Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections
Open accessAbstract
Viruses such as influenza suppress host immune function by a variety of methods. This may result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. PKH26-phagocytic cell labeling dye was administered intranasally to label resident alveolar macrophages (AMs) in a well-established murine model before influenza infection to determine turnover kinetics during the course of infection. More than 90% of resident AMs were lost in the first week after influenza, whereas the remaining cells had a necrotic phenotype. To establish the impact of this innate immune defect, influenza-infected mice were challenged with S. pneumoniae. Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice: ∼50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 h later. In mock-infected mice, by contrast, >95% of inocula up to 50-fold higher was efficiently cleared. Coinfection during the AM depletion phase caused significant body weight loss and mortality. Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection. Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia. We conclude that resident AM depletion occurs during influenza infection. Among other potential effects, this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia. This novel mechanism will inform development of novel therapeutic approaches to restore lung innate immunity against bacterial superinfections.
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Written from the paper’s full text.
TL;DR
Influenza infection depletes resident alveolar macrophages (AMs) in mice, impairing early clearance of *Streptococcus pneumoniae* and enabling lethal secondary bacterial pneumonia. Local GM-CSF treatment partially restores AM numbers and early bacterial clearance and protects more than 50% of co-infected mice.
Key findings
- More than 90% of resident AMs were depleted 7 days after PR8 influenza infection, with about 70% depletion by day 3; the 2009 pandemic H1N1 isolate caused comparable AM depletion. Remaining AMs showed a necrotic phenotype, and dead AM numbers were significantly higher in influenza-infected than mock-infected mice.
- Early pneumococcal clearance was severely impaired during AM depletion: influenza-infected mice could not clear a 200 CFU inoculum, with about 50% of the initial bacterial inoculum recoverable from alveolar airspace at 3 hours, whereas mock-infected mice cleared more than 95% of inocula up to 50-fold higher.
- Co-infection during the AM depletion phase caused significant body weight loss and mortality: all co-infected mice died within 3–5 days after pneumococcal inoculation, and 100% developed secondary pneumococcal pneumonia when bacteria were given 3, 5, or 7 days after influenza; pneumonia frequency fell to 60% at day 9 and 40% at day 11, with no pneumonia at day 1 or 14.
- Local GM-CSF treatment expanded the interstitial macrophage pool, partially replenished AMs, improved early pneumococcal clearance, and protected more than 50% of co-infected mice from secondary pneumococcal pneumonia, while all mock-treated co-infected mice developed pneumonia.
Methods
- Six- to 8-week-old female BALB/c mice were infected intranasally with PR8 influenza virus (25 TCID50) or pandemic H1N1 (600 TCID50), followed at specified time points by intranasal *S. pneumoniae* A66.1 (200 CFU). Resident lung macrophages were labeled intranasally with PKH26-PCL dye 5 days before infection.
- Flow cytometry distinguished AMs as CD11chi F4/80hi CD11b−ve, interstitial macrophages as CD11blo-int, and recruited exudate macrophages as CD11bhi; live/dead aqua dye measured dead cells, and PKH26 mean fluorescence intensity tracked resident macrophage dynamics.
- Outcomes included AM/IM absolute numbers, early pneumococcal clearance at 3 hours, in vivo bioluminescent imaging of pneumonia (flux >11,000 relative light units/min), body weight, and mortality. GM-CSF was given intranasally at 25 μg on days −1 and +1 relative to PR8 infection. Statistical comparisons used ANOVA, Student’s t-test, and log-rank chi-squared tests.
Limitations
- Stated: pulmonary GM-CSF treatment has inflammatory activity that could exacerbate inflammatory lung injury and make human use problematic; GM-CSF only partially replenished AMs and restored clearance, with some treated influenza-infected mice still unable to clear bacteria.
- Evident: the study is limited to a murine model with specific influenza strains (PR8 and pdm H1N1) and one *S. pneumoniae* strain (A66.1), with no direct human validation.
- Evident: the mechanism of AM death is characterized as secondary necrosis, but the upstream pathways are not fully dissected; the timing of AM depletion and GM-CSF protection is specific to this model.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
Influenza virus infection depletes resident alveolar macrophages in mice.
“We conclude that resident AM depletion occurs during influenza infection.”
- Also stated in: § Introduction · boosted
“We demonstrate that influenza virus depletes alveolar macrophages.”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Also stated in: § Introduction · boosted
- Findingown data
More than 90% of the resident alveolar macrophage pool is depleted in the first week after influenza infection in mice.
“More than 90% of resident AMs were lost in the first week after influenza, while the remaining cells had a necrotic phenotype.”
- Also stated in: § Influenza virus depletes alveolar macrophages · plain
“Seven days after influenza virus infection, more than 90% of the AM pool was depleted (Fig. 2A).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Also stated in: § Influenza virus depletes alveolar macrophages · plain
- Findingown data
In mock-infected mice, more than 95% of pneumococcal inocula up to 50-fold higher than the challenge dose are efficiently cleared.
“In mock-infected mice, by contrast, more than 95% of inocula up-to-50-fold higher was efficiently cleared.”
Quote in the paperSubstantial claim - Findingown data
Remaining alveolar macrophages in post-lavage lung homogenate are significantly depleted starting 3 days post-infection compared with mock-infected mice.
“These remaining AMs were significantly depleted starting 3 days p.i. compared with those in mock-infected mice (Fig. 3B).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Both subsets of lung-resident macrophages were intensely labeled by intranasally administered PKH26-PCL dye.
