Adaptive Immune Responses

Scientific questions:

 *   Which adaptive immune responses for IV may predispose the host to SP invasive disease?
 *   Which adaptive immune responses may alter SP carriage dynamics (density, duration)?
 *   Which adaptive immune responses may alter SP acquisition and transmission dynamics?
 *   Which innate immune responses to CI develop adaptive immunity?
 *   Which factors regulate the adaptive immunity to CI?
 *   Which adaptive immune responses are related to clearance of CI?
 *   Which adaptive changes to the host environment allow IV and SP to survive and thrive during the course of infection?
 *   Which viral and bacterial factors affect the normal development of adaptive immunity?
 *   What is the impact of CI on protective B cell responses?

Adaptive immunity on co-infection

 * Clearance of acute IV infection is dependent on the presence of a potent adaptive immune response (BLEVINS et al., 2014).

T Cells

 * T cells contribute to defense against IV-induced bacterial diseases: IV cross-reactive T cells reduce viral titers (HAYNES et al., 2012).
 * Emerging protective T-cell response (ROSSEAU et al., 2007).
 * CI could dysregulate Th17 and gamma delta T cells (WU et al., 2015).
 * Cure of IAV infection strongly depends on the adaptive immune response, in particular the generation of IV-specific T cells. This is reflected by the conspicuous T-cell-associated gene response 7 days after influenza infection, coinciding with the appearance of ex vivo measurable cytotoxic activity and cytokine production (ROSSEAU et al., 2007).

CD4+ T Cells
=> Type 1 helper cells produce IL-2, IFN-g and tumour necrosis factor-beta. It induces delayed-type hypersensitivity reactions and is cytolytic for antigen-presenting cells, including B lymphocytes.

=> Type 2 helper cells express IL-4, IL-5, IL-6 and IL-10. Helpers for B-cell antibody secretion, particularly IgE responses.
 * In the lung, lethal CI significantly decreased the number of CD4+ T cells (WU et al., 2015).
 * In mediastinal lymph nodes, lethal CI significantly decreased T follicular helper cells (WU et al., 2015).
 * At later times, levels of T follicular helper cells are elevated (BLEVINS et al., 2014).
 * The reduced number of lung effector cells in coinfected animals was associated with increased death, as well as a reduction in cytokine production in surviving cells (BLEVINS et al., 2014).
 * Elevated intrapulmonary levels of type-1 T-helper cell cytokines were observed in mice inoculated with CI with an interval of 2 days (METERSKY et al., 2012).

CD8+ T Cells

 * Severe cases of IV infection in humans have been associated with the lack of an effective CD8+ T cell response in the lung (BLEVINS et al., 2014).
 * CD8+ T cells were shown to mediate viral clearance through secretion of IFN-g, as well as cytolytic granule release (BLEVINS et al., 2014).
 * Infection of mice with IV, followed by the non-invasive EF3030 strain of SP, leads to a significant decrease in the virus-specific CD8+ T cell response in the lung (BLEVINS et al.,2014).

Lung T Cells

 * Lung T cells are compromised during secondary SP infection (LI; MOLTEDO; MORAN, 2012).
 * These cells are responsible for almost all IL-17 production (LI; MOLTEDO; MORAN, 2012).

B Cells

 * In the lung, lethal CI significantly decreased the number of B cells (WU et al., 2015).
 * In spleen, lethal CI significantly reduced  the B cells along the follicular developmental lineage (WU et al., 2015).
 * In mediastinal lymph nodes, lethal CI significantly decreased germinal center B cells (WU et al., 2015).
 * B cell response to IAV is altered in mice coinfected with IAV and SP and that this response differs, depending on the order of pathogen exposure (BLEVINS et al., 2014).
 * In mice exposed to SP prior to IAV, the initial virus-specific germinal center 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 cell numbers (BLEVINS et al., 2014).
 * At later times, levels of germinal centers are elevated. (BLEVINS et al., 2014).
 * Mice exposed to SP prior to IAV do not maintain the initially robust germinal center response in secondary lymphoid organs (BLEVINS et al., 2014).
 * Down-regulation of B-cell responses, probably reflecting a SP virulence strategy (ROSSEAU et al.,2007).

Antibodies

 * Adoptive transfer of IV-specific immune serum to co-infected mice improved survival, suggesting the protective functions of anti-IV Abs (WU et al., 2015).
 * Abs to nucleoprotein suppress induction of inflammation in the lung (HAYNES et al.,2012).
 * Secondary SP infection exaggerates early antiviral Ab-secreting cell formation (BLEVINS et al., 2014).
 * Ab-mediated neutropenia did not increase SP-susceptibility or compromise the ability to control SP growth (STEGEMANN et al., 2009).
 * Adoptive transfer of IV-specific immune serum to co-infected mice improved survival, suggesting the protective functions of anti-IV Abs (WU et al., 2015)
 * In the lung, lethal CI significantly decreased the level of virus specific IgG, IgM and IgA (WU et al., 2015).
 * Secondary SP infection exaggerates levels of antiviral serum IgG at later times (BLEVINS et al., 2014).
 * Mice exposed to SP prior to IAV exhibit reduced antiviral serum IgG with diminished virus neutralization activity a month after infection (BLEVINS et al., 2014).
 * Transmission was prevented when an IAV-neutralizing Ab was used to inhibit IAV replication (DIAVATOPOULOS et al., 2010).

Plasma Cells

 * In the lung and mediastinal lymph nodes, lethal CI significantly decreased the level of plasma cells (WU et al., 2015).

Regulation

 *  IFN-c probably facilitates induction of specific anti-IV adaptive immunity (SUN; METZGER, 2008).
 * Type I IFNs signal through a common receptor, IFN-α/β receptor (IFNAR), resulting in the expression of pro-inflammatory genes that not only inhibit viral replication, but also augment various aspects of adaptive immunity (SHAHANGIAN et al., 2009).