The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes

Abstract

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.

Towards re-purposing BH3-mimetics in Legionella and viral infections

“…Rather, inducing apoptosis likely prevents excessive inflammation associated with Legionella infections, as the levels of the major inflammatory cytokines remained low in BCL-XL-deficient mice [23]. Consistent with this, overexpression of BCL-2 in macrophages and other innate immune cells leads to increased production of inflammatory cytokines in L. pneumophila-infected mouse lungs [24].…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…In a model of IAV infection, blockage of CCR2, the receptor expressed on monocyte-derived cells that facilitates their entry into the lung, results in decreased inflammatory cell infiltrate, inflammation, tissue damage, and mortality without any effect on viral clearance (105,106). It has also been shown that failure of these cells to induce programmed cell death during the resolution of infection results in unregulated, prolonged inflammation which in turn decreases tolerance (107)(108)(109)(110)(111).…”

Targeting apoptosis pathways in infections

“…Mice overexpressing BCL-2 have also been used to determine the role of mitochondria-mediated cell death suggesting that apoptosis promotes pathogen clearance and/or dampens immune responses in infections. 21,50…”

“…116 The fungal pathogen Histoplasma capsulatum secretes calcium-binding protein 1 (Cbp1) to trigger BAX-and BAK-mediated caspase activation, which is sufficiently lytic to promote escape from macrophages. 117,118 Overexpression of BCL-2 also reduces macrophage death in late-stage Legionella infections, 21,119 suggesting that Legionella activates apoptosis to escape from spent cells. Other cell death pathways likely contribute to Legionella-mediated killing of macrophages as well.…”

“…[12][13][14]19,20 Overexpression of BCL-2 also prolongs neutrophil survival during infections resulting in increased inflammation. 21 Conversely, the BCL-2 related protein, myeloid cell leukemia sequence-1 (MCL-1), but not BCL-2 itself, prevents the death of regulatory T-cells, which suppress inflammatory immune responses that can lead to fatal autoimmunity. 22 Besides maintaining homeostasis of the immune system, apoptosis may elicit immune reactions to combat invading pathogens.…”