“Both subsets of lung-resident macrophages were intensely labeled by the dye, showing high means of the fluorescence intensity of PKH26-PCL dye (MFI-PKH26).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Alveolar macrophages are significantly depleted within 7 days after pdm H1N1 infection to levels comparable to PR8 infection.
“We found that AMs were significantly depleted within 7 days after pdm H1N1 infection to levels comparable to PR8 infection (Fig. 2B).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Interstitial macrophages show significantly lower PKH26-PCL mean fluorescence intensity than alveolar macrophages in both BALF and post-lavage lung homogenates.
“Nonetheless, significant differences in MFI-PKH26 were observed between AMs and IMs in both BALF and post-lavage lung homogenates, with IMs showing significantly lower MFI-PKH26 than AMs (Fig. 1B).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Alveolar macrophages are significantly depleted in the alveolar airspace shortly after PR8 infection, starting on the first day post-infection.
“We found that AMs were significantly depleted in the alveolar airspace shortly after PR8 infection starting on the first day p.i. (Fig. 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Secondary pneumococcal pneumonia development was less frequent in influenza-infected mice that were secondarily infected by pneumococcus on 9 or 11 days p.i., with only 60% or 40% of pneumonic mice, respectively.
“Secondary pneumococcal pneumonia development was less frequent in influenza-infected mice that were secondarily infected by pneumococcus on 9 or 11 days p.i., with only 60% or 40% of pneumonic mice, respectively (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
Early pneumococcal clearance was significantly impaired during PR8 infection from 3 until 9 days p.i.
“Early pneumococcal clearance was significantly impaired during PR8 infection from 3 until 9 days p.i. (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
Complete pneumococcal clearance was observed within 3 h after pneumococcal inoculation in naïve mice.
“Complete pneumococcal clearance was observed within 3 h after pneumococcal inoculation in naïve mice (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Later, the impaired early pneumococcal clearance was restored.
“Later, the impaired early pneumococcal clearance was restored (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
There is no significant difference between total numbers of dead interstitial macrophages in influenza-infected and mock-infected mice.
“In contrast, there was no significant difference between the total numbers of dead IMs in influenza-infected and mock-infected mice (Fig. 4B).”
Quote in the paperNot a substantial claim - Findingown data
Diff-Quick-stained cytospin slides of BALF cells from influenza-infected mice 3 days post-infection show many macrophages with cellular damage manifestations, characterized by distorted nuclei and more vacuoles in cytoplasm than in mock-infected mice.
“Diff-Quick -stained cytospin slides of BALF cells harvested from influenza-infected mice 3 days p.i. showed many macrophages with cellular damage manifestations. They were characterized by distorted nuclei and more vacuoles in cytoplasm than in mock-infected mice (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
There is no significant recruitment of PKH26-PCL-labeled alveolar macrophages to the mediastinal lymph node 7 days after PR8 influenza infection.
“To determine if AMs were lost due to recruitment to the lung-draining lymph nodes, we examined the mediastinal lymph node 7 days after PR8 influenza infection and didn’t observe significant recruitment of PKH26-PCL– labeled AMs to it (data not shown).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Recruited exudate macrophages with CD11bhigh phenotype show significantly high expression levels of Ly6C.
“In contrast, the recruited exudates macrophages with CD11bhigh phenotype showed significantly high expression levels of Ly6C (Supplemental Fig. 4).”
Quote in the paperNot a substantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Findingown data
Total numbers of dead alveolar macrophages are significantly higher in both BALF and post-lavage lungs of influenza-infected mice than in mock-infected mice.
“The total numbers of dead AMs were significantly higher in both BALF and post-lavage lungs of influenza-infected mice than in mock-infected mice (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
Influenza-infected mice show mild morbidity manifested as loss of approximately 10% of original body weight within 7 days after influenza infection.
“Influenza-infected mice showed mild morbidity manifested as loss of ~ 10% of their original body weight within 7 days after influenza infection (Fig. 5A).”
Quote in the paperNot a substantial claim - Findingown data
Among the influenza-infected mice, 100% developed secondary pneumococcal pneumonia when they were secondarily infected by pneumococcus 3, 5, or 7 days after influenza infection.
“Among the influenza-infected mice, 100% developed secondary pneumococcal pneumonia when they were secondarily infected by pneumococcus 3, 5, or 7 days after influenza infection.”
Quote in the paperSubstantial claim - Findingown data
All co-infected mice die within 3 to 5 days after pneumococcal inoculation.
“All co-infected mice died within 3 to 5 days after pneumococcal inoculation (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
All mock-treated co-infected mice developed pneumococcal pneumonia.
“Meanwhile, all mock-treated co-infected mice developed pneumococcal pneumonia (Fig. 7D).”
Quote in the paperSubstantial claim - Findingown data
Local GM-CSF treatment led to better early pneumococcal clearance in influenza-infected mice than in mock-treated mock-infected mice.
“Local GM-CSF treatment led to better early pneumococcal clearance in influenza-infected mice than in mock-treated mock-infected mice.”
Quote in the paperSubstantial claim - Findingown data
All co-infected mice that developed secondary pneumococcal pneumonia died within few days due to bacterial pneumonia.
“As expected in this model, all co-infected mice that developed secondary pneumococcal pneumonia died within few days due to bacterial pneumonia (Fig. 6C).”
Quote in the paperNot a substantial claim - Findingown data
Local GM-CSF treatment protected more than 50% of co-infected mice against secondary pneumococcal pneumonia.
“Local GM-CSF treatment protected more than 50% of co-infected mice against secondary pneumococcal pneumonia.”
