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Cited by 168Influenza Virus Research StudiesPneumonia and Respiratory InfectionsAntimicrobial Resistance in Staphylococcus

Influenza virus primes mice for pneumonia from Staphylococcus aureus.

Open access
Iverson, Amy R., Boyd, Kelli L., McAuley, Julie L., Plano, Lisa R., Hart, Mark E., McCullers, Jonathan A.·2011·The Journal of Infectious Diseases
DOI 10.1093/infdis/jiq113PMC PMC3071123
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Abstract

Superinfections from Staphylococcus aureus following influenza are an increasing concern. We assessed several laboratory and clinical strains in a mouse coinfection model with influenza virus. A methicillin-resistant USA300 clone and several recent clinical strains from patients with necrotizing pneumonia caused high mortality following influenza virus infection in mice. Both viral and bacterial lung titers were enhanced during coinfections compared with single infections. However, differences in titers did not correspond with differences in disease outcomes in a comparison of superinfections from a highly pathogenic strain with those from a poorly pathogenic strain. These strains did differ, however, in expression of Panton-Valentine leukocidin and in the degree of inflammatory lung damage each engendered. The viral cytotoxin PB1-F2 contributed to the negative outcomes. These data suggest that additional study of specific bacterial virulence factors involved in the pathogenesis of inflammation and lung damage during coinfections is needed.

AI snapshot

Written from the paper’s full text.

TL;DR

In a mouse coinfection model, influenza virus primes for severe *Staphylococcus aureus* pneumonia, with high mortality from USA300/USA400 and recent clinical strains. Disease severity tracks more with inflammatory lung damage and PB1-F2 expression than with bacterial titers.

Key findings

  • Influenza preinfection significantly enhanced mortality from *S. aureus* NRS-193 at 10^7, 10^8, and 10^9 CFUs, reaching 100% mortality at the highest dose; strain-specific differences were seen, with UAMS-1 killing 3 (50%) of 6 mice and ATCC 27733 killing 1 of 6 mice after influenza.
  • Coinfection increased both viral and bacterial lung titers, but strain-dependent outcomes were not explained by titers: NRS-193 and ATCC 27733 did not differ significantly in lung titers, while blood and spleen titers were significantly higher early after ATCC 27733 infection; both staphylococcal strains enhanced total viral lung load.
  • NRS-193 superinfection caused worse inflammatory lung damage than ATCC 27733, including massive alveolar and bronchiolar necrosis, interstitial consolidation, and protein-rich exudates; among surveyed virulence factors, only Panton-Valentine leukocidin (PVL) was present in NRS-193 and absent in ATCC 27733 and UAMS-1.
  • Lack of PB1-F2 significantly decreased mortality, expression of 1918 PB1-F2 increased mortality, and the 2009 pandemic H1N1 strain lacking functional PB1-F2 did not appreciably enhance disease at the doses used; depletion of neutrophils, CD4+ T cells, or macrophages had no effect on weight loss or bacterial lung titers.

Methods

  • Eight-week-old female BALB/c mice were infected intranasally with influenza viruses (A/California/7/09, PR8, PR8/ΔPB1-F2, PR8/1918 PB1-F2) or mock-infected, then challenged with *S. aureus* strains including USA300 LAC, USA400 NRS-193/NRS-194, recent clinical necrotizing pneumonia isolates, and laboratory strains by intranasal, intratracheal, or intravenous routes; mice were monitored for 21 days.
  • Outcomes included weight loss, mortality, bacterial and viral titers from blood, lung, and spleen, blinded semiquantitative histopathology scoring, RT-PCR for selected virulence genes, and cellular depletion of neutrophils, CD4+ T cells, or macrophages.
  • Survival was compared by log-rank test on Kaplan-Meier data; weight loss and titers were compared by analysis of variance, with P < .05 considered significant.

Limitations

  • Stated: the authors did not assess natural killer cell function, and they conclude that additional study of specific bacterial virulence factors involved in inflammation and lung damage during coinfection is needed.
  • Stated: the 2009 H1N1 strain did not appreciably enhance disease “at the doses used in this study,” indicating dose-dependent limits to that finding.
  • Evident from the text: this is a mouse model only; the virulence factor survey was limited to selected genes; and PVL presence is an association, not proven causation, since the paper notes PVL has shown few effects in mouse pneumonia models and other factors likely drive the phenotype.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/infdis/jiq113

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Differences in titers did not correspond with differences in disease outcomes in a comparison of superinfections from a highly pathogenic strain with those from a poorly pathogenic strain.

