Management of cell death in parasitic infections

Abstract

For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However, during their evolution, protozoan and helminth parasites have developed strategies to interfere with cell death so as to spread and survive in the infected host, thereby ascribing a more intriguing role to infection-associated cell death. In this review, we examine the mechanisms used by intracellular and extracellular parasites to respectively inhibit or trigger programmed cell death. We further dissect the role of the prototypical “eat-me signal” phosphatidylserine (PtdSer) which, by being exposed on the cell surface of damaged host cells as well as on some viable parasites via a process of apoptotic mimicry, leads to their recognition and up-take by the neighboring phagocytes. Although barely dissected so far, the engagement of different PtdSer receptors on macrophages, by shaping the host immune response, affects the overall infection outcome in models of both protozoan and helminth infections. In this scenario, further understanding of the molecular and cellular regulation of the PtdSer exposing cell-macrophage interaction might allow the identification of new therapeutic targets for the management of parasitic infection.

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

“…Multiple pairs of 'eat me' signals and receptors might be involved in macrophage-mediated efferocytosis in infectious diseases 30 . We previously investigated the role of the αvβ3 integrin in vitro and found that: i) peritoneal macrophages from T. cruzi-infected mice phagocytosed apoptotic naïve T cells in an integrin-dependent fashion, and ii) αvβ3-mediated efferocytosis exacerbated T. cruzi infection by inducing PGE-2, TGF-β, ornithine decarboxylase activity and polyamine production 13 .…”

“…Moreover, the phagocytosis of apoptotic cells (efferocytosis) by infected macrophages exacerbated T. cruzi infection in a TGF-βand polyamine-dependent manner 13 . Therefore, inhibitors of apoptosis and efferocytosis are potential therapeutic tools to potentiate immune responses to some parasite infections 21,[28][29][30] . Among the receptors involved in efferocytosis, TAM (Tyro3, Axl, and Mer) tyrosine kinase (TK) receptors 31,32 are especially promising as molecular targets because new selective inhibitors for Axl or Mer signalling have been used in clinical trials to treat cancer 33 .…”

Mediators of liver inflammation and carcinogenesis

“…The review by Bosurgi and Rothlin in this issue addresses the management of cell death in the context of parasitic infections [4]. The authors show that the recognition and phagocytosis of dead cells are of a major relevance for shaping the immune response.…”

A Cryptosporidium parvum vaccine candidate effect on immunohistochemical profiling of CD4+, CD8+, Caspase-3 and NF-κB in mice

“…Parasites, including protozoans and helminthes, have developed evolutionary strategies that can interfere with cell death to survive and multiply inside the host tissues [ 23 ]. Many studies suggested that C. parvum has multiple strategies to control apoptosis to facilitate its growth and life cycle completion.…”