Commentary: Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection

Toxoplasma gondii, a protozoan agent infecting several mammalian species, is responsible for almost 2 billion cases of human infections worldwide, with severe T. gondii-related/associated disease also occurring in immunocompromised hosts (Montoya and Liesenfeld, 2004).

Noteworthy, a key role for proteolysis has been recently demonstrated within T. gondii lysosomal organelle (Di Cristina et al., 2017). Indeed, the aforementioned paper reports that disruption of a cysteine protease enzyme located in the protozoan's vacuolar compartment (VAC) results in a strong reduction of T. gondii chronic neural infection, with previous accumulation of undigested autophagosomes in the parasitic cytoplasm (Di Cristina et al., 2017).

Albeit of significant relevance and also of potential therapeutic value toward this major zoonotic pathogen, the possibility that inhibiting T. gondii VAC-associated autophagic machinery may adversely affect the host's innate immunity against the infection should be seriously taken into account. In this respect, it has been demonstrated that all three genotypes of T. gondii elicit the production of “neutrophil extracellular traps” (NETs) on behalf of murine and human polymorphonuclear (PMN) leukocytes, both in vitro and in vivo (Abi Abdallah et al., 2012). These neutrophil-released components, the formation of which may be equally induced by other protozoan agents, such as Leishmania amazonensis (Guimarães-Costa et al., 2009) and Plasmodium falciparum, (Baker et al., 2008), have been shown to exert a powerful anti-microbial defense activity also against bacterial (Brinkmann et al., 2004) and fungal pathogens (Urban et al., 2009). Furthermore, NET release by PMN cells does not appear to depend upon active T. gondii invasion, nor upon host cell phagocytic function (Abi Abdallah et al., 2012), which could be also negatively impacted, in turn, by the aforementioned inhibition of T. gondii VAC-associated autophagic pathway (Di Cristina et al., 2017). Indeed, beside DNA and histones NETs contain several antimicrobial factors mimicking those normally found in PMN lysosomal compartment, like bacterial permeability-increasing protein (BPI), myeloperoxidase and neutrophil elastase (Brinkmann et al., 2004).

On the basis of the above, we cannot exclude a priori that the inhibition of T. gondii-dependent lysosomal machinery may result in a concurrent suppression of the aforementioned innate immune response mechanisms ensuring an efficient anti-protozoan defense.

Additional caution should be taken when dealing with the comparative neuropathology and neuropathogenesis of T. gondii infection, which could vary across different mammalian hosts. In this respect, while the cerebral inflammation's degree and severity in T. gondii meningoencephalitis-affected striped dolphins (Stenella coeruleoalba) (Di Guardo et al., 2010) has been shown to be positively correlated, on one side, with the brain tissue levels of 5-lipoxygenase (5-LOX) (Di Guardo et al., 2015)—a key enzyme of the eicosanoid pathway mediating inflammatory reactions (Pihlaja et al., 2017)—an excessive proinflammatory response has been reported, on the other side, in the brains of 5-LOX-deficient mice, which also succumbed to T. gondii infection at the early onset of chronic disease, following the development of severe encephalitic lesions (Aliberti et al., 2002).

In conclusion, with the aim of clarifying the open issues outlined above, further studies in both spontaneous and experimental disease models are needed, with special emphasis on T. gondii infection's neuropathogenesis and mutual host-parasite relationships.

Statements

Summary

Keywords

Toxoplasma gondii, autophagy, lysosomes, infection, neuropathogenesis

Citation

Di Guardo G (2017) Commentary: Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. Front. Microbiol. 8:1876. doi: 10.3389/fmicb.2017.01876

Received

03 August 2017

Accepted

13 September 2017

Published

26 September 2017

Volume

8 - 2017

Edited by

Rustam Aminov, University of Aberdeen, United Kingdom

Reviewed by

Claudio Silva, Federal University of Uberlandia, Brazil; Emma Harriet Wilson, University of California, Riverside, United States

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Copyright

© 2017 Di Guardo.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Giovanni Di Guardo gdiguardo@unite.it

This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

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