    “However, differences in titers did not correspond with differences in disease outcomes in a comparison of superinfections from a highly pathogenic strain with those from a poorly pathogenic strain.”
    Quote in the paperSubstantial claim
  • Findingnone given

    The viral cytotoxin PB1-F2 contributed to the negative outcomes.

    “The viral cytotoxin PB1-F2 contributed to the negative outcomes.”
    Quote in the paperSubstantial claim
  • Findingown data

    Both viral and bacterial lung titers were enhanced during coinfections compared with single infections.

    “Both viral and bacterial lung titers were enhanced during coinfections compared with single infections.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A methicillin-resistant USA300 clone and several recent clinical strains from patients with necrotizing pneumonia caused high mortality following influenza virus infection in mice.

    “A methicillinresistant USA300 clone and several recent clinical strains from patients with necrotizing pneumonia caused high mortality following influenza virus infection in mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    A mild inflammatory infiltrate could be seen in the airways without necrosis or hyperplasia in mice mock infected with PBS and then challenged with either bacterial strain.

    “A mild inflammatory infiltrate could be seen in the airways without necrosis or hyperplasia.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    The highly pathogenic and poorly pathogenic S. aureus strains differed in expression of Panton-Valentine leukocidin and in the degree of inflammatory lung damage each engendered.

    “These strains did differ, however, in expression of Panton-Valentine leukocidin and in the degree of inflammatory lung damage each engendered.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The lungs of mice mock infected with PBS and then challenged with either bacterial strain were indistinguishable; a mild, purulent perivascular inflammatory process consisting of macrophages and neutrophils admixed with fibrinous exudates was seen in a perivascular distribution and increased in severity between the 24- and 48-h time points.

    “The lungs of mice mock infected with PBS and then challenged with either bacterial strain were indistinguishable; a mild, purulent perivascular inflammatory process consisting of macrophages and neutrophils admixed with fibrinous exudates was seen in a perivascular distribution and increased in severity between the 24and 48-h time points (Figure 4C-E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    More weight loss was observed in mice preinfected with influenza virus than in mock-infected mice, and priming with virus significantly enhanced mortality at all 3 doses of S. aureus NRS-193, resulting in 100% mortality at the highest dose used.

    “More weight loss was observed in mice preinfected with influenza virus than in mock-infected mice, and priming with virus significantly enhanced mortality at all 3 doses, resulting in 100% mortality at the highest dose used (Figure 1A, B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NRS-193 has genes that code for the closely related gene SEB, which is absent in ATCC 27733.

    “However, NRS-193 has genes that code for the closely related gene SEB, which is absent in ATCC 27733.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The virus infectious dose for most experiments was 30 TCID50, which caused 10%-15% weight loss and no mortality when given alone.

    “The virus infectious dose for most experiments was 30 times the median tissue culture infective dose (TCID 50 ), which caused 10%-15% weight loss and no mortality when given alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In the staphylococcal superinfection model, lack of PB1-F2 significantly decreased mortality either using an isogenic virus or using the novel pandemic H1N1 strain that does not code for full-length PB1-F2, whereas expression of the more inflammatory PB1-F2 from the 1918 pandemic strain increased mortality.

    “Similarly, in the staphylococcal superinfection model, lack of PB1-F2 significantly decreased mortality either using an isogenic virus (Figure 5A) or using the novel pandemic H1N1 strain that does not code for full-length PB1-F2 (Figure 5B) [34], whereas expression of the more inflammatory PB1-F2 [25] from the 1918 pandemic strain increased mortality.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] McAuley, 2010, The effects of influenza A virus PB1-F2 protein on polymerase activity are strain specific and do not impact pathogenesis, J Virol source

      Not checked in the free run.

    • cites [25] McAuley, 2007, Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia, Cell Host Microbe source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Reversing the order of influenza virus and S. aureus administration or giving the virus and the bacteria together resulted in no excess weight loss or mortality over separate administration of the virus or the bacteria.

