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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.
Overview
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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.
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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
“We conclude that resident AM depletion occurs during influenza infection.”
- Also stated in: § Introduction · boosted
“We demonstrate that influenza virus depletes alveolar macrophages.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
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
“In mock-infected mice, by contrast, more than 95% of inocula up-to-50-fold higher was efficiently cleared.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
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
“These remaining AMs were significantly depleted starting 3 days p.i. compared with those in mock-infected mice (Fig. 3B).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Tracking of AMs and IMs dynamic changes during influenza infection
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > In vivo labeling of lung-resident macrophages can distinguish AMs from interstitial macrophages
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“We found that AMs were significantly depleted within 7 days after pdm H1N1 infection to levels comparable to PR8 infection (Fig. 2B).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza virus depletes alveolar macrophages
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > In vivo labeling of lung-resident macrophages can distinguish AMs from interstitial macrophages
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“We found that AMs were significantly depleted in the alveolar airspace shortly after PR8 infection starting on the first day p.i. (Fig. 3A).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Tracking of AMs and IMs dynamic changes during influenza infection
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza-infected mice demonstrate increased susceptibility to secondary pneumococcal pneumonia during the AM depletion phase
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
“Early pneumococcal clearance was significantly impaired during PR8 infection from 3 until 9 days p.i. (Fig. 6A).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza-infected mice demonstrate increased susceptibility to secondary pneumococcal pneumonia during the AM depletion phase
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 37
- Probably not a substantial claim. 14
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
“Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
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
“Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
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
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Influenza infection enhances susceptibility to secondary pneumococcal pneumonia · 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 AM pool was partially replenished 9 days p.i. (in BALF only), while complete replenishment appeared 11 days p.i. (Fig. 3A, 3B).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Tracking of AMs and IMs dynamic changes during influenza infection
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Tracking of AMs and IMs dynamic changes during influenza infection
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza-infected mice demonstrate increased susceptibility to secondary pneumococcal pneumonia during the AM depletion phase
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > AM depletion during influenza infection impairs early pneumococcal clearance
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § AM depletion during influenza infection impairs early pneumococcal clearance · 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
“Influenza-infected mice showed high susceptibility to secondary pneumococcal infection with a significant increase in morbidity and continuous body weight loss (Fig. 5A).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza infection enhances susceptibility to secondary pneumococcal pneumonia
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Tracking of AMs and IMs dynamic changes during influenza infection
What the sources say
- Not checked yetcites [24] Landsman, 2007, Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages, J. Immunol. source
- Not checked yetcites [32] Lehnert, 1992, Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung, Environ. Health Perspect. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“Only co-infected mice developed serious pneumococcal infections; pneumonia occurred within 48–72 h after pneumococcal inoculation (Fig. 5C).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza infection enhances susceptibility to secondary pneumococcal pneumonia
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
“In contrast, all single influenza- or single pneumococcus-infected mice recovered quickly with no mortality (Fig. 5A, 5B).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Influenza infection enhances susceptibility to secondary pneumococcal pneumonia
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
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · 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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > Local GM-CSF treatment decreases secondary pneumococcal pneumonia development in influenza-infected mice
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
“emitting high fluorescence intensity for at least 19 days based on our findings.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
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.
In the paper
“Influenza-infected patients are vulnerable to bacterial super-infections, suggesting defects in some or all of these resistance and clearance mechanisms.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
What the sources say
- Not checked yetcites [3] McCullers, 2011, Preventing and treating secondary bacterial infections with antiviral agents, Antivir. Ther. (Lond.) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Certain bacterial pathogens have been commonly isolated from patients with secondary bacterial infections, such as Streptococcus pneumoniae, (4, 11, 12).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
What the sources say
- Not checked yetcites [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 yetcites [11] Wang, 2011, Influenza and bacterial pathogen coinfections in the 20th century, Interdiscip. Perspect. Infect. Dis. source
- Not checked yetcites [12] McCullers, 2006, Insights into the interaction between influenza virus and pneumococcus, Clin. Microbiol. Rev. source
Strength:plain· not yet calibratedCausal:correlational· 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.
