<figure><img src="image_93.png" /></figure>

To investigate *T. gondii* evasion of host autophagic clearance *in vivo*, the role of EGF and EGFR was demonstrated in transgenic mice that express a dominant-negative (DN) mutant of EGFR that impairs EGFR autophosphorylation and EGFR transactivation. Expression of DN EGFR exclusively in endothelial cells was accompanied by a reduction in parasite load and histopathology in the brain and retina after *T. gondii* infection [457].

In summary, the main host mechanisms that operate *in vitro* against *T. gondii* have been investigated in mouse models of infection. Remarkably, in contrast to toxoplasmicidal actions triggered by INF-γ that are not operative across species, parasite strains, or host cell types, autophagic killing functions in all scenarios. This feature points to autophagy modulation (or impairment of *T. gondii* evasion of autophagy) as a potential strategy for drug development against toxoplasmosis.

## Effect of parasite autophagy on apicomplexan infections *in vivo*

Few *in vivo* infection studies have been performed on parasite autophagy in apicomplexans for two main reasons. First, much of the work on autophagy in malaria parasites has been done with *P. falciparum*, for which animal models are limited. Second, as noted above, many ATG proteins in apicomplexans are essential for parasite replication because of their non-canonical role in apicoplast inheritance. Since conditional disruption of ATG proteins involved in apicoplast inheritance severely affects parasite replication, the impact on *in vivo* infection is assumed to be equally pronounced.

As noted above, overexpressing ATG8 by 2-fold significantly delayed the liver stage development of rodent infective *P. berghei* parasites in infected mice [175], likely due to disrupting both the canonical and non-canonical roles of ATG8.

In the case of *T. gondii*, two studies have examined the canonical role of the parasite ATG9 in autophagy during experimental infection of mice [180,458]. The first study showed that complete ablation or conditional knockdown of TgATG9 markedly reduced parasite burden during acute infection and significantly attenuated parasite virulence, resulting in >70% mouse survival with the knockout strain and or 100% mouse survival from the conditional knockdown [180]. This is particularly notable given that the mutants were created in a highly virulent strain of *T. gondii* that normally causes 100% mortality. Disruption of TgATG9 also reduced parasite levels in mouse macrophages. Since macrophages are known to restrict *T. gondii* by limiting certain essential amino acids and by generating reactive oxygen species, the authors suggested that parasite autophagy supports parasite survival by recycling amino acids or turning over oxidatively damaged parasite proteins, structures, or organelles. The second study knocked out TgATG9 in an avirulent *T. gondii* strain that is competent for differentiating from the acute to chronic stage [458]. Consistent with the earlier study, mice infected
<figure><img src="image_94.png" /></figure>

with parasites lacking TgATG9 showed 100% survival compared to 70-80%
survival of mice infected with parental or genetically complemented strains.
Also, ~5-fold fewer TgATG9 parasites were detected upon dissemination to
the brain on day 7 post-infection, further supporting a role for canonical
autophagy during acute infection. However, TgATG9 deficient parasites
showed a >200-fold loss of parasite burden in the brain at 5 weeks post-
infection during the chronic stage. Death of chronic stage TgATG9 deficient
parasites in vitro was associated with markedly abnormal mitochondria,
implying a critical role for autophagy in support of mitochondrial home-
ostasis. Whether the canonical autophagy pathway in *T. gondii* has additional
roles during persistence warrants further investigation.

**Concluding remarks**

In this work, we have reviewed the biological cycle of pathogenic protists and
the participation of the autophagic pathway in the different stages of their
cycles. The particular lifestyles of these parasites, which alternate between
vertebrate and invertebrate hosts, in addition to the necessity to adapt to
different environments, allow the conservation of cellular processes like
autophagy. We have seen that autophagy displayed different levels of com-
plexity through this early evolutionary branch of the eukaryote domain, from
a rudimentary process observed in the *Giardia* genus up to the more complex
pathway displayed in Trypanosomatids and Apicomplexa families with the
diversification of autophagic proteins such as Atg4 and Atg8 in a similar way
to what is observed in humans, a feature whose presence is still not com-
pletely understood. Parasite autophagy has been shown to participate in
many processes, including survival under nutrient deprivation, formation
and turnover of organelles, and cell and nuclear death during specific situa-
tions. Contrary to these physiological functions, autophagy is activated in the
presence of antiprotist drugs as a quick survival response to the stress
generated by the treatment. Since this is a phenomenon observed with
most drugs, the use of inhibitors of parasite autophagy as adjuvants of anti-
parasitic drugs could be interesting to explore in the future.

The interaction of pathogenic parasites with the host autophagy has also
been reviewed. In most cases, autophagy is activated in the host cell after
infection, being a protective response for the host, which can be subverted by
the pathogen to favor growth and survival. Therefore, depending on para-
meters like type of the host cell-targeted, time of infection, and life-styles and
virulence of pathogenic protists, host autophagy plays two opposite roles,
promoting parasite survival or parasite death. More complex is the scenario
when the function of autophagy is studied on *in vivo* models of infection,
where the immune system can modulate the autophagy response and vice
versa, modifying the fate of infection. Finally, we have to consider that
<figure><img src="image_95.png" /></figure>

parasitic autophagy can also play an important role in the intracellular protist life, another aspect that should be considered for future treatments. In summary, protist autophagy is needed at different stages of the protist life-cycle, in axenic environments, or inside host cells. On the other way, host cells have developed different mechanisms to destroy parasites during infection. They are carried out by canonical or selective autophagy pathways, autophagy proteins, and/or autophagy-related processes to finally kill the pathogen. However, virulent pathogens can take advantage of host autophagy responses to resist destruction. The application of this knowledge in the search and design of new drugs that interrupt the mechanisms of resistance of protists in addition to the improvement of immune responses and cell-autonomous processes of hosts will allow the discovery of efficient therapies against these still successful pathogens in the future.

## Acknowledgments

We thank Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina and Gonçalo Moniz Institute, Fiocruz Bahia, Brazil for financial and institutional support.P.S.R. holds a research grant from Agencia Nacional de Promoción Científica y Tecnológica, Argentina (PICT 2017-1456 and PICT 2019-00640); P.S.T. V. holds a grant for productivity in research from CNPq (305235/2019-2). This work was supported by JSPS KAKENHI Grant Number 21K20643 to T.A. V.B.C is supported by US National Institutes of Health grants R01 AI120607 and R21 AI160610). Work by L.F. J. and C.Y.H. are supported by Singapore Ministry of Education Research Grants (MOE-T2EP30221-0002 and R-154-000-C60-114). We also wish to thank Mr. Ng Jun Jie, Angus for technical assistance in the experiments shown in Fig. 4. The authors would like to thank Andris K. Walter for English language revision and manuscript copyediting assistance. AD is supported by the Canadian Institutes of Health Research (grant PJT-156416) and is the holder of the Canada Research Chair on the Biology of intracellular parasitism.

## Funding

This work was supported by the CNPQ [305235/2019-2]; Singapore Ministry of Education Research Grants [MOE-T2EP30221-0002, R-154-000-C60-114]); National Institutes of Health [R01 AI120607, R21 AI160610]; JSPS KAKENHI [Grant Number 21K20643]; Agencia Nacional de Promoción Científica y Tecnológica [PICT 2017-1456, PICT 2019-00640].

## ORCID

Patricia Silvia Romano http://orcid.org/0000-0002-2843-1668
<figure><img src="image_96.png" /></figure>

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