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Review
. 2024 Jul 17;11(7):321.
doi: 10.3390/vetsci11070321.

Microbial Matryoshka: Addressing the Relationship between Pathogenic Flagellated Protozoans and Their RNA Viral Endosymbionts (Family Totiviridae)

Alexandra Ibañez-Escribano  1 , Maria Teresa Gomez-Muñoz  2   3 , Marta Mateo  1   2   3 , Cristina Fonseca-Berzal  1 , Esperanza Gomez-Lucia  4 , Raquel Garcia Perez  2 , Jose M Alunda  2   3 , Javier Carrion  2   3
Affiliations
Review

Microbial Matryoshka: Addressing the Relationship between Pathogenic Flagellated Protozoans and Their RNA Viral Endosymbionts (Family Totiviridae)

Alexandra Ibañez-Escribano et al. Vet Sci. .

Abstract

Three genera of viruses of the family Totiviridae establish endosymbiotic associations with flagellated protozoa responsible for parasitic diseases of great impact in the context of One Health. Giardiavirus, Trichomonasvirus, and Leishmaniavirus infect the protozoa Giardia sp., Trichomonas vaginalis, and Leishmania sp., respectively. In the present work, we review the characteristics of the endosymbiotic relationships established, the advantages, and the consequences caused in mammalian hosts. Among the common characteristics of these double-stranded RNA viruses are that they do not integrate into the host genome, do not follow a lytic cycle, and do not cause cytopathic effects. However, in cases of endosymbiosis between Leishmaniavirus and Leishmania species from the Americas, and between Trichomonasvirus and Trichomonas vaginalis, it seems that it can alter their virulence (degree of pathogenicity). In a mammalian host, due to TLR3 activation of immune cells upon the recognition of viral RNA, uncontrolled inflammatory signaling responses are triggered, increasing pathological damage and the risk of failure of conventional standard treatment. Endosymbiosis with Giardiavirus can cause the loss of intestinal adherence of the protozoan, resulting in a benign disease. The current knowledge about viruses infecting flagellated protozoans is still fragmentary, and more research is required to unravel the intricacies of this three-way relationship. We need to develop early and effective diagnostic methods for further development in the field of translational medicine. Taking advantage of promising biotechnological advances, the aim is to develop ad hoc therapeutic strategies that focus not only on the disease-causing protozoan but also on the virus.

Keywords: Giardiavirus; Leishmaniavirus; RNA virus; Totiviridae; Trichomonasvirus; viral endosymbiont.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Genomic organization of the five genera of Totiviridae. GenBank accession number of the type species is shown in each genus. ORF1 is shown in green. ORF2 is shown in red. UTR, untranslated region. RdRp, RNA-dependent RNA polymerase. This review focuses on the three genera that infect flagellated protozoans.
Figure 2
Figure 2
Classes of Totiviridae according to the origin of the RdRp. (A) Class I, fusion protein encoded in two different frames. (B) Class II, fusion protein encoded by the two adjacent ORFs in the same frame. (C) Class III, non-fusion protein encoded by ORF2. IRES, internal ribosome entry site, allowing initiation of translation by host translation machinery.
Figure 3
Figure 3
Replication cycle. In the Totiviridae, viruses replicate in the cytoplasm of the host cell. For this purpose, the virion can enter the protozoan cell by an endocytosis-mediated process. Transcription of the dsRNA genome by the viral polymerase occurs inside the virion so that the dsRNA is never exposed to the cytoplasm. The dsRNA contained in the cytoplasmic vesicles is cleaved into two ssRNAs. The positive-sense RNA (+RNA) leaves the vesicle and is translated by the ribosomes, generating the capsid proteins and RdRp. These begin to assemble, and RdRp polymerizes the complementary negative-sense RNA (−RNA), both in the vesicles and in the newly formed viral particles, a process that is repeated several times, resulting in new mature virions.
Figure 4
Figure 4
Schematic model of G. lamblia GLV+ interaction in a mammalian host. The process is initiated (1) by the ingestion of food or water contaminated with GLV-free virions and G. lamblia cysts. Once the cysts reach the small intestine, (2) excystation occurs, releasing the parasitic trophozoites. At this point, depending on the susceptibility of the G. lamblia isolate, two possible scenarios are shown. In a susceptible isolate (3A), GLV enters the trophozoite by receptor-mediated endocytosis, establishing endosymbiosis that may limit the ability of the trophozoites to adhere to the gastrointestinal epithelium and further growth. This is associated with a hypovirulent clinical phenotype of giardiosis. In a resistant isolate (3B), the trophozoite lacks GLV-binding receptors, there is no endosymbiosis, and the trophozoite adheres to intestinal cells, producing a conventional pathogenesis of giardiosis.
Figure 5
Figure 5
Schematic model of T. vaginalis TVV+ interaction in a human host. The trophozoites are sexually transmitted (1) and adhere to the genitourinary epithelium cells through the interaction of their surface LPG and adhesins, among other molecules, with different host ligands. The parasite triggers virulence factors that determine the clinical course of the disease (i.e., P270 and cysteine proteinases), with an increased inflammatory reaction in the presence of TVV. After the initiation of antiprotozoal treatment with metronidazole (2), two scenarios are shown depending on the presence or absence of the TVV endosymbiont. If the infection is caused by T. vaginalis TVV+ (3A), treatment with metronidazole results in the death of the protozoan and the release of virions and viral genetic material available for endocytic entry into the cells of the vaginal epithelium and interaction with TLR3 of the host endosome. This results in a hypervirulent phenotype of the disease, accompanied by its complications, which may exacerbate the clinical signs and are particularly relevant in pregnant women. However, if the infection is caused by T. vaginalis TVV− (3B), treatment with metronidazole is successful, and the disease is controlled.
Figure 6
Figure 6
Schematic model of L. guyanensis LRV1+ interaction in a mammal host. Infectious promastigotes are released by the phlebotomine sandfly bite (1) during a blood meal and enter target phagocytic cells (macrophages). Depending on whether the promastigotes carry LRV1 or not, two possible scenarios are shown. In the case of L. guyanensis LRV1+ infection (2A), promastigotes transform into amastigotes inside the cell phagosome, and viral RNA can be released, which interacts with TLR3 inside the phagosome and triggers both the hyperinflammatory Th17 cascade (leading to metastatic lesions) and the activation of the autophagic machinery, resulting in the deactivation of the inflammasome platform, thus favoring parasitic persistence associated with treatment failure. In cases of L. guyanensis LRV1- infection (2B), the disease course progresses in a conventional manner, and disease control can be achieved with successful antimonial treatment.
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