    “Reversing the order or giving the virus and the bacteria together resulted in no excess weight loss or mortality over separate administration of the virus or the bacteria (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The degree of inflammatory involvement, the severity of airway necrosis, and the extent of fibrinous exudate were clearly worse in the lungs of mice superinfected with NRS-193 than in mice superinfected with ATCC 27733.

    “The degree of inflammatory involvement, the severity of airway necrosis, and the extent of fibrinous exudate were clearly worse in the lungs of mice superinfected with NRS-193 than in mice superinfected with ATCC 27733 (Figure 4E-G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The osteomyelitis isolate UAMS-1 killed only 3 (50%) of 6 mice following influenza, and the ATCC strain 27733 killed only 1 of 6 mice.

    “The osteomyelitis isolate UAMS-1 killed only 3 (50%) of 6 mice following influenza, and the ATCC strain 27733 killed only 1 of 6 mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no significant difference between NRS-193 lung titers and ATCC 27733 lung titers for influenza-infected mice, nor was there a significant difference for mock-infected mice.

    “Although significant differences in NRS-193 lung titers could be seen between mock-infected mice and mice preinfected with influenza virus, there was no significant difference between NRS-193 lung titers and ATCC 27733 lung titers for infected mice, nor was there a significant difference for mock-infected mice (Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mice preinfected with influenza, the inflammatory infiltrate was more severe, extending into the interstitium and the pleura, and focal areas of airway necrosis were observed, together with significant hyperplasia.

    “In mice preinfected with influenza, the inflammatory infiltrate was more severe, extending into the interstitium and the pleura, and focal areas of airway necrosis were observed, together with significant hyperplasia (Figure 4F,G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spleens and livers from PBS-primed mice were normal.

    “Spleens and livers from PBS-primed mice were normal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S. aureus significantly increased viral lung titers during the coinfection by means of an unclear mechanism, although the importance of this for pathogenesis is questionable, since the low-virulence S. aureus strain enhanced viral titers to the same extent as the high-virulence strain.

    “In addition, S. aureus significantly increased viral lung titers during the coinfection by means of an unclear mechanism, although the importance of this for pathogenesis is questionable, since the low-virulence S. aureus strain enhanced viral titers to the same extent as the high-virulence strain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Administering S. aureus 3 or 7 days after influenza virus resulted in 100% mortality, an effect that was no longer evident when S. aureus was administered 14 days after virus infection.

    “Administering S. aureus 3 or 7 days after influenza virus resulted in 100% mortality, an effect that was no longer evident when S. aureus was administered 14 days after virus infection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both staphylococcal strains enhanced the total viral lung load in the mice, but the virus was not found outside the lungs.

    “Both staphylococcal strains enhanced the total viral lung load in the mice (Figure 3D), but the virus was not found outside the lungs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Livers from both groups of virus-primed mice showed perivascular infiltrates and scattered inflammatory foci, whereas the corresponding spleens showed mild lymphoid follicular hyperplasia.

    “The livers from both groups of virus-primed mice showed perivascular infiltrates and scattered inflammatory foci, whereas the corresponding spleens showed mild lymphoid follicular hyperplasia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An intranasal administration of 10^9 CFUs of heat-killed S. aureus resulted in modest disease and some deaths following influenza, but 10^8 CFUs of live bacteria caused significantly more mortality than the heat-killed preparation or the spent media from 10^9 CFUs of bacteria.

    “Although an intranasal administration of 10 9 CFUs of heat-killed bacteria did result in modest disease and some deaths following influenza, 10 8 CFUs of live bacteria caused significantly more mortality than the heat-killed preparation or the spent media from 10 9 CFUs of bacteria (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When macrophage depletion was repeated and mice were challenged with a higher dose (10^8 CFUs) of S. aureus, bacterial titers were significantly higher in the nondepleted group, but weight loss and histopathology scores did not differ.

    “Although bacterial titers were significantly higher in the nondepleted group (data not shown), weight loss and histopathology scores did not differ (Figure 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both NRS-193 and ATCC 27733 strains lack the genes for the F component of the gamma-toxin (hlgB), the staphylococcal toxic shock syndrome superantigen TSST-1, and exfoliative toxins A and B (ETA, ETB).

