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Increased susceptibility for superinfection with Streptococcus pneumoniae during influenza virus infection is not caused by TLR7-mediated lymphopenia.

Stegemann S, Dahlberg S, Kröger A, Gereke M, Bruder D, Henriques-Normark B, Gunzer M - PLoS ONE (2009)

Bottom Line: We previously demonstrated that triggering of TLR7 causes immune incompetence in mice by induction of lymphopenia.In contrast to SP-infection alone co-infected animals were unable to control the exponential growth of SP.However, lymphopenia forced by TLR7-triggering or antibody-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth.

View Article: PubMed Central - PubMed

Affiliation: Otto-von-Guericke University, Institute of Molecular and Clinical Immunology, Magdeburg, Germany.

ABSTRACT
Influenza A virus (IAV) causes respiratory tract infections leading to recurring epidemics with high rates of morbidity and mortality. In the past century IAV induced several world-wide pandemics, the most aggressive occurring in 1918 with a death toll of 20-50 million cases. However, infection with IAV alone is rarely fatal. Instead, death associated with IAV is usually mediated by superinfection with bacteria, mainly Streptococcus pneumoniae. The reasons for this increased susceptibility to bacterial superinfection have not been fully elucidated. We previously demonstrated that triggering of TLR7 causes immune incompetence in mice by induction of lymphopenia. IAV is recognized by TLR7 and infections can lead to lymphopenia. Since lymphocytes are critical to protect from S. pneumoniae it has long been speculated that IAV-induced lymphopenia might mediate increased susceptibility to superinfection. Here we show that sub-lethal pre-infections of mice with IAV-PR8/A/34 strongly increased their mortality in non-lethal SP infections, surprisingly despite the absence of detectable lymphopenia. In contrast to SP-infection alone co-infected animals were unable to control the exponential growth of SP. However, lymphopenia forced by TLR7-triggering or antibody-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth. Thus, the immune-incompetence caused by transient lympho- or leukopenia is not sufficient to inhibit potent antibacterial responses of the host and mechanisms distinct from leukodepletion must account for increased bacterial superinfection during viral defence.

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Influenza A virus infection predisposes for invasive disease through Streptococcus pneumoniae.(A) C57Bl/6 mice were intranasally inoculated with medium, 0.04 MLD50 Influenza A virus (IAV) PR8/A/34 or 1×105 CFU Streptococcus pneumoniae TIGR4 (T4) and weighed daily. Body weight is shown as % relative to the starting weight. (B) S. pneumoniae CFU counts in tracheal lavage of survivors seven days after i.n. infection. (C) Survival rates of C57Bl/6 mice after i.n. infection with IAV PR8/A/34 alone (day 0), S. pneumoniae T4 alone (day 7) or S. pneumoniae T4 (day 7) following IAV (day 0). (D) CFU counts in lung homogenates of S. pneumoniae only infected and Influenza A virus pre-infected C57Bl/6 mice in which infection was lethal. All data shown are compiled from at least two independent experiments with groups of 5 or more mice. No bacteria could be detected in the lungs of mice surviving the infections (not shown).
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pone-0004840-g001: Influenza A virus infection predisposes for invasive disease through Streptococcus pneumoniae.(A) C57Bl/6 mice were intranasally inoculated with medium, 0.04 MLD50 Influenza A virus (IAV) PR8/A/34 or 1×105 CFU Streptococcus pneumoniae TIGR4 (T4) and weighed daily. Body weight is shown as % relative to the starting weight. (B) S. pneumoniae CFU counts in tracheal lavage of survivors seven days after i.n. infection. (C) Survival rates of C57Bl/6 mice after i.n. infection with IAV PR8/A/34 alone (day 0), S. pneumoniae T4 alone (day 7) or S. pneumoniae T4 (day 7) following IAV (day 0). (D) CFU counts in lung homogenates of S. pneumoniae only infected and Influenza A virus pre-infected C57Bl/6 mice in which infection was lethal. All data shown are compiled from at least two independent experiments with groups of 5 or more mice. No bacteria could be detected in the lungs of mice surviving the infections (not shown).

Mentions: To establish a model system for IAV/S. pneumoniae synergism in the mouse we established two sublethal infections with either the mouse-adapted viral strain PR8/A/34 or the pneumococcal strain TIGR4. 0.04 MLD50 of IAV caused a mild disease with a transient mean loss of max. 10% body weight up to day 7 of the infection, which was resolved by day 12 post infection (Fig. 1A). Likewise, a sublethal course of S. pneumoniae was established after infection with 1×105 CFU that was not detectable by weight changes of infected animals (Fig. 1A). A productive infection was verified from nasopharyngeal lavages at day 7 p.i. in all infected animals (Fig. 1B). Survival-curves showed that both infections were sublethal to 80% (IAV) or 88% (S. pneumoniae) of all animals although single individuals could still succumb to the infection as seen elsewhere [10]. The combined sublethal infections with IAV followed by S. pneumoniae 7 days later were highly synergistic leading to 63% mortality within 2 days after the bacterial superinfection (Fig. 1C). The lung homogenates of animals succumbing to the co-infection showed high CFU in their tissues similar to the levels observed in the rare cases of lethal courses from single infections (Fig. 1D).