Quote in the paperSubstantial claim - Findingown data
Some of the GM-CSF-treated influenza-infected mice could efficiently clear the bacterial inoculum, while others could not.
“Interestingly, some of the GM-CSF-treated influenza-infected mice could efficiently clear the bacterial inoculum, while others could not.”
Quote in the paperNot a substantial claim - Findingown data
Early pneumococcal clearance remained impaired in mock-treated, influenza-infected mice.
“Conversely, early pneumococcal clearance remained impaired in mock-treated, influenza-infected mice (Fig. 7C).”
Quote in the paperSubstantial claim - Findingreasoning
Further characterization showed the ability of Ly6C marker to differentiate between resident and recruited phagocytes and their maturation stage in influenza-infected lungs.
“Further characterization showed the ability of Ly6C marker to differentiate between resident and recruited phagocytes and their maturation stage in influenza-infected lungs.”
Quote in the paperNot a substantial claim - Findingown data
The AM population showed the highest MFI-PKH26 at various times during the first 2 weeks after influenza infection.
“Nevertheless, the AM population showed the highest MFI-PKH26 at various times during the first 2 weeks after influenza infection.”
Quote in the paperSubstantial claim - Findingown data
Expansion of the AM pool during the recovery phase was accompanied by significant decrease in their MFI-PKH26.
“For instance, expansion of the AM pool during the recovery phase was accompanied by significant decrease in their MFI-PKH26.”
Quote in the paperSubstantial claim - Findingown data
Monitoring changes of MFI-PKH26 for lung-resident macrophages reflected the dynamic changes in their absolute numbers during influenza infection.
“Furthermore, monitoring changes of MFI-PKH26 for lung-resident macrophages reflected the dynamic changes in their absolute numbers during influenza infection.”
Quote in the paperSubstantial claim - Findingown data
Local recombinant GM-CSF treatment in influenza-infected mice induced significant expansion of the IM pool.
“We found that local recombinant GM-CSF treatment in influenza-infected mice induced significant expansion of the IM pool.”
Quote in the paperSubstantial claim - Findingreasoning
They manifested improved protection against secondary pneumococcal pneumonia.
“Furthermore, they manifested improved protection against secondary pneumococcal pneumonia.”
Quote in the paperSubstantial claim - Findingown data
Absolute numbers of AMs increased under this treatment regimen in influenza-infected mice.
“In addition, absolute numbers of AMs increased under this treatment regimen in influenza-infected mice.”
Quote in the paperNot a substantial claim - Premisecitation
Resident alveolar macrophages are considered the most important first line of defense against respiratory pneumococcal infections.
“Among host innate immune players, resident alveolar macrophages (AMs) are considered to be the most important first line of defense against respiratory pneumococcal infections (13), through their high phagocytic capacity (14–16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Knapp, 2005, Pneumonia models and innate immunity to respiratory bacterial pathogens, Shock source
Not checked in the free run.
- Premisecitation
Resident alveolar macrophages have high phagocytic capacity.
“Among host innate immune players, resident alveolar macrophages (AMs) are considered to be the most important first line of defense against respiratory pneumococcal infections (13), through their high phagocytic capacity (14–16).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [14] Franke-Ullmann, 1996, Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro, J. Immunol. source
Not checked in the free run.
- cites [15] Dockrell, 2003, Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection, J. Immunol. source
Not checked in the free run.
- cites [16] Marriott, 2007, The role of the macrophage in lung disease mediated by bacteria, Exp. Lung Res. source
Not checked in the free run.
- Study design and conductown data
In vivo PKH26-PCL labeling confirmed the validity of the flow cytometric gating strategy for lung-resident macrophage subsets.
“Thus, in vivo labeling method confirmed the validity of our flow cytometric gating strategy for the lung-resident macrophage subsets.”
Quote in the paperNot a substantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Premisecitation
Strategies for differentiation of resident macrophage subsets in the airways and lung tissues are insufficient to distinguish alveolar macrophages from lung interstitial macrophages or inflammatory monocytic cells invading the lung in response to infections.
“However, the strategies for differentiation of resident macrophage subsets in the airways and lung tissues are insufficient to distinguish AMs from lung interstitial macrophages or inflammatory monocytic cells invading the lung in response to infections.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [17] Herold, 2008, Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand, J. Exp. Med. source
Not checked in the free run.
- cites [18] Bradley, 2012, Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling, PLoS Pathog. source
Not checked in the free run.
- cites [19] Bedoret, 2009, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J. Clin. Invest. source
Not checked in the free run.
- Interpretationown data
Three days after PR8 influenza infection is the earliest time point of significant whole lung alveolar macrophage depletion.
“Consequently, 3 days after PR8 influenza infection was identified as the earliest time point of significant whole lung AM depletion.”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Interpretationown data
The period of early pneumococcal clearance impairment closely mirrors the phase of the AM pool depletion observed during PR8 infection.
“This period of early pneumococcal clearance impairment closely mirrors the phase of the AM pool depletion observed during PR8 infection (Fig. 3A, 3B).”
Quote in the paperSubstantial claim - Interpretationown data
Alveolar macrophage cell death during influenza infection is due to a secondary necrotic process.
“This suggests that cell death was due to a secondary necrotic process.”
Quote in the paperNot a substantial claim - Study design and conductown data
PKH26-PCL dye demonstrates efficient labeling and stability inside lung-resident macrophages for at least 14 days after mock infection (19 days after labeling).
