In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection.
An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-γ- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-γ neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-γ and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-γ and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies.
['Sharma-Chawla|Niharika|N|', 'Stegemann-Koniszewski|Sabine|S|', 'Christen|Henrike|H|', 'Boehme|Julia D|JD|', 'Kershaw|Olivia|O|', 'Schreiber|Jens|J|', 'Guzmán|Carlos A|CA|', 'Bruder|Dunja|D|', 'Hernandez-Vargas|Esteban A|EA|']
D000465:Algorithms D000818:Animals D057134:Antibodies, Neutralizing D060085:Coinfection D016207:Cytokines D005260:Female D006801:Humans D009980:Influenza A virus D007371:Interferon-gamma D015850:Interleukin-6 D008168:Lung D008810:Mice, Inbred C57BL D018448:Models, Immunological D009500:Neutralization Tests D009976:Orthomyxoviridae Infections D011008:Pneumococcal Infections D011014:Pneumonia D013296:Streptococcus pneumoniae
Streptococcus pneumoniae mathematical modeling IL-6 neutralization IFN-γ neutralization Influenza Virus co-infection