    “Both strains lack the genes for the F component of the c-toxin (hlgB), the staphylococcal toxic shock syndrome superantigen TSST-1, and exfoliative toxins A and B (ETA, ETB).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The viral cytotoxin PB1-F2 contributed to mortality in this model in a manner similar to that seen with pneumococcus, and expression of the pandemic 1918 PB1-F2 enhanced mortality.

    “The viral cytotoxin PB1-F2 contributed to mortality in this model in a manner similar to that seen with pneumococcus [25], and expression of the pandemic 1918 PB1-F2 enhanced mortality.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] McAuley, 2007, Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia, Cell Host Microbe source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During the 1957-1958 pandemic, staphylococci assumed a novel prominence as the leading etiologic agent of secondary bacterial disease.

    “During the 1957-1958 pandemic, however, staphylococci assumed a novel prominence as the leading etiologic agent of secondary bacterial disease [6,7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Martin, 1959, Asian influenza A in Boston, 1957-1958. II. Severe staphylococcal pneumonia complicating influenza, AMA Arch Intern Med source

      Not checked in the free run.

    • cites [7] Oseasohn, 1959, Clinicopathologic study of thirty-three fatal cases of Asian influenza, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It has been estimated that >95% of all fatal influenza cases during the 1918-1919 pandemic were complicated by secondary bacterial pneumonia.

    “It has been estimated that .95% of all fatal influenza cases during the 1918-1919 pandemic were complicated by to secondary bacterial pneumonia [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] 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.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    USA300 and USA400 strains are now frequently being identified as agents of bacterial pneumonia, particularly in children with influenza.

    “These strains are now frequently being identified as agents of bacterial pneumonia, particularly in children with influenza [10,11].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Centers for Disease Control and Prevention, 2007, Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza—Louisiana and Georgia, December 2006-January 2007, MMWR Morb Mortal Wkly Rep

      Not checked in the free run.

    • cites [11] Finelli, 2008, Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection, Pediatrics source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Although few data are available, bacterial pneumonia is complicating around 30% of fatal cases of the 2009 novel pandemic H1N1 influenza, with S. aureus the most commonly recognized pathogen.

    “Although few data are available, it seems that bacterial pneumonia is complicating around 30% of fatal cases, with S. aureus the most commonly recognized pathogen [12,15,16].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Murray, 2010, Community-acquired pneumonia due to pandemic A(H1N1)2009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection, PLoS One source

      Not checked in the free run.

    • cites [15] Centers for Disease Control and Prevention, 2009, Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)—United States, May-August 2009, MMWR Morb Mortal Wkly Rep

      Not checked in the free run.

    • cites [16] Cheng, 2009, Fatal co-infection with swine origin influenza virus A/H1N1 and community-acquired methicillin-resistant Staphylococcus aureus, J Infect source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The epidemiological characteristics of S. aureus pneumonia have changed during the past decade with the emergence of the USA300 and USA400 clones of methicillin-resistant S. aureus.

    “The epidemiological characteristics of S. aureus pneumonia have changed during the past decade with the emergence of the USA300 and USA400 clones of methicillin-resistant S. aureus [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Hageman, 2006, Severe community-acquired pneumonia due to Staphylococcus aureus, 2003–04 influenza season, Emerg Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bacterial superinfections are a common cause of excess mortality following influenza, particularly in pandemic years.

    “Bacterial superinfections are a common cause of excess mortality following influenza, particularly in pandemic years [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] McCullers, 2006, Insights into the interaction between influenza virus and pneumococcus, Clin Microbiol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Secondary staphylococcal disease continued to be seen through the second wave of the Asian flu in 1960-1961, but for the following several decades staphylococci once again became uncommon as a cause of either primary or secondary pneumonia.

    “Secondary staphylococcal disease continued to be seen through the second wave of the ''Asian flu '' in 1960-1961 [8], but for the following several decades staphylococci once again became uncommon as a cause of either primary or secondary pneumonia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Miller, 1962, Staphylococcal pneumonia in influenza—5 cases, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Influenza-associated S. aureus pneumonia is characterized as fulminant, with short intervals between onset of illness and diagnosis of pneumonia (<7 days) and rapid (often within <24 h) progression to severe disease with multilobar involvement.