“PKH26-PCL dye demonstrated efficient labeling and stability inside the lung-resident macrophages for at least 14 days after mock-infection (i.e. 19 days after labeling), thereby covering the tracking period during which we did the kinetics analyses (Supplemental Fig. 3).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
- Interpretationown data
The increased permissiveness of influenza-infected lungs to pneumococcal outgrowth suggests a defect in the host innate immune defenses that establishes a niche for bacterial infections.
“The increased permissiveness of influenza-infected lungs to pneumococcal outgrowth suggests a defect in the host innate immune defenses that establishes a niche for bacterial infections.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
- Interpretationown data
This influenza-associated damaging effect on AMs is correlated with enhanced vulnerability to secondary pneumococcal pneumonia.
“This influenza-associated damaging effect on AMs is correlated with enhanced vulnerability to secondary pneumococcal pneumonia.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
- Premisecitation
Ly6C expression is down-regulated during differentiation of blood monocytes or macrophages into tissue resident macrophages after migration to tissue.
“However, Ly6C expression is down-regulated during differentiation of blood monocytes or macrophages into tissue resident macrophages after migration to tissue.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Gordon, 2005, Monocyte and macrophage heterogeneity, Nat. Rev. Immunol. source
Not checked in the free run.
- Interpretationreasoning
The significantly high MFI-PKH26 of AMs, even during their replenishment phase, implies that the AM pool was replenished mainly via differentiation of the PKH26-labeled IMs into an AM surface phenotype rather than maturation of PKH26-unlabeled recruited blood macrophages.
“Interestingly, this significantly high MFI-PKH26 of AMs, even during their replenishment phase, implies that the AM pool was replenished mainly via differentiation of the PKH26-labeled IMs into an AM surface phenotype rather than maturation of PKH26-unlabeled recruited blood macrophages.”
Quote in the paperNot a substantial claim - Interpretationown data
These results support the findings that the origin of the AM pool is mainly through differentiation of intermediate lung macrophages rather than self-proliferation.
“These results support the findings that the origin of the AM pool is mainly through differentiation of intermediate lung macrophages rather than self-proliferation (24).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Landsman, 2007, Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages, J. Immunol. source
Not checked in the free run.
- Interpretationreasoning
This appears mainly to be because of the use of high doses of pneumococcus (≥ 1×106 CFU) to induce a robust and reproducible pneumonia, doses which overwhelm the phagocytic capacity of resident AMs.
“This appears mainly to be because of the use of high doses of pneumococcus (≥ 1×106 CFU) to induce a robust and reproducible pneumonia, doses which overwhelm the phagocytic capacity of resident AMs.”
Quote in the paperSubstantial claim - Premisereasoning
Other studies were not able to identify depletion of resident AMs because of some limitations in their analyses.
“Other studies were not able to identify depletion of resident AMs; because of some limitations in their analyses.”
Quote in the paperNot a substantial claim - Interpretationown data
In the perhaps more physiologically relevant setting of a relatively small dose of pneumococcus (200 CFU) after sublethal mild influenza infection, we can demonstrate a strong effect mediated by AMs.
“However, in the perhaps more physiologically relevant setting of a relatively small dose of pneumococcus (200 CFU) after sublethal mild influenza infection, we can demonstrate a strong effect mediated by AMs.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
- Interpretationreasoning
The quick drop in MFI-PKH26 of IMs in the first week after influenza infection, without apparent changes in their absolute cell numbers, suggests that influenza infection may induce partial depletion of the IM pool.
“In contrast, the quick drop in MFI-PKH26 of IMs in the first week after influenza infection, without apparent changes in their absolute cell numbers, suggests that influenza infection may induce partial depletion of the IM pool.”
Quote in the paperNot a substantial claim - Premisecitation
In most studies of primary or secondary pneumococcal pneumonia in animal models, AM-mediated protection has not been rigorously studied.
“In most studies of primary or secondary pneumococcal pneumonia in animal models, AM-mediated protection has not been rigorously studied (21).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat. Med. source
Not checked in the free run.
- Interpretationreasoning
Considering the higher proliferative capacity of IMs over AMs, our short treatment regimen could significantly expand the pool of IMs more than AMs.
“Considering the higher proliferative capacity of IMs over AMs, our short treatment regimen could significantly expand the pool of IMs more than AMs.”
Quote in the paperSubstantial claim- Rests on an assumption: IMs have a higher proliferative capacity than AMs.
- Interpretationreasoning
As a result of partial replenishment of the AM pool with pulmonary GM-CSF treatment, influenza-infected mice had partial restoration of efficient early pneumococcal clearance.
“As a result of partial replenishment of the AM pool with pulmonary GM-CSF treatment, influenza-infected mice had partial restoration of efficient early pneumococcal clearance.”
Quote in the paperSubstantial claim - Premisecitation
GM-CSF enhances proliferation of resident pulmonary macrophages.
“enhances proliferation of resident pulmonary macrophages (28)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Gordon, 2005, Monocyte and macrophage heterogeneity, Nat. Rev. Immunol. source
Not checked in the free run.
- Interpretationreasoning
Analyzing AMs at a single time point (day 9 p.i) is not conclusive regarding the AM depletion event during influenza infection.
“Therefore, analyzing AMs at single time point (day 9 p.i) is not conclusive regarding AM depletion event during influenza infection.”
Quote in the paperSubstantial claim - Interpretationreasoning
Analyzing cells in BAL fluid only may dismiss significant numbers of AMs remaining adherent in the lungs after lavage leading to underestimation of resident AM pool size during comparison between influenza-infected and mock-infected mice.
“Furthermore, analyzing cells in BAL fluid only may dismiss significant numbers of AMs remaining adherent in the lungs after lavage leading to underestimation of resident AM pool size during comparison between influenza-infected and mock-infected mice.”
