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Rats vary in their susceptibilities toToxoplasma gondii infection depending on the rat strain. Compared to theT. gondii -susceptible Brown Norway (BN) rat, the Lewis (LEW) rat is extremely resistant toT. gondii . Thus, these two rat strains are ideal models for elucidating host mechanisms that are important for host resistance toT. gondii infection. Therefore, in our efforts to unravel molecular factors directing the protective early innate immune response in the LEW rat, we performed RNA sequencing analysis of the LEW versus BN rat with or withoutT. gondii infection. We identified three candidate smallG TPaseim munity-a ssociatedp roteins (GIMAPs) that were upregulated (false discovery rate, 0.05) in the LEW rat in response toT. gondii infection. Subsequently, we engineeredT. gondii -susceptible NR8383 rat macrophage cells for overexpression of LEW rat-derived candidate GIMAP 4, 5, and 6. By immunofluorescence analysis we observed that GIMAP 4, 5, and 6 inT. gondii -infected NR8383 cells each colocalized with GRA5, a parasite parasitophorous vacuole membrane (PVM) marker protein, suggesting their translocation to the PVM. Interestingly, overexpression of each candidate GIMAP inT. gondii -infected NR8383 cells induced translocation of LAMP1, a lysosome marker protein, to theT. gondii surface membrane. Importantly, overexpression of GIMAP 4, 5, or 6 individually inhibited intracellularT. gondii growth, with GIMAP 4 having the highest inhibitory effect. Together, our findings indicate that upregulation of GIMAP 4, 5, and 6 contributes to the robust refractoriness of the LEW rat toT. gondii through induction of lysosomal fusion to the otherwise nonfusogenic PVM.

Small GTPase Immunity-Associated Proteins Mediate Resistance to Toxoplasma gondii Infection in Lewis Rat