus infection and quantification.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“This suggested that the mechanisms responsible for the effect of influenza virus on pneumococcal colonization might be distinct from those proposed for secondary pneumonia (23).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
What the sources say
- Not checked yetcites [23] source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Strain P1121, a type 23F isolate obtained from a study of experimental human colonization, was selected for its ability to efficiently colonize the murine nasopharynx (15,16,18).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Methods
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, this response did not seem to be sufficient to impact colonization, since pneumococcal colonization alone was unaltered in Ifnar -/-mice.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This demonstrated that pore formation by pneumolysin plays a crucial role in the type I IFN-dependent exacerbation of pneumococcal colonization by influenza virus.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the reduced numbers of URT macrophages in the setting of synergistic stimulation of type I IFNs could explain the increased colonization density seen on day 7 after infection.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 10
- Probably not a substantial claim. 5
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this impairs the recruitment of macrophages, which are required for pneumococcal clearance, due to decreased production of the chemokine CCL2.”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“The synergistic increase in IFN-β expression during coinfection was associated with an inhibition of macrophage, but not neutrophil, recruitment (Figure 3G)”
- Also stated in: § Discussion · plain
“The expression of CCL2 and influx of F4/80 + macrophages into the URT was inhibited during coinfection or by treatment with poly-ICLC.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, there was no loss of macrophage recruitment or decrease in Ccl2 expression in coinfected Ifnar -/-mice (Figure 4, B and C).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no effect of poly-ICLC treatment on the numbers of luminal neutrophils or levels of mRNA for the chemokine KC, which triggers neutrophil recruitment (Figure 2, D and E).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Nasal poly-ICLC treatment impacts pneumococcal colonization.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NF-κB activation was inhibited by poly-ICLC or IFN-β, providing a direct demonstration that type I IFNs are sufficient to inhibit Nod2 signaling.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When strain P1121 was given on day 6 following intranasal administration of PR8 (1,000 TCID 50 ), there was no synergistic stimulation of type I IFNs or significant effect of antecedent viral infection on the density of pneumococcal colonization at day 7 (data not shown).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 7A, IFN-β mRNA expression was reduced in macrophages stimulated with either mutant strain and restored when ply was replaced in the deletion mutant.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Type I IFN induction by S. pneumoniae is dependent on a pore-forming toxin, pneumolysin.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“due to decreased production of the chemokine CCL2”
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
“which correlated with decreased expression of Ccl2, but not KC (Figure 3H).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Synergistic production of the type I IFNs by influenza virus increases pneumococcal colonization density. · plain
None of the sources cited for this claim have been checked yet.
In the paper
“which promotes the recruitment of macrophages and bacterial clearance”
- Also stated in: § Introduction · plain
“Recruitment of these cells correlates with the expression of the chemokine CCL2 and is deficient in mice lacking its receptor, CCR2, which is also required for early clearance (15,17).”
- Also stated in: § Discussion · plain
“We recently showed that production of chemokine CCL2 and its recognition by CCR2 drive the influx of macrophages into the lumen of the URT during pneumococcal colonization (15,17).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Abstract
What the sources say
- Not checked yetcites [15] Zhang, 2009, J Clin Invest.
- Not checked yetcites [17] Davis, 2011, J Clin Invest. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Introduction · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, macrophages could be both the source of CCL2 and the target of type I IFNs, which act to block the CCR2-dependent recruitment of additional macrophages to the site of infection.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Ifnar -/-mice lacking the IFN-αβ receptor were provided by S. Weiss (University of Pennsylvania) (39).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Mice.
What the sources say
- Not checked yetcites [39] Muller, 1994, Science. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since colonization precedes pneumonia, both mechanisms -increased bacterial load in the URT and compromised innate immunity in the LRT -could contribute to the high rates of disease during coinfection.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: Colonization precedes pneumonia.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Macrophage differentiation was confirmed by flow cytometry.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Influenza virus infection and quantification.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN-β transcription was detected by qRT-PCR, and transcription of NF-κB-dependent cytokines was confirmed in all macrophage genetic backgrounds.”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Influenza virus infection and quantification.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No cytotoxicity was observed following stimulation or cytochalasin D treatment, as measured using the Cytotoxicity Detection Kit (LDH) according to the manufacturer's protocol (Roche).”
§ Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice > Influenza virus infection and quantification.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The mouse model of upper respiratory tract coinfection is representative of human coinfection.
“and suggest that this may contribute to the higher rates of disease associated with coinfection in humans.”
“our report offers a mechanistic explanation for the association of acute viral infections and the increased rates of pneumococcal disease and its markedly seasonal pattern (5,20).”
The paper relies on this without support.
Colonization precedes pneumonia.
“Since colonization precedes pneumonia, both mechanisms -increased bacterial load in the URT and compromised innate immunity in the LRT -could contribute to the high rates of disease during coinfection.”
The paper relies on this without support.
The type I IFN response is common to many viruses.
“Since the IFN response is common to many viruses, our report offers a mechanistic explanation for the association of acute viral infections and the increased rates of pneumococcal disease and its markedly seasonal pattern (5,20).”
The paper relies on this without support.
Poly-ICLC is a synthetic analog of viral dsRNA.