Quote in the paperSubstantial claim - Premisecitation
GM-CSF expands the pool of resident AMs.
“and expands the pool of resident AMs (39).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Huang, 2011, GM-CSF in the lung protects against lethal influenza infection, Am. J. Respir. Crit. Care Med. source
Not checked in the free run.
- Premisecitation
Although the same in vivo labeling method was used before, AM depletion couldn't be identified during influenza.
“In addition, although the same in vivo labeling method was used before, AM depletion couldn’t be identified during influenza (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat. Med. source
Not checked in the free run.
- Premisecitation
Pulmonary GM-CSF treatment has some drawbacks such as inflammatory activity that can render its use in humans problematic by exacerbating inflammatory lung injury.
“Although pulmonary GM-CSF treatment has some drawbacks such as inflammatory activity (43) that can render its use in humans problematic by exacerbating inflammatory lung injury, the results of our study are promising.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Hamilton, 2008, Colony-stimulating factors in inflammation and autoimmunity, Nat. Rev. Immunol. source
Not checked in the free run.
- Interpretationown data
Overall, this study suggests a novel mechanism of influenza-mediated immune suppression that resulted in increased vulnerability of influenza-infected hosts to bacterial super-infections.
“Overall, this study suggests a novel mechanism of influenza-mediated immune suppression that resulted in increased vulnerability of influenza-infected hosts to bacterial super-infections.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
- May combine two claims. 37
- Classified as probably not a substantial claim. 14
May combine two claims.
Findingown dataTwo weeks after influenza infection, the alveolar macrophage population is fully replenished and early innate host protection is re-established.
“Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLocal GM-CSF treatment partially restores impaired early bacterial clearance and provides efficient protection against secondary pneumococcal pneumonia.
“Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEarly alveolar macrophage-mediated bacterial clearance is significantly impaired in influenza-infected mice, with about 50% of the initial bacterial inoculum recoverable from the alveolar airspace 3 hours after challenge.
“Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice - about 50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 hours later.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCo-infection during the alveolar macrophage depletion phase causes significant body weight loss and mortality in mice.
“Co-infection during the AM depletion phase caused significant body weight loss and mortality.”
- Also stated in: § Influenza infection enhances susceptibility to secondary pneumococcal pneumonia · plain
“All co-infected mice died within 3 to 5 days after pneumococcal inoculation (Fig. 5B).”
Quote in the paperSubstantial claim- Also stated in: § Influenza infection enhances susceptibility to secondary pneumococcal pneumonia · plain
May combine two claims.
Findingown dataThe alveolar macrophage pool is partially replenished 9 days post-infection in BALF only, and complete replenishment appears 11 days post-infection.
“The AM pool was partially replenished 9 days p.i. (in BALF only), while complete replenishment appeared 11 days p.i. (Fig. 3A, 3B).”
Quote in the paperNot a substantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
May combine two claims.
Findingown dataThe interstitial macrophage pool is not significantly depleted during the course of influenza infection and is expanded at later time points.
“Conversely, the IM pool was not significantly depleted during the course of influenza infection; indeed, it was expanded at later time points (Fig. 3A, 3B).”
Quote in the paperNot a substantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
May combine two claims.
Findingown dataAll influenza-infected mice that were secondarily infected either 1 days or 14 days p.i. cleared the bacterial dose efficiently and did not develop secondary pneumococcal pneumonia.
“In contrast, all influenza-infected mice that were secondarily infected either 1 days or 14 days p.i. cleared the bacterial dose efficiently and did not develop secondary pneumococcal pneumonia (Fig. 6B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEarly pneumococcal clearance is significantly impaired in the alveolar airspace of influenza-infected mice compared with mock-infected controls; mock-infected mice cleared more than 95% of up to 50-fold higher doses while influenza-infected mice were unable to clear the basal inoculum.
“This experiment demonstrated that early pneumococcal clearance was significantly impaired in the alveolar airspace of influenza-infected mice compared with mock-infected controls.”
- Also stated in: § AM depletion during influenza infection impairs early pneumococcal clearance · plain
“Mock-infected mice could efficiently clear more than 95% of up to 50-fold higher doses of pneumococcus, while influenza virus-infected mice were unable to clear the basal inoculum (Fig. 5D).”
Quote in the paperSubstantial claim- Also stated in: § AM depletion during influenza infection impairs early pneumococcal clearance · plain
May combine two claims.
Findingown dataInfluenza-infected mice show high susceptibility to secondary pneumococcal infection with a significant increase in morbidity and continuous body weight loss.
“Influenza-infected mice showed high susceptibility to secondary pneumococcal infection with a significant increase in morbidity and continuous body weight loss (Fig. 5A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataResident alveolar macrophages do not express surface Ly6C, while resident lung interstitial macrophages express intermediate levels.
“We found that resident AMs didn’t express surface Ly6C, while resident lung IMs express intermediate levels, reflecting their intermediate stage of maturation and supporting the previous studies suggesting them as precursors for AMs (24, 32).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24] Landsman, 2007, Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages, J. Immunol. source
Not checked in the free run.
- cites [32] Lehnert, 1992, Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung, Environ. Health Perspect. source
Not checked in the free run.
- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
May combine two claims.
Findingown dataOnly co-infected mice develop serious pneumococcal infections; pneumonia occurs within 48-72 hours after pneumococcal inoculation.
“Only co-infected mice developed serious pneumococcal infections; pneumonia occurred within 48–72 h after pneumococcal inoculation (Fig. 5C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll single influenza- or single pneumococcus-infected mice recover quickly with no mortality.
