High-resolution comparative atomic structures of two Giardiavirus prototypes infecting G. duodenalis parasite.

The Giardia lamblia virus (GLV) is a non-enveloped icosahedral dsRNA and endosymbiont virus that infects the zoonotic protozoan parasite Giardia duodenalis (syn. G. lamblia, G. intestinalis), which is a pathogen of mammals, including humans. Elucidating the transmission mechanism of GLV is crucial for gaining an in-depth understanding of the virulence of the virus in G. duodenalis. GLV belongs to the family Totiviridae, which infects yeast and protozoa intracellularly; however, it also transmits extracellularly, similar to the phylogenetically, distantly related toti-like viruses that infect multicellular hosts. The GLV capsid structure is extensively involved in the longstanding discussion concerning extracellular transmission in Totiviridae and toti-like viruses. Hence, this study constructed the first high-resolution comparative atomic models of two GLV strains, namely GLV-HP and GLV-CAT, which showed different intracellular localization and virulence phenotypes, using cryogenic electron microscopy single-particle analysis. The atomic models of the GLV capsids presented swapped C-terminal extensions, extra surface loops, and a lack of cap-snatching pockets, similar to those of toti-like viruses. However, their open pores and absence of the extra crown protein resemble those of other yeast and protozoan Totiviridae viruses, demonstrating the essential structures for extracellular cell-to-cell transmission. The structural comparison between GLV-HP and GLV-CAT indicates the first evidence of critical structural motifs for the transmission and virulence of GLV in G. duodenalis. Author summary: We determined the first atomic structure of a unique dsRNA virus known as the Giardia lamblia virus (GLV). The structure of GLV is important for two reasons. First, the GLV structure is the representative structure of a primitive group of viruses that infects unicellular parasites but has adapted an extracellular lifestyle. Hence, by comparing the structure of GLV with that of other dsRNA viruses, we could identify essential surface loop structures that have evolved to enable dsRNA viruses to infect their hosts extracellularly. Second, the GLV structure empowers us to formulate a strategy for engineering GLV, with a focus on its future therapeutic applications. G. duodenalis, a common zoonotic parasite, can infect both humans and domestic animals, often leading to severe diarrhea. Conventional anti-parasitic drugs are employed to treat G. duodenalis symptomatic infections; however, cases of refractories to these drugs are increasingly being reported. A new alternative approach gaining interest is virotherapy, which harnesses viruses that infect parasites to combat infections. An in-depth structural comparison between two GLV prototypes revealed significant structural mechanisms that potentially enhance the virulence of GLV for efficiently clearing Giardia parasites from infected patients. [ABSTRACT FROM AUTHOR]