Perforins and Cholesterol-Dependent Cytolysins in Immunity and Pathogenesis

Humans and other mammals deploy pore-forming proteins as part of immune surveilance to promote their own survival. For example, C9 along with other serum proteins forms the membrane attack complex of complement to permeabilize the envelopes of gram-negative bacteria and kill them. Killer lymphocytes degranulate and deploy Perforin to destroy virally infected or cancerous cells. More recent studies have shown that the product of macrophage expressed gene 1 (Mpeg1), dubbed Perforin-2 by the late Eckhard R. Podack (1943–2015), is constitutively expressed at relatively high levels in human and murine macrophages and plays an essential role in the destruction of phagocytosed bacteria. In humans and other mammals, the complement system and Perforins are significant components of the innate immune system. Structural studies have shown that these molecules polymerize with the membrane attack complex-perforin (MACPF) domains of each monomer deploying amphipathic β-strands through target lipid bilayers to form pores. Proteins with MACPF domains are not restricted to mammals but found across diverse eukaryotic taxa including plants, fungi, and invertebrates such as corals and sponges, as well as in archaea. Although some of these proteins may have evolved other functions, it is likely that many have retained their ability to perforate lipid bilayers to perform immunologic roles if the few that have been characterized are representative of the larger group. Noteworthy, different MACPF proteins are also present in a variety of protozoan parasites, including malaria parasites, and here have been shown to play key roles during host cell infection. Finally, it should be noted that MACPF domains have also been identified in some prokaryotes including pathogenic species of Chlamydia .

Structural studies have revealed that members of the MACPF family share a canonical fold with the cholesterol-dependent cytolysins (CDCs). These latter proteins are significant virulence factors in several gram-positive bacterial species. For example, the escape of Listeria monocytogenes from phagosomes –and phagosomal Perforin-2– is dependent upon permeabilization of the phagosomal membrane by listeriolysin. Streptolysin O lyses a variety of eukaryotic cells and thus impairs the ability of phagocytes to clear group A streptococci from necrotizing soft tissue infections. Likewise, perfringolysin O of Clostridium perfringens kills macrophages, contributes to tissue necrosis and the progression of gas gangrene. Although a few other CDCs have been well characterized, the roles of many others are less well known. Nevertheless, it is clear that members of the MACPF/CDC superfamily often have opposing roles in host defense and pathogenesis.

The purpose of this Research Topic is to highlight the significant immunological and pathological roles of MACPF/CDC pore-forming proteins. To foster discourse and development within this field, we welcome Original Research, Method, Review, Mini Review, and Perspective articles that contribute to a greater understanding of MACPF/CDC family members including:

1. Immunological contributions of MACPF/CDC proteins
2. Mechanism of pore formation; including structure-based studies
3. Expression and deployment of MACPF/CDCs in response to infectious organisms
4. Contributions of microbial MACPF/CDCs to pathogenesis
5. Comparative studies in various species including invertebrates