The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Lethal Synergism between Influenza Virus and Streptococcus pneumoniae: Characterization of a Mouse Model and the Role of Platelet‐Activating Factor Receptor
Abstract
A lethal synergism exists between influenza virus and pneumococcus, which likely accounts for excess mortality from secondary bacterial pneumonia during influenza epidemics. Characterization of a mouse model of synergy revealed that influenza infection preceding pneumococcal challenge primed for pneumonia and led to 100% mortality. This effect was specific for viral infection preceding bacterial infection, because reversal of the order of administration led to protection from influenza and improved survival. The hypothesis that influenza up-regulates the platelet-activating factor receptor (PAFr) and thereby potentiates pneumococcal adherence and invasion in the lung was examined in the model. Groups of mice receiving CV-6209, a competitive antagonist of PAFr, had survival rates similar to those of control mice, and lung and blood bacterial titers increased during PAFr inhibition. These data suggest that PAFr-independent pathways are operative in the model, prompting further study of receptor interactions during pneumonia and bacteremia. The model of lethal synergism will be a useful tool for exploring this and other mechanisms underlying viral-bacterial interactions.
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In the citing paper
“The timing of infection with the 2 organisms in coinfection models affects outcomes.”
From Influenza virus primes mice for pneumonia from Staphylococcus aureus. (2011) · cites this paper as [23]
In the citing paper
“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].”
From Influenza virus primes mice for pneumonia from Staphylococcus aureus. (2011) · cites this paper as [23]
In the citing paper
“Little to no enhancement of disease is seen if the bacterial infection precedes exposure to the virus or the organisms are encountered together [23].”
From Influenza virus primes mice for pneumonia from Staphylococcus aureus. (2011) · cites this paper as [23]
In the citing paper
“Roughly 3-10 days after viral infection, a proinflammatory state characterized by granulocyte and monocyte influx into the lungs amplifies host responses to bacteria, resulting in poor outcomes [23,25,43].”
From Influenza virus primes mice for pneumonia from Staphylococcus aureus. (2011) · cites this paper as [23]
In the citing paper
“There seems to be biphasic response to the virus that alters innate responses to the secondary bacterial pathogen.”
From Influenza virus primes mice for pneumonia from Staphylococcus aureus. (2011) · cites this paper as [23]
Citations
Cites
Principles and Practice of Infectious Diseases.
(1991) · Annals of Internal Medicine · doi:10.7326/0003-4819-114-9-818_5 · Cited by 12,045
Cundell, D. R., Gerard, N. P., Gerard, C. J., Idänpään‐Heikkilä, I., & TUOMANEN, E. I. (1995) · Nature · doi:10.1038/377435a0 · Cited by 741
The impact of influenza epidemics on mortality: introducing a severity index.
Simonsen, L., Clarke, M. J., Williamson, G. D., Stroup, D. F., Arden, N. H., & Schonberger, L. B. (1997) · American Journal of Public Health · doi:10.2105/ajph.87.12.1944 · Cited by 587
Options for the control of influenza III
Ada, G., Tannock, G. A., & Hampson, A. W. (1997) · Vaccine · doi:10.1016/s0264-410x(96)00191-0 · Cited by 587
STUDIES ON INFLUENZA IN THE PANDEMIC OF 1957-1958. II. PULMONARY COMPLICATIONS OF INFLUENZA*†
Louria, D. B., Blumenfeld, H. L., Ellis, J. T., Kilbourne, E. D., & Rogers, D. E. (1959) · Journal of Clinical Investigation · doi:10.1172/jci103791 · Cited by 479
The Impact of Influenza Epidemics on Hospitalizations
Simonsen, L., Fukuda, K., Schonberger, L. B., & Cox, N. J. (2000) · The Journal of Infectious Diseases · doi:10.1086/315320 · Cited by 476
Apoptosis: a mechanism of cell killing by influenza A and B viruses
Hinshaw, V. S., Olsen, C. W., Dybdahl-Sissoko, N., & Evans, D. T. (1994) · Journal of Virology · doi:10.1128/jvi.68.6.3667-3673.1994 · Cited by 424
Zhang, J., Mostov, K. E., Lamm, M. E., Nanno, M., Shimida, S.-I., Ohwaki, M., & TUOMANEN, E. I. (2000) · Cell · doi:10.1016/s0092-8674(00)00071-4 · Cited by 418
Pathogenesis of Pneumococcal Infection
TUOMANEN, E. I., AUSTRIAN, R. C., & Masure, H. R. (1995) · New England Journal of Medicine · doi:10.1056/nejm199505113321907 · Cited by 381
Respiratory viral infection predisposing for bacterial disease: a concise review.
