Dynamics and Outcomes of Plasmodium Infections in Grammomys surdaster (Grammomys dolichurus) Thicket Rats versus Inbred Mice.

Investigations of malaria infection are often conducted by studying rodent Plasmodium species in inbred laboratory mice, but the efficacy of vaccines or adjunctive therapies observed in these models often does not translate to protection in humans. This raises concerns that mouse malaria models do not recapitulate important features of human malaria infections. African woodland thicket rats (Grammomys surdaster) are the natural host for the rodent malaria parasite Plasmodium berghei and the suspected natural host for Plasmodium vinckei vinckei. Previously, we reported that thicket rats are highly susceptible to diverse rodent parasite species, including P. berghei, Plasmodium yoelii, and Plasmodium chabaudi chabaudi, and are a more stringent model to assess the efficacy of whole-sporozoite vaccines than laboratory mice. Here, we compare the course of infection and virulence with additional rodent Plasmodium species, including various strains of P. berghei, P. yoelii, P. chabaudi, and P. vinckei, in thicket rats versus laboratory mice. We present evidence that rodent malaria parasite growth typically differs between the natural versus nonnatural host; G. surdaster limit infection by multiple rodent malaria strains, delaying and reducing peak parasitemia compared with laboratory mice. The course of malaria infection in thicket rats varied depending on parasite species and strain, resulting in self-cure, chronic parasitemia, or rapidly lethal infection, thus offering a variety of rodent malaria models to study different clinical outcomes in the natural host.

γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations.

Whole-sporozoite vaccines confer sterilizing immunity to malaria-naive individuals by unknown mechanisms. In the first PfSPZ Vaccine trial ever in a malaria-endemic population, Vδ2 γδ T cells were significantly elevated and Vγ9/Vδ2 transcripts ranked as the most upregulated in vaccinees who were protected from Plasmodium falciparum infection. In a mouse model, absence of γδ T cells during vaccination impaired protective CD8 T cell responses and ablated sterile protection. γδ T cells were not required for circumsporozoite protein-specific Ab responses, and γδ T cell depletion before infectious challenge did not ablate protection. γδ T cells alone were insufficient to induce protection and required the presence of CD8α+ dendritic cells. In the absence of γδ T cells, CD8α+ dendritic cells did not accumulate in the livers of vaccinated mice. Altogether, our results show that γδ T cells were essential for the induction of sterile immunity during whole-organism vaccination.