Date Published: December 14, 2016
Publisher: Public Library of Science
Author(s): Pia Gamradt, Yun Xu, Nina Gratz, Kellyanne Duncan, Lester Kobzik, Sandra Högler, Pavel Kovarik, Thomas Decker, Amanda M. Jamieson, Mary O’Riordan.
Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation. Myeloid cell subsets play roles in tissue repair, immune response resolution, and maintenance of homeostasis, so excessive PCD may also influence host resilience in this way. In addition, myeloid cell death is one mechanism used to control pathogen replication and dissemination. Many of these functions for PCD have been well defined in vitro, but the role in vivo is less well understood. We created a mouse that constitutively expresses the pro-survival B-cell lymphoma (bcl)-2 protein in myeloid cells (CD68(bcl2tg), thus decreasing PCD specifically in myeloid cells. Using this mouse model we explored the impact that decreased cell death of these cells has on infection with two different bacterial pathogens, Legionella pneumophila and Streptococcus pyogenes. Both of these pathogens target multiple cell death pathways in myeloid cells, and the expression of bcl2 resulted in decreased PCD after infection. We examined both pathogen clearance and host resilience and found that myeloid cell death was crucial for host resilience. Surprisingly, the decreased myeloid PCD had minimal impact on pathogen clearance. These data indicate that the most important role of PCD during infection with these bacteria is to minimize inflammation and increase host resilience, not to aid in the clearance or prevent the spread of the pathogen.
Pathogen clearance and host resilience/tolerance are both important in surviving a given infection [1,2]   . A main purpose of the immune response is to identify and clear invading pathogens. However, highly resilient hosts can survive infection with a given pathogen, independent of the ability of the immune response to clear it. One aspect of host resilience is prevention and repair of extensive tissue damage. Both the immune response and pathogens themselves can cause damage to the infected host    . So while the immune system must act to clear a pathogen, it must also be carefully controlled in order to prevent excessive damage. This study seeks to understand the role that myeloid cells, cells of the innate immune response, play in both pathogen clearance and host resilience.
Pathogen clearance and host resilience are both important in surviving a given infection. While many studies have examined different mechanisms of pathogen clearance, recent studies have highlighted the importance that host resilience plays in survival of a given infection    . The fact that cells of the myeloid lineage play important roles in both of these important processes [6–9]  [8,11–13]   , we sought to determine how manipulation of myeloid cell death influenced the response to two bacterial pathogens. To do this we developed a mouse model that has decreased myeloid PCD. Ectopic expression of bcl-2 decreased PCD in response to numerous stimuli in myeloid cells of these mice (Figs 2, 3, 5, 9 and 13) . We used two pathogens that interact with myeloid cells, but infect different areas of the host. The first pathogen, L. pneumophila, infects lung macrophages and remains confined to the lung [45,47,48] [46,75], while the second pathogen S. pyogenes spreads systemically    . When myeloid cell death is prevented during systemic infection with S. pyogenes there is a significant decrease in host resilience (Figs 11, 12 and 14). Infected transgenic mice have decreased survival compared to littermate controls, and increased systemic inflammation. There is not a significant increase in bacterial load in the transgenic mice. The effects of decreased cell death during a pulmonary infection with L. pneumophila on host resilience are milder, but there is also an increase in inflammation in the lung. This increased inflammation precedes the small increase in bacterial load that is seen at the later stages of infection. Unlike infection with S. pyogenes both littermate and transgenic mice survive infection with L. pneumophila, indicating that the myeloid cell death has a greater impact on the systemic infection with S. pyogenes than on the pulmonary infection with L. pneumophila. In both infection models the primary cell type that is increased are neutrophils, which are known to cause tissue damage . Also in both infection models the increase in inflammatory cytokine levels appears to be linked to the increased number of immune cells, and not by increased cytokine production on a per cell basis.