The impact of innate immunity on malaria parasite infection dynamics

1Decades of research have investigated the molecular and cellular mechanisms that control the immune response to malaria. Yet, many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to probe for consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate and statistically analyse infection dynamics in immune deficient or augmented mice to identify and quantify consensus and identify sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohens h) for the difference in parasite burden between treatment and control groups ranging from 0.1498 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 6-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effects sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these explanations is necessary to translate understanding from model systems to human malaria infections, manage immunopathology, and facilitate realism in mathematical models.