    “The disease is characterized as fulminant, with short intervals between onset of illness and diagnosis of pneumonia (,7 days) and rapid (often within ,24 h) progression to severe disease with multilobar involvement [6,7,9,11,12].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [6] Martin, 1959, Asian influenza A in Boston, 1957-1958. II. Severe staphylococcal pneumonia complicating influenza, AMA Arch Intern Med source

      Not checked in the free run.

    • cites [7] Oseasohn, 1959, Clinicopathologic study of thirty-three fatal cases of Asian influenza, N Engl J Med source

      Not checked in the free run.

    • cites [9] Hageman, 2006, Severe community-acquired pneumonia due to Staphylococcus aureus, 2003–04 influenza season, Emerg Infect Dis source

      Not checked in the free run.

    • cites [11] Finelli, 2008, Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection, Pediatrics source

      Not checked in the free run.

    • cites [12] Murray, 2010, Community-acquired pneumonia due to pandemic A(H1N1)2009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Death in fatal cases of influenza-associated S. aureus pneumonia follows rapidly after the diagnosis of severe pneumonia, with the clinical course seemingly unaffected by the appropriateness and timing of antibiotic administration.

    “Death in fatal cases follows rapidly after the diagnosis of severe pneumonia, with the clinical course seemingly unaffected by the appropriateness and timing of antibiotic administration [6][7][8][9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6][7][8][9]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intravenous administration of S. aureus in agar allows targeted delivery of bacteria to the lungs and prevents the rapid clearance seen when the organisms are suspended in saline.

    “Intravenous administration in agar allows targeted delivery of bacteria to the lungs and prevents the rapid clearance seen when the organisms are suspended in saline [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Sawai, 1997, Role of coagulase in a murine model of hematogenous pulmonary infection induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads, Infect Immun source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The staphylococcal and pneumococcal models differ in that significantly larger amounts of bacteria are required for expression of lung disease with S. aureus than with S. pneumoniae, bacterial strain-dependent differences in outcomes following influenza appear to be more dependent on inflammatory potential than on lung titer with S. aureus, and no synergistic enhancement of disease was seen 2 wkks

    “Significantly larger amounts of bacteria are required for expression of lung disease with S. aureus than with S. pneumoniae, bacterial strain-dependent differences in outcomes following influenza appear to be more dependent on inflammatory potential than on lung titer with S. aureus, and no synergistic enhancement of disease was seen 2 weeks after influenza when S. aureus was the secondary”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In the pneumococcal secondary infection model, influenza virus enhances the bacterial load of S. pneumoniae recovered from the lungs and blood of mice, and strain-specific differences between outcomes are directly related to the total bacterial lung load.

    “In the pneumococcal secondary infection model, influenza virus enhances the bacterial load of S. pneumoniae recovered from the lungs and blood of mice, and strain-specific differences between outcomes are directly related to the total bacterial lung load [23,32,33].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] 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 [32] McCullers, 2010, Influenzaenhances susceptibility to natural acquisition and disease from Streptococcus pneumoniae in ferrets, J Infect Dis source

      Not checked in the free run.

    • cites [33] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Microscopic evaluation of lungs was performed by an experienced veterinary pathologist blinded to study purpose and design and to group composition.

    “Microscopic evaluation of lungs was performed by an experienced veterinary pathologist (K.L.B.) blinded to study purpose and design and to group composition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PVL has been proposed as a marker for the enhanced virulence of USA300 and USA400 clones, particularly when their ability to cause necrotizing pneumonia in humans has been considered.

    “which has been proposed as a marker for the enhanced virulence of USA300 and USA400 clones, particularly when their ability to cause necrotizing pneumonia in humans has been considered [30,31].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Gillet, 2002, Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients, Lancet source

      Not checked in the free run.

    • cites [31] Gillet, 2007, Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Although coinfection with virus and either S. aureus strain enhances the growth of each strain in clinically relevant organs, strain-specific differences in the degree of these increases do not account for differences in outcomes between strains.

    “We conclude from these data that, although coinfection with virus and either S. aureus strain enhances the growth of each strain in clinically relevant organs, strain-specific differences in the degree of these increases do not account for differences in outcomes between strains.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Viability of the inocula was confirmed by means of plate counts with each experiment.

