Coinfection with Streptococcus pneumoniae Modulates the B Cell Response to Influenza Virus

Abstract

Pathogen-specific antibodies (Abs) protect against respiratory infection with influenza A virus (IAV) and Streptococcus pneumoniae and are the basis of effective vaccines. Sequential or overlapping coinfections with both pathogens are common, yet the impact of coinfection on the generation and maintenance of Ab responses is largely unknown. We report here that the B cell response to IAV is altered in mice coinfected with IAV and S. pneumoniae and that this response differs, depending on the order of pathogen exposure. In mice exposed to S. pneumoniae prior to IAV, the initial virus-specific germinal center (GC) B cell response is significantly enhanced in the lung-draining mediastinal lymph node and spleen, and there is an increase in CD4 ؉ T follicular helper (TFH) cell numbers. In contrast, secondary S. pneumoniae infection exaggerates early antiviral antibody-secreting cell formation, and at later times, levels of GCs, TFH cells, and antiviral serum IgG are elevated. Mice exposed to S. pneumoniae prior to IAV do not maintain the initially robust GC response in secondary lymphoid organs and exhibit reduced antiviral serum IgG with diminished virus neutralization activity a month after infection. Our data suggest that the history of pathogen exposures can critically affect the generation of protective antiviral Abs and may partially explain the differential susceptibility to and disease outcomes from IAV infection in humans. IMPORTANCERespiratory tract coinfections, specifically those involving influenza A viruses and Streptococcus pneumoniae, remain a top global health burden. We sought to determine how S. pneumoniae coinfection modulates the B cell immune response to influenza virus since antibodies are key mediators of protection.

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

“…Recently, Wolf et al also reported that coinfection could modulate the B cell response and demonstrated that sequential infection with influenza virus followed by pneumococcus increased the antibody response to influenza virus (20). The discrepancy in results between the study by Wolf et al and the current study could be due to the different infectious models being used.…”

“…Notably, the study of Wolf et al (20), on day 10 post-PR8 infection, coinfected mice had lower virus-specific IgG amounts in the lung, as well as fewer Tfh and GCB cells in mLN although there was no statistical significance. On the other hand, the current study used a lethal coinfection model and provided an earlier kinetics, showing that on day 8 post-PR8 infection, the virus-specific IgG, IgM, and IgA levels in the lung, as well as the related cellular support from the lung, mLN, and spleen, including Tfh, GCB, and plasma cells, were significantly decreased.…”

“…In the study of Wolf et al (20), coinfection enhanced virusspecific IgG in the lung and serum, as well as the number of total and virus-specific antibody-secreting cells in mLN. Since mice suffered from nonlethal coinfection and since the cellular response was examined on day 34 post-PR8 infection, it is logical that the mice that were still alive on day 34 would have had a greater antibody response in order to recover as otherwise they might have died from the coinfection.…”

“…A recent study performed by Wolf et al demonstrated that nonlethal coinfection with influenza virus followed by pneumococcus could enhance anti-influenza antibody production (20). However, clinical data from the 1918 Spanish pandemic and subsequent experimental studies in mice demonstrated that coinfection significantly increased mortality.…”

Viral–bacterial interactions in the respiratory tract

“…Whereas Wolf et al (2014) described increased levels of virus-specific IgG in a rather mild murine model of postinfluenza bacterial pneumonia, others found a severe impairment of IgG, IgM and IgA production in co-infected mice (Wu et al, 2015). These contrasting findings have mainly been explained with differences in the experimental models (sub-lethal vs lethal co-infection).…”