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

Abstract

Secondary Streptococcus pneumoniae infection after influenza is a significant clinical complication resulting in morbidity and sometimes mortality. Prior influenza virus infection has been demonstrated to impair the macrophage and neutrophil response to the subsequent pneumococcal infection. In contrast, how a secondary pneumococcal infection after influenza can affect the adaptive immune response to the initial influenza virus infection is less well understood. Therefore, this study focuses on how secondary pneumococcal infection after influenza may impact the humoral immune response to the initial influenza virus infection in a lethal coinfection mouse model. Compared to mice infected with influenza virus alone, mice coinfected with influenza virus followed by pneumococcus had significant body weight loss and 100% mortality. S econdary bacterial infection of the respiratory tract following influenza is a severe complication that often increases morbidity (1). Streptococcus pneumoniae is one of the pathogens that commonly cause the coinfection (2). Pneumococcus is also the major pathogen associated with mortality in both the 1918 Spanish influenza pandemic (3-5) and the 2009 H1N1 pandemic (6, 7). Given this clinical importance, it is imperative that we understand how the host immune response can be modulated after the coinfection.Prior influenza virus infection has been demonstrated to impair the immune defense against subsequent pneumococcal growth and infection (8, 9). For example, influenza virus can desensitize epithelial cells and alveolar macrophages to Toll-like receptor (TLR) signals for defense against bacteria (10). Gamma interferon (IFN-␥) induced by influenza virus can inhibit the phagocytosis of pneumococcus by macrophages (11). The type I IFN induced by influenza virus can impair neutrophils (12) and macrophages (13) in the defense against pneumococcus. Influenza virus can decrease tumor necrosis factor alpha (TNF-␣) production from natural killer cells in the lung, which allows an increase bacterial growth (14).In contrast, how secondary pneumococcal infection after influenza can influence the immune response to the initial influenza virus is relatively less well understood. The host adaptive immune response is largely responsible for controlling the influenza virus infection. It has been reported that coinfection could dysregulate Th17 (15) and gamma/delta T cells (16). However, whether the B cell response would be modulated during the coinfection is still not clear. It is reported that vaccine-induced immunity to influenza virus

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).…”

“…Blevins et al (2014) found that co-infection of influenza-infected mice with S. pneumoniae affects the ongoing T-cell response to the virus not only by reducing the number of virus-specific CD8 + T-cells in the lungs, but also by reducing their cytokine production. Likewise, Wu et al (2015) showed the CD4 + T-cell population to be reduced during post-influenza pneumococcal infection. Moreover, influenza virus infection has been demonstrated to impair the release of IL-17 by TH17 cells and IL-17-producing gd T-cells during secondary infection of mice with bacteria (Kudva et al, 2011;Li et al, 2012).…”

Immune-responsiveness of CD4+ T cells during Streptococcus suis serotype 2 infection

“…More precisely, S. pneumoniae was found to mediate a significant reduction in the formation of Ag-specific splenic T follicular helper and germinal center B cells and antibody-secreting cells in the spleen and bone marrow in response to OVA32. Similarly, in a lethal coinfection model of influenza virus and S. pneumoniae , coinfection caused depletion of CD4 + T cells and B cells in mediastinal lymph nodes and spleen, with concomitant reduction in virus-specific antibody responses33. In this regard, a transient depletion of CD4 + T cells in the spleen was observed during a primary S. suis infection.…”

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

“…In reported in vivo models of co-infection, animals are commonly challenged with S. pneumoniae 3-7 days after IAV, corresponding to the most pronounced changes to morbidity and mortality (100,182). However, influenza still predisposes mice to S. pneumoniae infection at later times of challenge, and clinically there are positive correlations between influenza and severe pneumococcal pneumonia with up to 4 weeks separating the two infectious agents, suggesting the IAV imparts long term effects in the host (183,184).…”