Hament, J.-M., Kimpen, J. L. L., Fleer, A., & Wolfs, T. F. W. (1999) · FEMS Immunology & Medical Microbiology · doi:10.1111/j.1574-695x.1999.tb01389.x · Cited by 306
Role of Staphylococcus protease in the development of influenza pneumonia
Tashiro, M., Ciborowski, P. S., Klenk, H., Pulverer, G., & ROTT, R. (1987) · Nature · doi:10.1038/325536a0 · Cited by 272
A kinetic study of immune mediators in the lungs of mice infected with influenza A virus
Hennet, T., Ziltener, H. J., Frei, K., & Peterhans, E. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.149.3.932 · Cited by 233
Plotkowski, M.-C., Puchelle, E., Beck, G., Jacquot, J., & Hannoun, C. (1986) · American Review of Respiratory Disease · doi:10.1164/arrd.1986.134.5.1040 · Cited by 231
BACTERIOLOGY AND HISTOPATHOLOGY OF THE RESPIRATORY TRACT AND LUNGS IN FATAL ASIAN INFLUENZA
Hers, J. F. P., Masurel, N., & Mulder, J. (1958) · The Lancet · doi:10.1016/s0140-6736(58)92404-8 · Cited by 201
Synergistic role of staphylococcal proteases in the induction of influenza virus pathogenicity.
Tashiro, M., Ciborowski, P., Reinacher, M., Pulverer, G., Klenk, H.-D., & Rott, R. (1987) · Virology · doi:10.1016/0042-6822(87)90284-4 · Cited by 152
Colamussi, M. L., White, M. R., Crouch, E. C., & Hartshorn, K. L. (1999) · Blood · doi:10.1182/blood.v93.7.2395 · Cited by 146
Idänpään‐Heikkilä, I., Simon, P. M., Zopf, D. A., Vullo, T., Cahill, P. T., Sokol, K. A., & TUOMANEN, E. I. (1997) · The Journal of Infectious Diseases · doi:10.1086/514094 · Cited by 141
Adenovirus infection enhances in vitro adherence of Streptococcus pneumoniae.
Håkansson, A., Kidd, A., Wadell, G., Sabharwal, H., & Svanborg, C. (1994) · Infection and Immunity · doi:10.1128/iai.62.7.2707-2714.1994 · Cited by 134
CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo.
Terashita, Z., Imura, Y., Takatani, M., Tsushima, S., & Nishikawa, K. (1987) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)39063-4 · Cited by 128
Abramson, J. S., Giebink, G. S., & Quie, P. G. (1982) · Infection and Immunity · doi:10.1128/iai.36.1.289-296.1982 · Cited by 115
Otitis Media: The Chinchilla Model1
Giebink, G. S. (1999) · Microbial Drug Resistance · doi:10.1089/mdr.1999.5.57 · Cited by 113
Pathogenesis of Pneumococcal Pneumonia
Johnston, R. B. (1991) · Clinical Infectious Diseases · doi:10.1093/clinids/13.supplement_6.s509 · Cited by 112
PULMONARY COMPLICATIONS OF INFLUENZA
Scadding, J. G. (1952) · The Lancet · doi:10.1016/s0140-6736(52)92362-3 · Cited by 107
Vital Statistics: A Memorial Volume of Selections from the Reports and Writings of William Farr
FARR, W. B. (1975) · Medical Entomology and Zoology · Cited by 92
Molecular pathogenesis of pneumococcal pneumonia
Jonathan, A. M. (2001) · Frontiers in bioscience · doi:10.2741/mccullers · Cited by 89
C3 as Substrate for Adhesion ofStreptococcus pneumoniae
Smith, B. L., & Hostetter, M. K. (2000) · The Journal of Infectious Diseases · doi:10.1086/315722 · Cited by 82
Hartshorn, K. L., Liou, L. S., White, M. R., Kazhdan, M., Tauber, J., & Tauber, A. I. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.8.3952 · Cited by 77
Tong, H. H., McIver, M. A., Fisher, L. M., & DeMaria, T. F. (1999) · Microbial Pathogenesis · doi:10.1006/mpat.1998.0257 · Cited by 77
Pulmonary antibacterial defenses during mild and severe influenza virus infection
Nickerson, C. L., & Jakab, G. J. (1990) · Infection and Immunity · doi:10.1128/iai.58.9.2809-2814.1990 · Cited by 75
The Molecular Basis of Pneumococcal Infection: A Hypothesis
Cundell, D. R., Masure, H. R., & TUOMANEN, E. I. (1995) · Clinical Infectious Diseases · doi:10.1093/clind/21.supplement_3.s204 · Cited by 75
PAF Receptor Anchors Streptococcus Pneumoniae to Activated Human Endothelial Cells
Cundell, D. R., Gerard, C. J., Idänpään‐Heikkilä, I., TUOMANEN, E. I., & Gerard, N. P. (1996) · Advances in experimental medicine and biology · doi:10.1007/978-1-4899-0179-8_16 · Cited by 67
Abrahams, A., Hallows, N., & French, H. (1919) · The Lancet · doi:10.1016/s0140-6736(01)22115-1 · Cited by 64
The Biology of Pneumococcal Infection
TUOMANEN, E. I. (1997) · Pediatric Research · doi:10.1203/00006450-199709000-00001 · Cited by 59
Surveillance and impact of influenza in the United States.