“In contrast, all single influenza- or single pneumococcus-infected mice recovered quickly with no mortality (Fig. 5A, 5B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataInfluenza infection induces a significant depletion of the AM pool across a limited time period, with about 70% depletion after 3 days and a nadir (>90% depletion) 7 days after PR8 infection.
“We found that influenza infection induces depletion of AM pool for certain period during which early clearance of small pneumococcal inocula is significantly impaired.”
- Also stated in: § Discussion · plain
“Using this to track lung-resident macrophages during influenza infection, we found a significant depletion of the AM pool across a limited time period after infection.”
- Also stated in: § Discussion · plain
“About 70% of AMs were depleted after 3 days, reaching a nadir (> 90% depletion) 7 days after PR8 influenza infection.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
May combine two claims.
Findingown dataGM-CSF treatment in influenza-infected mice resulted in a significant expansion of the IM pool with partial replenishment of the AM pool.
“GM-CSF treatment in influenza-infected mice resulted in a significant expansion of the IM pool with partial replenishment of the AM pool (Fig. 7B).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe PKH26-PCL dye emits high fluorescence intensity for at least 19 days based on our findings.
“emitting high fluorescence intensity for at least 19 days based on our findings.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationInfluenza-infected patients are vulnerable to bacterial super-infections, suggesting defects in some or all resistance and clearance mechanisms.
“Influenza-infected patients are vulnerable to bacterial super-infections, suggesting defects in some or all of these resistance and clearance mechanisms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] McCullers, 2011, Preventing and treating secondary bacterial infections with antiviral agents, Antivir. Ther. (Lond.) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCertain bacterial pathogens, such as Streptococcus pneumoniae, are commonly isolated from patients with secondary bacterial infections.
“Certain bacterial pathogens have been commonly isolated from patients with secondary bacterial infections, such as Streptococcus pneumoniae, (4, 11, 12).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Morens, 2008, Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness, J. Infect. Dis. source
Not checked in the free run.
- cites [11] Wang, 2011, Influenza and bacterial pathogen coinfections in the 20th century, Interdiscip. Perspect. Infect. Dis. source
Not checked in the free run.
- cites [12] McCullers, 2006, Insights into the interaction between influenza virus and pneumococcus, Clin. Microbiol. Rev. source
Not checked in the free run.
May combine two claims.
Interpretationown dataResident alveolar macrophage depletion during influenza infection establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia.
“this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs resulting in pneumococcal outgrowth and lethal pneumonia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMost influenza-related mortality is not due to the viral infection alone; secondary bacterial pneumonia complicates many severe cases in influenza-infected hosts.
“Most influenza-related mortality is not due to the viral infection alone. Instead, secondary bacterial pneumonia complicates many severe cases in influenza-infected hosts (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] McCullers, 2011, Preventing and treating secondary bacterial infections with antiviral agents, Antivir. Ther. (Lond.) source
Not checked in the free run.
May combine two claims.
Study design and conductreasoningAlveolar macrophages can be gated as CD11chi F4/80hi CD11b−ve and interstitial macrophages as CD11chi F4/80hi CD11blo-int in both bronchoalveolar lavage fluid and post-lavage lung homogenate.
“Thus, AMs could be gated as CD11chi F4/80hi CD11b−ve and interstitial macrophages (IMs) as CD11chi F4/80hi CD11blo-int in both bronchoalveolar lavage fluid (BALF) and post-lavage lung homogenate (Fig. 1A).”
Quote in the paperSubstantial claim- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
May combine two claims.
Interpretationown dataThe innate defect of alveolar macrophage depletion impairs early bacterial clearance, supporting development of secondary bacterial pneumonia.
“This innate defect impairs early bacterial clearance, supporting development of secondary bacterial pneumonia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGating on CD11c and F4/80 markers only will not differentiate the various types of cells during influenza infection, potentially leading to erroneous conclusions about the absolute numbers of resident macrophages.
“Thus, gating on these two markers only will not differentiate the various types of cells during influenza infection, potentially leading to erroneous conclusions about the absolute numbers of resident macrophages.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [17] Herold, 2008, Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand, J. Exp. Med. source
Not checked in the free run.
- cites [18] Bradley, 2012, Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling, PLoS Pathog. source
Not checked in the free run.
- cites [19] Bedoret, 2009, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J. Clin. Invest. source
Not checked in the free run.
May combine two claims.
PremisecitationCD11c and F4/80 surface markers are highly expressed on alveolar macrophages, but some inflammatory macrophages/dendritic cells can express these markers as well.
“Indeed, CD11c and F4/80 surface markers are highly expressed on AM surface, but some inflammatory macrophages/dendritic cells can express these markers as well (17–19).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [17] Herold, 2008, Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand, J. Exp. Med. source
Not checked in the free run.
- cites [18] Bradley, 2012, Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling, PLoS Pathog. source
Not checked in the free run.
- cites [19] Bedoret, 2009, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J. Clin. Invest. source
Not checked in the free run.
May combine two claims.
PremisecitationResident AMs are essential for early bacterial clearance and protection against bacterial infections.
“Resident AMs are essential for early bacterial clearance and protection against bacterial infections (13, 21).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Knapp, 2005, Pneumonia models and innate immunity to respiratory bacterial pathogens, Shock source
Not checked in the free run.
- cites [21] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat. Med. source
Not checked in the free run.
May combine two claims.
PremisecitationLy6C antigen is expressed by circulating blood monocytes and macrophages which can be recruited to tissues under inflammation conditions.