    “Viability of the inocula was confirmed by means of plate counts with each experiment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Virus-induced inflammatory responses contribute to poor outcomes during combined influenza-staphylococcal pneumonia, but no single cell type is responsible for the observed lung injury.

    “We conclude from these data that virus-induced inflammatory responses contribute to poor outcomes during combined influenza-staphylococcal pneumonia but that no single cell type is responsible for the observed lung injury.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Influenza virus infection in mice enhances secondary bacterial pneumonia from S. pneumoniae.

    “We have previously demonstrated that influenza virus infection in mice enhances secondary bacterial pneumonia from S. pneumoniae [23][24][25]27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23][24][25]27]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Influenza-staphylococcal coinfections have increased following the emergence of the USA300 and USA400 lineages, and S. aureus has been identified as a common cause of death during the recent H1N1 influenza pandemic.

    “Influenza-staphylococcal coinfections have increased following the emergence of the USA300 and USA400 lineages [9,11,30,31], and S. aureus has been identified as a common cause of death during the recent H1N1 influenza pandemic [12,15].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [9] Hageman, 2006, Severe community-acquired pneumonia due to Staphylococcus aureus, 2003–04 influenza season, Emerg Infect Dis source

      Not checked in the free run.

    • cites [11] Finelli, 2008, Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection, Pediatrics source

      Not checked in the free run.

    • cites [30] Gillet, 2002, Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients, Lancet source

      Not checked in the free run.

    • cites [31] Gillet, 2007, Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin, Clin Infect Dis source

      Not checked in the free run.

    • cites [12] Murray, 2010, Community-acquired pneumonia due to pandemic A(H1N1)2009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection, PLoS One source

      Not checked in the free run.

    • cites [15] Centers for Disease Control and Prevention, 2009, Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)—United States, May-August 2009, MMWR Morb Mortal Wkly Rep

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In both scenarios, function of the effector cells is impaired by influenza virus infection, so only the harmful effects of the inflammatory response are realized.

    “In both scenarios, function of the effector cells is impaired by influenza virus infection, so only the harmful effects of the inflammatory response are realized [33,[44][45][46].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [33] Sun, 2008, Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection, Nat Med source

      Not checked in the free run.

    • cites [44] Abramson, 1982, Depression of monocyte and polymorphonuclear leukocyte oxidative metabolism and bactericidal capacity by influenza A virus, Infect Immun source

      Not checked in the free run.

    • cites [45] White, 2005, Respiratory innate immune proteins differentially modulate the neutrophil respiratory burst response to influenza A virus, Am J Physiol Lung Cell Mol Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Late after infection, when virus has cleared (>12 days), desensitization of pattern recognition receptors to stimuli reverses this effect, preventing beneficial inflammatory responses from contributing to bacterial clearance.

    “Late after infection, when virus has cleared (.12 days), desensitization of pattern recognition receptors to stimuli reverses this effect, preventing beneficial inflammatory responses from contributing to bacterial clearance [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Didierlaurent, 2008, Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection, J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the context of the Louria classification scheme, S. aureus is likely to be a secondary invader primarily during concomitant viral-bacterial pneumonia, whereas pneumococcus is equally well suited as a late secondary pathogen following the clearance of the virus.

    “In the context of the Louria classification scheme [13], S. aureus is likely to be a secondary invader primarily during concomitant viral-bacterial pneumonia, whereas pneumococcus is equally well suited as a late secondary pathogen following the clearance of the virus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Louria, 1959, Studies on influenza in the pandemic of 1957–58. II. Pulmonary complications of influenza, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Little to no enhancement of disease is seen if the bacterial infection precedes exposure to the virus or the organisms are encountered together.

    “Little to no enhancement of disease is seen if the bacterial infection precedes exposure to the virus or the organisms are encountered together [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] 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.

43 of 43

  • The paper relies on this without support.

    There is a dearth of information regarding the true incidence and clinical features of mild influenza-associated S. aureus pneumonia.

    “Because it is difficult to define the etiological characteristics of secondary bacterial pneumonia, there is a dearth of information regarding the true incidence and clinical features of mild disease.”

  • The paper relies on this without support.

    The 2009 H1N1 strain lacks a functional PB1-F2.

    “the 2009 H1N1 strain, which lacks a functional PB1-F2”

  • The paper relies on this without support.