Klimov, A., Simonsen, L., Fukuda, K., & Cox, N. (1999) · Vaccine · doi:10.1016/s0264-410x(99)00104-8 · Cited by 57
THE SUSCEPTIBILITY OF SWINE TO THE VIRUS OF HUMAN INFLUENZA
Shope, R. E., & Francis, T. (1936) · The Journal of Experimental Medicine · doi:10.1084/jem.64.5.791 · Cited by 56
Combined Infection of Mice with H. Influenzae and Influenza Virus by the Intranasal Route
Francis, T., & De Torregrosa, M. V. (1945) · Journal of Infectious Diseases · doi:10.1093/infdis/76.1.70 · Cited by 56
Ishizuka, S., Yamaya, M., Suzuki, T., Nakayama, K., Kamanaka, M., Shiroh, I. D. A., Sekizawa, K., & Sasaki, H. (2001) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.24.4.4248 · Cited by 54
Kleinerman, E. S., Daniels, C. A., Polisson, R. P., & D, R. S. M. (1976) · PubMed Central · Cited by 53
Linder, T. E., LIM, D. J., & DeMaria, T. F. (1992) · Microbial Pathogenesis · doi:10.1016/0882-4010(92)90039-q · Cited by 40
Pathogenesis of pneumococcal pneumonia.
Novak, R., & TUOMANEN, E. I. (1999) · PubMed · Cited by 34
Experimental Alteration of Chinchilla Middle Ear Mucosae by Bacterial Neuraminidase
LaMarco, K. L., Diven, W. F., & Glew, R. H. (1986) · Annals of Otology Rhinology & Laryngology · doi:10.1177/000348948609500319 · Cited by 30
SULFONAMIDE CHEMOTHERAPY OF COMBINED INFECTION WITH INFLUENZA VIRUS AND BACTERIA
Harford, C. G., Smith, M. R., & Wood, W. B. (1946) · Journal of Experimental Medicine · doi:10.1084/jem.83.6.505 · Cited by 28
INFLUENZA AND ITS COMPLICATIONS
Stuart‐Harris, C. H. (1959) · British Medical Bulletin · doi:10.1093/oxfordjournals.bmb.a069767 · Cited by 27
A mouse model of dual infection with influenza virus and Streptococcus pneumoniae
McCullers, J. A., & Webster, R. G. (2001) · International Congress Series · doi:10.1016/s0531-5131(01)00631-8 · Cited by 19
Self-citationASIATIC INFLUENZA IN THE MIDDLE EAST AN OUTBREAK IN A SMALL COMMUNITY
Guthrie, J., Forsyth, D. M., & Montgomery, H. (1957) · The Lancet · doi:10.1016/s0140-6736(57)90079-x · Cited by 18
BACTERIOLOGICAL AND PATHOLOGICAL OBSERVATIONS ON INFLUENZA AS SEEN IN FRANCE DURING 1918
Wilson, W. J., & Steer, P. (1919) · BMJ · doi:10.1136/bmj.1.3047.634 · Cited by 17
Tashiro, M., & ROTT, R. (1996) · Seminars in Virology · doi:10.1006/smvy.1996.0030 · Cited by 17
NOTES ON CASES OF INFLUENZA IN A BASE HOSPITAL IN ITALY
Barratt, J. O. W. (1919) · BMJ · doi:10.1136/bmj.1.3049.705 · Cited by 2
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Syndemics and public health: Reconceptualizing disease in bio-social context
Singer, M., & Clair, S. (2003) · Medical Anthropology Quarterly · doi:10.1525/maq.2003.17.4.423 · Cited by 1,140
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Weiser, J. N., Ferreira, D. M., & Paton, J. C. (2018) · Nature Reviews Microbiology · doi:10.1038/s41579-018-0001-8 · Cited by 1,152
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McCullers, J. A. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3231 · Cited by 722
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Metadata
- Authors
- McCullers, J. A., & Rehg, J. E.
- Affiliations
- St. Jude Children's Research Hospital (US)
- ORCID
- Rehg, Jerold E.
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-08
- Volume
- 186
- Issue
- 3
- Pages
- 341-350
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- OpenAlex
- W2105680176
- Cited by
- 423
- References
- 48
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 9 · 2023: 16 · 2022: 17 · 2021: 20 · 2020: 23 · 2019: 26 · 2018: 18 · 2017: 17 · 2016: 31 · 2015: 23 · 2014: 32 · 2013: 32 · 2012: 20
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1k08ai049178-01)
- National Cancer Institute (CA21765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (AI-49178)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Keywords
- influenza virus, Streptococcus pneumoniae, secondary bacterial pneumonia, platelet-activating factor receptor, CV-6209, bacteremia, mouse model, host-pathogen interaction
- MeSH terms
- Animals, Disease Models, Animal, Female, Lung, Mice, Inbred BALB C, Orthomyxoviridae, Orthomyxoviridae Infections, Platelet Membrane Glycoproteins, Pneumonia, Pneumococcal, Pyridinium Compounds, Receptors, Cell Surface, Streptococcus pneumoniae, Receptors, G-Protein-Coupled, Mice
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