“Ly6C antigen is expressed by circulating blood monocytes and macrophages which can be recruited to tissues under inflammation conditions (27).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Auffray, 2009, Blood monocytes: development, heterogeneity, and relationship with dendritic cells, Annu. Rev. Immunol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn another influenza infection model using a different strain, percentage of resident AMs - gated as CD11chigh Mac-1−ve- decreased on day 3 p.i, which is consistent with our findings.
“Interestingly, in another influenza infection model using a different strain, percentage of resident AMs – gated as CD11chigh Mac-1−ve– decreased on day 3 p.i (35), which is consistent with our findings.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Duan, 2012, Distinct macrophage subpopulations characterize acute infection and chronic inflammatory lung disease, J. Immunol. source
Not checked in the free run.
May combine two claims.
PremisecitationThe PKH26-PCL dye used to label macrophages forms fluorescent microparticles, which can be taken up by resident phagocytes in lungs and remain stable for more than 21 days.
“The PKH26-PCL dye used to label macrophages forms fluorescent microparticles, which can be taken up by resident phagocytes in lungs and remain stable for more than 21 days (21)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat. Med. source
Not checked in the free run.
May combine two claims.
InterpretationcitationThis partial depletion can be quickly re-compensated by the proliferative capacity of IMs, maturation of the recruited macrophages, or both.
“However, this partial depletion can be quickly re-compensated by the proliferative capacity of IMs, maturation of the recruited macrophages, or both (14, 24).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [14] Franke-Ullmann, 1996, Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro, J. Immunol. source
Not checked in the free run.
- cites [24] Landsman, 2007, Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages, J. Immunol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAn influx of neutrophils in the setting of development of type-specific antibody, the second line of innate immune defense coupled with the early adaptive response, was found in these models to be important for host protection against primary pneumococcal pneumonia.
“Instead, an influx of neutrophils in the setting of development of type-specific antibody, the second line of innate immune defense coupled with the early adaptive response, was found in these models to be important for host protection against primary pneumococcal pneumonia (36).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] van der Sluijs, 2004, IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection, J. Immunol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataIn vivo labeling of lung-resident macrophages was done to validate our gating strategy and to distinguish between resident AMs and recruited macrophages.
“Moreover, in vivo labeling of lung-resident macrophages was done to validate our gating strategy and to distinguish between resident AMs and recruited macrophages.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataIn vivo labeling of lung-resident macrophages in this study was a novel approach that allowed successful differentiation of AMs from recruited macrophages.
“In vivo labeling of lung-resident macrophages in this study was a novel approach that allowed successful differentiation of AMs from recruited macrophages.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThis low bacterial inoculum successfully caused lethal secondary pneumococcal pneumonia within 48-72 h after bacterial inoculation, pneumonia that was dependent on an absence of AMs.
“This low bacterial inoculum successfully caused lethal secondary pneumococcal pneumonia within 48–72 h after bacterial inoculation, pneumonia that was dependent on an absence of AMs.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
May combine two claims.
PremisecitationGating for a single marker like F4/80 antigen or macrophage-specific esterase staining of macrophages isolated from BAL fluid during influenza infection is targeting mixed populations of resident and recruited macrophages whose total cell numbers increase during infection.
“For example, gating for a single marker like F4/80 antigen or macrophage-specific esterase staining of macrophages isolated from BAL fluid during influenza infection is targeting mixed populations of resident and recruited macrophages whose total cell numbers increase during infection (37).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Hashimoto, 2007, Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice, J. Immunol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningMostly they used gating strategies not sufficient to distinguish between resident AMs, IMs and recruited exudate macrophages.
“Mostly they used gating strategies not sufficient to distinguish between resident AMs, IMs and recruited exudate macrophages.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationThis matches the previously established boundaries for maximum synergism in the secondary bacterial infection model, which parallel the typical order and timing of infections in humans.
“This matches the previously established boundaries for maximum synergism in the secondary bacterial infection model (33), which parallel the typical order and timing of infections in humans (34).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [33] McCullers, 2002, Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor, J. Infect. Dis. source
Not checked in the free run.
- cites [34] Brundage, 2008, Deaths from bacterial pneumonia during 1918-19 influenza pandemic, Emerg. Infect. Dis. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationRecent studies showed that GM-CSF over expression in lungs has prophylactic activity against lethal influenza and pneumococcal pneumonias.
“Recent studies showed that GM-CSF over expression in lungs has prophylactic activity against lethal influenza and pneumococcal pneumonias (39, 41, 42).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [39] Huang, 2011, GM-CSF in the lung protects against lethal influenza infection, Am. J. Respir. Crit. Care Med. source
Not checked in the free run.
- cites [41] Sever-Chroneos, 2011, GM-CSF modulates pulmonary resistance to influenza A infection, Antiviral Res. source
Not checked in the free run.
- cites [42] Steinwede, 2011, Local delivery of GM-CSF protects mice from lethal pneumococcal pneumonia, J. Immunol. source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenThey analyzed AM numbers on day 9 after influenza infection in BAL fluid only.
“They analyzed AM numbers on day 9 after influenza infection in BAL fluid only.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGM-CSF has an important role in pulmonary surfactant homeostasis.
“It also has an important role in pulmonary surfactant homeostasis (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Yoshida, 2001, GM-CSF regulates protein and lipid catabolism by alveolar macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenBased on their analysis, they gated AMs as CD11c+ve PKH26+ve which may be mixed with IMs.