    Findings from the mouse model of influenza-staphylococcal superinfection can be extrapolated to human disease.

    “This likely explains the changed epidemiological character that has been observed during the past decade, as S. aureus coinfections with influenza have become more common [10,11,47].”
3 of 3

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 mouse models, pre-infection with influenza before S. aureus exposure increases lung damage and bacterial density.

    “Increased lung damage and bacterial density has also been shown (DeLeo and Musser, 2010; Lee M.H. et al., 2010; Iverson et al., 2011).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Iverson et al., 2011

  • In mouse models, pre-infection with influenza before S. aureus exposure increases morbidity and mortality compared with S. aureus exposure alone.

    “mouse models have highlighted increased morbidity and mortality in mice that are pre-infected with influenza before they are exposed to S. aureus vs. those just exposed to S. aureus.”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Iverson et al., 2011

  • PB1-F2 helps reduce bacterial clearance, increasing occurrence and severity of co/secondary bacterial infection, by causing cell death in host monocytes.

    “It also helps reduce bacterial clearance, increasing the occurrence and severity of co/secondary bacterial infection, by causing cell death in host monocytes (Conenello and Palese, 2007; Iverson et al., 2011).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Iverson et al., 2011

  • Influenza A virus can produce viral cytotoxin PB1-F2, which increases inflammation, host cell damage, bacterial adherence, mortality and morbidity.

    “Influenza A virus can produce a viral cytotoxin PB1-F2 (Conenello and Palese, 2007; Iverson et al., 2011) which plays a role in increasing inflammation and therefore host cell damage and bacterial adherence, increasing mortality and morbidity (Lee et al., 2016).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Iverson et al., 2011

  • A number of studies have documented an increase in viral load as viral clearance is reduced during bacterial co-infection.

    “A number of studies have documented an increase in viral load as viral clearance is reduced during bacterial co-infection.”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Iverson et al., 2011

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ATCC strain number differs between Methods and Results

    Minor

    The Methods identify the laboratory strain as ATCC-49755, but the Results call it 49775 when describing the strain-comparison experiment.

  • Figure 2 caption assigns timing comparison to the route panel

    Minor

    The caption assigns administration routes to panel B and infection intervals to panel C, but its significance note attributes the comparison between intervals to panel B.

2 of 2

The citation lists haven’t been fetched yet

References 58 · Cited by 168

Authors
Iverson, A. R., Boyd, K. L., McAuley, J. L., Plano, L. R., Hart, M. E., & McCullers, J. A.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Vanderbilt University (US)
  • University of Miami (US)
  • National Center for Toxicological Research (US)
ORCID
Venue
The Journal of Infectious Diseases
Publisher
Oxford University Press (OUP)
Published
2011-03-15
Volume
203
Issue
6
Pages
880-888
ISSN
  • 0022-1899 (ISSN-L)
  • 1537-6613
DOI
10.1093/infdis/jiq113
PMC
PMC3071123
OpenAlex
W2104556654
Semantic Scholar
a869de7a8be7557b85c92392d401dbefeb8deaaf
Cited by
168
References
58
Citations by year
2026: 4 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 12 · 2019: 6 · 2018: 13 · 2017: 9 · 2016: 15 · 2015: 11 · 2014: 17 · 2013: 19 · 2012: 12
FWCI
13.44
Type
journal article
Language
en
Open access
Locations
  • The Journal of Infectious Diseases (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Lebanese Syrian Associated Charities
  • National Institute of Allergy and Infectious Diseases (AI66349, R01AI066349)
Topics
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
  • Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
Keywords
influenza virus, Staphylococcus aureus, co-infection, superinfection, necrotizing pneumonia, methicillin-resistant Staphylococcus aureus, USA300, Panton-Valentine leukocidin, lung inflammation, bacterial virulence factors, mouse model
MeSH terms
Animals, Cytotoxins, Disease Models, Animal, Female, Humans, Influenza, Human, Liver, Lung, Mice, Inbred BALB C, Influenza A virus, Pneumonia, Staphylococcal, Spleen, Staphylococcus aureus, Superinfection, Survival Analysis, Polymerase Chain Reaction, Mice, Methicillin-Resistant Staphylococcus aureus

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.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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