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
“this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs resulting in pneumococcal outgrowth and lethal pneumonia.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
What the sources say
- Not checked yetcites [3] McCullers, 2011, Preventing and treating secondary bacterial infections with antiviral agents, Antivir. Ther. (Lond.) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Results > In vivo labeling of lung-resident macrophages can distinguish AMs from interstitial macrophages
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: PKH26-PCL dye remains associated with the labeled resident macrophages and is not transferred to other cells during influenza infection.
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
“This innate defect impairs early bacterial clearance, supporting development of secondary bacterial pneumonia.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [19] Bedoret, 2009, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J. Clin. Invest. source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [19] Bedoret, 2009, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J. Clin. Invest. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Resident AMs are essential for early bacterial clearance and protection against bacterial infections (13, 21).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Ly6C antigen is expressed by circulating blood monocytes and macrophages which can be recruited to tissues under inflammation conditions (27).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [27] Auffray, 2009, Blood monocytes: development, heterogeneity, and relationship with dendritic cells, Annu. Rev. Immunol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [35] Duan, 2012, Distinct macrophage subpopulations characterize acute infection and chronic inflammatory lung disease, J. Immunol. source
Strength:plain· not yet calibratedCausal:correlational· 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. It may state two separate claims as one.
In the paper
“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)”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [21] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat. Med. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, this partial depletion can be quickly re-compensated by the proliferative capacity of IMs, maturation of the recruited macrophages, or both (14, 24).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [14] Franke-Ullmann, 1996, Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro, J. Immunol. source
- Not checked yetcites [24] Landsman, 2007, Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages, J. Immunol. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [36] van der Sluijs, 2004, IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection, J. Immunol. source
Strength:plain· not yet calibratedCausal:direct· 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
“Moreover, in vivo labeling of lung-resident macrophages was done to validate our gating strategy and to distinguish between resident AMs and recruited macrophages.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
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. It may state two separate claims as one.
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
“In vivo labeling of lung-resident macrophages in this study was a novel approach that allowed successful differentiation of AMs from recruited macrophages.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It 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
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Influenza infection increases susceptibility to secondary bacterial infections such as pneumococcal pneumonia.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [37] Hashimoto, 2007, Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice, J. Immunol. source
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
“Mostly they used gating strategies not sufficient to distinguish between resident AMs, IMs and recruited exudate macrophages.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
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.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [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 yetcites [34] Brundage, 2008, Deaths from bacterial pneumonia during 1918-19 influenza pandemic, Emerg. Infect. Dis. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent studies showed that GM-CSF over expression in lungs has prophylactic activity against lethal influenza and pneumococcal pneumonias (39, 41, 42).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [39] Huang, 2011, GM-CSF in the lung protects against lethal influenza infection, Am. J. Respir. Crit. Care Med. source
- Not checked yetcites [41] Sever-Chroneos, 2011, GM-CSF modulates pulmonary resistance to influenza A infection, Antiviral Res. source
- Not checked yetcites [42] Steinwede, 2011, Local delivery of GM-CSF protects mice from lethal pneumococcal pneumonia, J. Immunol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“They analyzed AM numbers on day 9 after influenza infection in BAL fluid only.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“It also has an important role in pulmonary surfactant homeostasis (40).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [40] Yoshida, 2001, GM-CSF regulates protein and lipid catabolism by alveolar macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol. source
Strength:plain· not yet calibratedCausal:direct· 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 states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Based on their analysis, they gated AMs as CD11c+ve PKH26+ve which may be mixed with IMs.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Strength:hedged· not yet calibratedCausal:conditional· 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.
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
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Strength:hedged· not yet calibratedCausal:conditional· 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. It 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
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Strength:hedged· not yet calibratedCausal:conditional· 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. It may state two separate claims as one.
In the paper
“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).”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [17] Herold, 2008, Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand, J. Exp. Med. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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
“Thus, our data support the previous studies showing GM-CSF enhances the proliferation capacity of lung-resident macrophages and maturation of AMs.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Among these activities, it regulates AM differentiation and activation (23, 38)”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
What the sources say
- Not checked yetcites [23] Guth, 2009, Lung environment determines unique phenotype of alveolar macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol. source
- Not checked yetcites [38] Shibata, 2001, GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1, Immunity source
Strength:plain· not yet calibratedCausal:direct· 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. It 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
“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.”
§ Depletion of alveolar macrophages during influenza infection facilitates bacterial super-infections > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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?
In the citing paper
“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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Metadata
- 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.
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