Increased susceptibility for superinfection with Streptococcus pneumoniae during influenza virus infection is not caused by TLR7-mediated lymphopenia.

Stegemann S, Dahlberg S, Kröger A, Gereke M, Bruder D, Henriques-Normark B, Gunzer M - PLoS ONE (2009)

Influenza A virus infection predisposes for invasive disease through Streptococcus pneumoniae.(A) C57Bl/6 mice were intranasally inoculated with medium, 0.04 MLD50 Influenza A virus (IAV) PR8/A/34 or 1×105 CFU Streptococcus pneumoniae TIGR4 (T4) and weighed daily. Body weight is shown as % relative to the starting weight. (B) S. pneumoniae CFU counts in tracheal lavage of survivors seven days after i.n. infection. (C) Survival rates of C57Bl/6 mice after i.n. infection with IAV PR8/A/34 alone (day 0), S. pneumoniae T4 alone (day 7) or S. pneumoniae T4 (day 7) following IAV (day 0). (D) CFU counts in lung homogenates of S. pneumoniae only infected and Influenza A virus pre-infected C57Bl/6 mice in which infection was lethal. All data shown are compiled from at least two independent experiments with groups of 5 or more mice. No bacteria could be detected in the lungs of mice surviving the infections (not shown).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654096&req=5

pone-0004840-g001: Influenza A virus infection predisposes for invasive disease through Streptococcus pneumoniae.(A) C57Bl/6 mice were intranasally inoculated with medium, 0.04 MLD50 Influenza A virus (IAV) PR8/A/34 or 1×105 CFU Streptococcus pneumoniae TIGR4 (T4) and weighed daily. Body weight is shown as % relative to the starting weight. (B) S. pneumoniae CFU counts in tracheal lavage of survivors seven days after i.n. infection. (C) Survival rates of C57Bl/6 mice after i.n. infection with IAV PR8/A/34 alone (day 0), S. pneumoniae T4 alone (day 7) or S. pneumoniae T4 (day 7) following IAV (day 0). (D) CFU counts in lung homogenates of S. pneumoniae only infected and Influenza A virus pre-infected C57Bl/6 mice in which infection was lethal. All data shown are compiled from at least two independent experiments with groups of 5 or more mice. No bacteria could be detected in the lungs of mice surviving the infections (not shown).
Mentions: To establish a model system for IAV/S. pneumoniae synergism in the mouse we established two sublethal infections with either the mouse-adapted viral strain PR8/A/34 or the pneumococcal strain TIGR4. 0.04 MLD50 of IAV caused a mild disease with a transient mean loss of max. 10% body weight up to day 7 of the infection, which was resolved by day 12 post infection (Fig. 1A). Likewise, a sublethal course of S. pneumoniae was established after infection with 1×105 CFU that was not detectable by weight changes of infected animals (Fig. 1A). A productive infection was verified from nasopharyngeal lavages at day 7 p.i. in all infected animals (Fig. 1B). Survival-curves showed that both infections were sublethal to 80% (IAV) or 88% (S. pneumoniae) of all animals although single individuals could still succumb to the infection as seen elsewhere [10]. The combined sublethal infections with IAV followed by S. pneumoniae 7 days later were highly synergistic leading to 63% mortality within 2 days after the bacterial superinfection (Fig. 1C). The lung homogenates of animals succumbing to the co-infection showed high CFU in their tissues similar to the levels observed in the rare cases of lethal courses from single infections (Fig. 1D).

Bottom Line: We previously demonstrated that triggering of TLR7 causes immune incompetence in mice by induction of lymphopenia.In contrast to SP-infection alone co-infected animals were unable to control the exponential growth of SP.However, lymphopenia forced by TLR7-triggering or antibody-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth.

View Article: PubMed Central - PubMed

Affiliation: Otto-von-Guericke University, Institute of Molecular and Clinical Immunology, Magdeburg, Germany.

ABSTRACT
Influenza A virus (IAV) causes respiratory tract infections leading to recurring epidemics with high rates of morbidity and mortality. In the past century IAV induced several world-wide pandemics, the most aggressive occurring in 1918 with a death toll of 20-50 million cases. However, infection with IAV alone is rarely fatal. Instead, death associated with IAV is usually mediated by superinfection with bacteria, mainly Streptococcus pneumoniae. The reasons for this increased susceptibility to bacterial superinfection have not been fully elucidated. We previously demonstrated that triggering of TLR7 causes immune incompetence in mice by induction of lymphopenia. IAV is recognized by TLR7 and infections can lead to lymphopenia. Since lymphocytes are critical to protect from S. pneumoniae it has long been speculated that IAV-induced lymphopenia might mediate increased susceptibility to superinfection. Here we show that sub-lethal pre-infections of mice with IAV-PR8/A/34 strongly increased their mortality in non-lethal SP infections, surprisingly despite the absence of detectable lymphopenia. In contrast to SP-infection alone co-infected animals were unable to control the exponential growth of SP. However, lymphopenia forced by TLR7-triggering or antibody-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth. Thus, the immune-incompetence caused by transient lympho- or leukopenia is not sufficient to inhibit potent antibacterial responses of the host and mechanisms distinct from leukodepletion must account for increased bacterial superinfection during viral defence.

Show MeSH
Related in: MedlinePlus