Malaria is a mosquito-borne disease caused by the P. falciparum parasite that has a high prevalence in sub-Sahara Africa and south Asia that infects millions of people causing hundreds of thousands of deaths globally each year. Pharmacological treatment is available; however, its efficacy is dependent on the type of malaria, severity of disease, and patients’ health status. Current efforts are in progress to identify an effective vaccine for the infection. With increased efforts in vaccine development, members of the Prlic laboratory (Vaccine and Infectious Disease Division) at Fred Hutch in collaboration with the University of Basel sought to better understand the effects of infection on the innate immune response. The innate response affects the subsequent adaptive response, which is important in the context of vaccine efficacy. Currently, most studies of malaria are performed with a mouse model and it has not yet been demonstrated how well this model translates to human malaria infection. To better understand human infection this study focused on the downstream innate immune response in human volunteers.
The first immune feature analyzed was the effect of early infection on a group of innate immune cells including: Natural killer (NK) cells, invariant natural killer T (iNKT) cells, and mucosal-associated invariant T (MAIT) cells. NK cells are cytotoxic lymphocytes that recognize stressed cells in the absence of antibody. iNKT cells are T cells that express similar surface markers and act similar to NK cells. MAIT cells are present in the blood, liver, lungs and mucosa and have effector like qualities. These cells act by responding quickly to inflammatory signals, such as IL-12, IL-15, and IL-18, which in turn causes them to activate an effector function leading to expression of interferon-gamma and granzyme B. These molecules are important for early parasite and disease control. Because of their function early in infection, the Prlic Lab used a controlled human malaria infection (CHMI) cohort from Tanzania to study changes in this population of cells. For the study 11 volunteers were infected with 10,000 P. falciparum sporazoites (PfSPZs) and 10 volunteers with 25,000 PfSPZs. From these volunteers, blood was drawn at day 0 (prior to infection) day 9, 28, 56, and 168. Blood smears were taken over the course of the study to monitor the onset of blood parasitemia and once detected, treatment with Coartem was given to clear infection.
Looking at the big picture, the group found differences in the frequency of innate and innate-like lymphocytes based on PfSPZ dose. Specifically, the frequency of MAIT cells increased after infection and stayed elevated through day 168 in the 25,000 dose volunteers (see figure). The NK cell frequencies were reduced at days 28 and 56. In contrast, the iNKT cell frequency did not change in either group. Since MAIT cell population changed the most, researchers followed this population throughout the rest of the paper. Looking more closely at the MAIT population and the blood stage infection, they found that the frequency of MAIT cells drops during parasitemia but recovers by day 28. Even though the MAIT cell population is elevated there was only a limited increase in CD69 (marker of T cell activation) expression and no significant effector function. To access if the MAIT cell population had the ability to respond, cells were isolated and stimulated ex vivo; these cells uniformly responded to stimulation and expressed granzyme B as expected. This shows that the cells had the ability to be activated and respond but did not. Finally, the group used single cell RNAseq analysis to look for differences in gene expression and cellular clonality. This analysis did not identify any significant changes. When asked about the paper’s overall contributions to the field Dr. Prlic stated, “We found that controlled human malaria infection (CHMI) leads to a long-lasting alteration in the composition of the innate and innate-like lymphocyte pool. It is still unclear if the functional properties of the NK and MAIT populations are altered in the months following CHMI and possibly remain altered for prolonged time periods. I think this is a key question that will need to be addressed in future studies to fully understand the significance of these changes.”
Mpina M, Maurice NJ, Yajima M, Slichter CK, Miller HW,Dutta M, McElrath MJ, Stuart KD, De Rosa SC, McNevin JP, Linsley PS, Abdulla S, Tanner M, Hoffman SL, Gottardo R, Daubenberger CA, Prlic M. 2017. Controlled Human Malaria Infection Leads to Long-Lasting Changes in Innate and Innate-like Lymphocyte Populations. J Immunol.
This work was supported by the National Institutes of Health and the Swiss Tropical and Public Health Institutes.