“Polyinosinic-polycytidylic acid condensed with poly-l-lysine (poly-ICLC, Hiltonol), a synthetic analog of viral dsRNA, was supplied by Oncovir Inc.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In experimental in vitro models, viral infections increase the colonization rates of various bacteria in the URT (90–95), including S. pneumoniae and H. influenzae (86–88).”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [94]
Citations
Cites
Virus interference. I. the interferon
Isaacs, A., & Lindenmann, J. (1957) · Proceedings of the Royal Society of London. Series B - Biological Sciences · doi:10.1098/rspb.1957.0048 · Cited by 3,451
Functional Role of Type I and Type II Interferons in Antiviral Defense
Müller, U., Steinhoff, U., Reis, L. F. L., Hemmi, S., Pavlovic, J., Zinkernagel, R. M., & Aguet, M. (1994) · Science · doi:10.1126/science.8009221 · Cited by 2,453
Streptococcus pneumoniae colonisation: the key to pneumococcal disease
Bogaert, D., de Groot, R., & Hermans, P. (2004) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(04)00938-7 · Cited by 1,929
Morens, D. M., Taubenberger, J. K., & Fauci, A. S. (2008) · The Journal of Infectious Diseases · doi:10.1086/591708 · Cited by 1,625
TYPE I INTERFERONS (α/β) IN IMMUNITY AND AUTOIMMUNITY
Theofilopoulos, A. N., Baccalà, R., Beutler, B., & Kono, D. H. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115843 · Cited by 1,205
Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
Clarke, T. B., Davis, K. M., Lysenko, E. S., Zhou, A. Y., Yu, Y., & Weiser, J. N. (2010) · Nature Medicine · doi:10.1038/nm.2087 · Cited by 1,154
Self-citationInduction of Bystander T Cell Proliferation by Viruses and Type I Interferon in Vivo
Tough, D. F., Borrow, P., & Sprent, J. (1996) · Science · doi:10.1126/science.272.5270.1947 · Cited by 1,081
Insights into the Interaction between Influenza Virus and Pneumococcus
McCullers, J. A. (2006) · Clinical Microbiology Reviews · doi:10.1128/cmr.00058-05 · Cited by 846
Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection
Malley, R., Henneke, P., Morse, S. C., Cieslewicz, M. J., Lipsitch, M., Thompson, C. M., Kurt‐Jones, E. A., Paton, J. C., Wessels, M. R., & Golenbock, D. T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0435928100 · Cited by 704
Gautier, G., Humbert, M., Deauvieau, F., Scuiller, M., Hiscott, J. B., Bates, E. E. M., Trinchieri, G., Caux, C., & Garrone, P. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041964 · Cited by 548
Flagged first, then by citations
Research works printed but not linked: 1
- Zhang, 2009, J Clin Invest., 119, 1899
Cited by
Sorted by citations
Type I interferons in infectious disease
McNab, F., Mayer-Barber, K., Sher, A., Wack, A., & O'Garra, A. (2015) · Nature Reviews Immunology · doi:10.1038/nri3787 · Cited by 2,780
Shared and Distinct Functions of Type I and Type III Interferons
Lazear, H. M., Schoggins, J. W., & Diamond, M. S. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.025 · Cited by 1,138
Streptococcus pneumoniae: transmission, colonization and invasion
Weiser, J. N., Ferreira, D. M., & Paton, J. C. (2018) · Nature Reviews Microbiology · doi:10.1038/s41579-018-0001-8 · Cited by 1,162
Self-citationRespiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia.
Hanada, S., Pirzadeh, M., Carver, K. Y., & Deng, J. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02640 · Cited by 495
The Pneumococcus: Epidemiology, Microbiology, and PathogenesisPreprint
Henriques‐Normark, B., & TUOMANEN, E. I. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a010215 · Cited by 436
Metadata
- Authors
- Nakamura, S., Davis, K. M., & Weiser, J. N.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Weiser, Jeffrey N.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-09-01
- Volume
- 121
- Issue
- 9
- Pages
- 3657-3665
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3163966
- OpenAlex
- W2032969319
- Semantic Scholar
- 1b00bdd73ee8802930f9ae6efc3a98191ebab20b
- Cited by
- 280
- References
- 44
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 17 · 2023: 11 · 2022: 17 · 2021: 21 · 2020: 20 · 2019: 18 · 2018: 27 · 2017: 16 · 2016: 20 · 2015: 19 · 2014: 31 · 2013: 22 · 2012: 22
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Institute of Allergy and Infectious Diseases (R01AI038446, U19AI083022, AI 38446, R21AI044231, R01AI044231, T32AI060516, AI44231, R37AI038446)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- influenza virus, Streptococcus pneumoniae, co-infection, type I interferon, MCP-1, macrophage recruitment, pneumococcal carriage, NOD2, pneumolysin, secondary bacterial infection, invasive pneumococcal disease, chemokines, innate immunity
- MeSH terms
- Animals, Cells, Cultured, Female, Interferon Type I, Macrophages, Male, Mice, Inbred C57BL, Orthomyxoviridae, Orthomyxoviridae Infections, Pneumococcal Infections, Streptococcus pneumoniae, Trachea, Mice, Knockout, Chemokine CCL2, Mice, Nod2 Signaling Adaptor Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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