Killing of Microbes and Cancer by the Immune System with Three Mammalian Pore-Forming Killer Proteins

Abstract

Immunology is the science of biological warfare between the defenses of our immune systems and offensive pathogenic microbes and cancers. Over the course of his scientific career, Eckhard R. Podack made several seminal discoveries that elucidated key aspects of this warfare at a molecular level. When Eckhard joined the complement laboratory of Müller-Eberhard in 1974, he was fascinated by two questions: (1) what is the molecular mechanism by which complement kills invasive bacteria? and (2) which one of the complement components is the killer molecule? Eckhard’s quest to answer these questions would lead to the discovery C9 and later, two additional pore-forming killer molecules of the immune system. Here is a brief account of how he discovered poly-C9, the pore-forming protein of complement in blood and interstitial fluids: Perforin-1, expressed by natural killer cells and cytotoxic T lymphocytes; and Perforin-2 (MPEG1), expressed by all cell types examined to date. All the three killing systems are crucial for our survival and health.

Single cell analyses reveal specific distribution of anti‐bacterial molecule Perforin‐2 in human skin and its modulation by wounding and Staphylococcus aureus infection

“…P‐2 is a highly conserved innate protein with unique properties to kill intracellular (both Gram‐positive and Gram‐negative) bacteria. P‐2, encoded by mpeg1 gene, is a transmembrane protein inserted in membrane vesicles that forms pores on targets (intracellular bacteria) entrapped by membrane vesicles . In professional phagocytic cells, P‐2 is expressed constitutively, where in other cells, P‐2 expression can be induced by interferon (IFN), LPS and TNF‐α, or by bacterial infection …”

“…Perforin‐2 (P‐2) is a membrane‐attack‐complex‐perforin (MACPF) domain‐containing protein important for killing Gram‐positive and Gram‐negative intracellular bacteria . The data suggest that upon bacterial infection, P‐2 vesicles translocate to bacterium containing endosomes phagosomes or the plasma membrane.…”

“…After membrane fusion, the MACPF domain of the Perforin‐2 is located next to the bacterial surface. P‐2 polymerization and insertion into the bacterial wall results in pore formation and killing of the bacterium . Importantly, we have previously shown that P‐2 constitutive expression in the epidermis plays important role in protection from infection and invasion by S. aureus in a mouse model .…”

“…P-2 polymerization and insertion into the bacterial wall results in pore formation and killing of the bacterium. [15] Importantly, we have previously shown that P-2 constitutive expression in the epidermis plays important role in protection from infection and invasion by S. aureus in a mouse model. [16] As a consequence of bacteremia, P-2 −/− mice rapidly lost weight suggesting forthcoming mortality.…”

Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy

“…NK cells perform a similar function as part of the innate immune system, recognizing surface molecules called killer-cell immunoglobulin-like receptors, and through major histocompatibility complex binding. 8 The NK cells also possess a regulatory function by secreting IL-10 to prevent T-cell activation 9 and function to support the role of T-regulatory cells. 10 Together, these checks and balances produce a targeted strike preventing the cytokine storm that develops during HLH.…”