Ecological rules governing helminth-microparasite coinfection

Abstract

Coinfection of a host by multiple parasite species has important epidemiological and clinical implications. However, the direction and magnitude of effects vary considerably among systems, and, until now, there has been no general framework within which to explain this variation. Community ecology has great potential for application to such problems in biomedicine. Here, metaanalysis of data from 54 experiments on laboratory mice reveals that basic ecological rules govern the outcome of coinfection across a broad spectrum of parasite taxa. Specifically, resource-based ("bottom-up") and predator-based ("top-down") control mechanisms combined to determine microparasite population size in helminth-coinfected hosts. Coinfection imposed bottom-up control (resulting in decreased microparasite density) when a helminth that causes anemia was paired with a microparasite species that requires host red blood cells. At the same time, coinfection impaired top-down control of microparasites by the immune system: the greater the helminth-induced suppression of the inflammatory cytokine interferon (IFN)-gamma, the greater the increase in microparasite density. These results suggest that microparasite population growth will be most explosive when underlying helminths do not impose resource limitations but do strongly modulate IFN-gamma responses. Surprisingly simple rules and an ecological framework within which to analyze biomedical data thus emerge from analysis of this dataset. Through such an interdisciplinary lens, predicting the outcome of coinfection may become tractable.

Fig. 1.

Effect sizes for changes in microparasite density induced by helminth coinfection, based on data from 54 experiments. For the 40 experiments for which data on variance were available, the 95% C.I. is depicted. Helminth coinfection resulted in significantly reduced microparasite density in 23% of experiments, increased density in 50%, and no effect (C.I. overlapping zero) in 27%.

Fig. 2.

Mean effect sizes for changes in microparasite density due to helminth coinfection, according to whether the helminth limits resource availability (here, host RBCs) for the microparasite. Data from 54 coinfection experiments were metaanalyzed to assess whether changes in peak microparasite density depended on helminth-induced RBC limitation (means ± bootstrapped 95% C.I. shown). Each pair of parasite species was identified a priori as possessing potential or no potential for RBC limitation (see Methods). RBC-limiting coinfection tended to decrease microparasite density, whereas microparasite density was increased when helminth coinfection did not impose RBC limitation for the microparasite.

Fig. 3.

Helminth-induced alterations in microparasite-specific immunity as a predictor of microparasite density effect size. IFN-γ is a potent immunological molecule involved in defense against microparasites. Metaanalysis of data from 14 experiments revealed a negative relationship between microparasite density and IFN-γ effect sizes induced by helminth coinfection (point estimate ± variance shown). The greater the helminth-induced reduction in microparasite-specific production of IFN-γ, the greater the increase in microparasite density. Host genotype [analyzed with A/J (gray triangle) omitted: tested for effects of C57BL/6 (filled diamonds) versus BALB/c (open diamonds) genotype] did not explain the pattern, and the pattern remained significant even when the data point at the bottom right was excluded from analysis.

Fig. 4.

Conceptual diagram of a unified bottom-up/top-down ecological framework within which to analyze helminth–microparasite coinfection. Helminth-induced changes in immunity or resource availability (in gray region) have effects on microparasite density (in white region) that correspond to top-down and bottom-up ecological processes. For example, decreased production of the cytokine IFN-γ reduced top-down control, as evidenced by the increased density of microparasites (see Fig. 3). At the same time, decreased RBC density enhanced bottom-up control, as evidenced by the decreased density of microparasites requiring that cell type (see Fig. 2). The solid arrows correspond to these scenarios. However, how helminth-induced changes in immunity and resource availability might interact to shape microparasite populations is unknown, as represented by dashed lines. For example, in cases in which immunity fails to explain observed microparasite densities, might resource limitation be operating? In biomedicine, the two lines of inquiry are virtually never pursued together, whereas the science of ecology provides a conceptual and statistical/mathematical framework in which to understand interactions between bottom-up and top-down processes (represented by the ecological toolbox). Ecology may thus be able to explain and predict a wider range of coinfection outcomes than biomedical subdisciplines have yet managed, including cases in which helminth coinfection does not alter microparasite density or does so in apparently counterintuitive ways.