“Based on their analysis, they gated AMs as CD11c+ve PKH26+ve which may be mixed with IMs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningMissing important marker that distinguishes between different lung-resident macrophage subsets and recruited monocytic cells or using BAL fluid only for analyzing resident AMs may lead to erroneous conclusions regarding their kinetics during infections.
“Taken together, missing important marker that distinguishes between different lung-resident macrophage subsets and recruited monocytic cells or using BAL fluid only for analyzing resident AMs may lead to erroneous conclusions regarding their kinetics during infections.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThis increase was not to the degree as that of IMs, possibly because they were analyzed at an early time point (3 days p.i).
“This increase was not to the degree as that of IMs, possibly because they were analyzed at an early time point (3 days p.i).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn another study they didn't show AM depletion because of missing CD11b marker in their AM gating, as well as harvesting only BAL fluid for kinetics analysis.
“Likewise, in another study they didn’t show AM depletion; because of missing CD11b marker in their AM gating, as well as harvesting only BAL fluid for kinetics analysis (17).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Herold, 2008, Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand, J. Exp. Med. source
Not checked in the free run.
May combine two claims.
Interpretationown dataOur data support the previous studies showing GM-CSF enhances the proliferation capacity of lung-resident macrophages and maturation of AMs.
“Thus, our data support the previous studies showing GM-CSF enhances the proliferation capacity of lung-resident macrophages and maturation of AMs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGM-CSF regulates AM differentiation and activation.
“Among these activities, it regulates AM differentiation and activation (23, 38)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [23] Guth, 2009, Lung environment determines unique phenotype of alveolar macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol. source
Not checked in the free run.
- cites [38] Shibata, 2001, GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1, Immunity source
Not checked in the free run.
May combine two claims.
Interpretationown dataResident AM depletion during influenza infection establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, thereby allowing pneumococcal outgrowth causing lethal pneumococcal pneumonia.
“Resident AM depletion during influenza infection establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, thereby allowing pneumococcal outgrowth causing lethal pneumococcal pneumonia.”
Quote in the paperSubstantial claim- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
The paper relies on this without support.
PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
“PKH26-PCL dye demonstrated efficient labeling and stability inside the lung-resident macrophages for at least 14 days after mock-infection (i.e. 19 days after labeling), thereby covering the tracking period during which we did the kinetics analyses (Supplemental Fig. 3).”
The paper relies on this without support.
Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
“Influenza is well known to increase susceptibility to secondary bacterial infections, such as secondary pneumococcal pneumonia.”
The paper relies on this without support.
IMs have a higher proliferative capacity than AMs.
“Considering the higher proliferative capacity of IMs over AMs, our short treatment regimen could significantly expand the pool of IMs more than AMs.”
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?
Prior viral infections dysregulate both alveolar macrophages and neutrophils, thereby inhibiting bactericidal activity.
“Prior viral infections dysregulate both alveolar macrophages (64, 131–136) and neutrophils (65, 128, 129), thereby inhibiting bactericidal activity.”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [133]
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Xu, M., Yang, W., Wang, X., & Nayak, D. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.584310 · Cited by 48 · see citing works
Ahmed-Hassan, H., Sisson, B., Shukla, R. K., Wijewantha, Y., Funderburg, N. T., Li, Z., Hayes, D., Demberg, T., & Liyanage, N. P. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01979 · Cited by 47 · see citing works
Ashley, J. W., Hancock, W. D., Nelson, A. J., Bone, R. N., Tse, H. M., Wohltmann, M., TURK, J. W., & Ramanadham, S. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.754945 · Cited by 47 · see citing works
Isolation and In Vitro Culture of Murine and Human Alveolar Macrophages
Nayak, D. K., Mendez, O. A., Bowen, S. K., & Mohanakumar, T. (2018) · Journal of Visualized Experiments · doi:10.3791/57287 · Cited by 51 · see citing works
IL-22-binding protein exacerbates influenza, bacterial super-infection
Abood, R. N., McHugh, K. J., Rich, H. E. A., Ortiz, M. A., Tobin, J. M., Ramanan, K., Robinson, K. M., Bomberger, J. M., Kolls, J. K., Manni, M. L., et al. (2019) · Mucosal Immunology · doi:10.1038/s41385-019-0188-7 · Cited by 47 · see citing works
- Authors
- Ghoneim, H. E., Thomas, P. G., & McCullers, J. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- McCullers, Jonathan A
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-08-01
- Volume
- 191
- Issue
- 3
- Pages
- 1250-1259
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4907362
- OpenAlex
- W2108100953
- Semantic Scholar
- 33c6fb14dfe3f1778c1f4919538e09a8e36d1cfb
- Cited by
- 394
- References
- 44
- Citations by year
- 2026: 29 · 2025: 33 · 2024: 26 · 2023: 28 · 2022: 36 · 2021: 27 · 2020: 45 · 2019: 28 · 2018: 40 · 2017: 25 · 2016: 26 · 2015: 24 · 2014: 22 · 2013: 5
- FWCI
- 18.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- St. Jude Children's Research Hospital (CA021765, P30 CA021765)
- American Lebanese Syrian Associated Charities (CA021765)
- National Cancer Institute (CA021765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI107625)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Keywords
- alveolar macrophages, influenza, Streptococcus pneumoniae, secondary bacterial infection, macrophage depletion, innate immunity, GM-CSF, co-infection, lung immunity
- MeSH terms
- Animals, Female, Lung, Mice, Inbred BALB C, Organic Chemicals, Orthomyxoviridae Infections, Pneumococcal Infections, Streptococcus pneumoniae, Superinfection, Macrophages, Alveolar, Mice, Coinfection
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
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