Analysis of a summary network of co-infection in humans reveals that parasites interact most via shared resources

Abstract

Simultaneous infection by multiple parasite species (viruses, bacteria, helminths, protozoa or fungi) is commonplace. Most reports show co-infected humans to have worse health than those with single infections. However, we have little understanding of how co-infecting parasites interact within human hosts. We used data from over 300 published studies to construct a network that offers the first broad indications of how groups of co-infecting parasites tend to interact. The network had three levels comprising parasites, the resources they consume and the immune responses they elicit, connected by potential, observed and experimentally proved links. Pairs of parasite species had most potential to interact indirectly through shared resources, rather than through immune responses or other parasites. In addition, the network comprised 10 tightly knit groups, eight of which were associated with particular body parts, and seven of which were dominated by parasite-resource links. Reported co-infection in humans is therefore structured by physical location within the body, with bottom-up, resource-mediated processes most often influencing how, where and which co-infecting parasites interact. The many indirect interactions show how treating an infection could affect other infections in co-infected patients, but the compartmentalized structure of the network will limit how far these indirect effects are likely to spread.

Keywords: degree distribution; ecological network; indirect interactions; modularity; parasite ecology; polymicrobial infection.

Figure 1.

Illustrative diagrams of network analyses undertaken: (a) node degree, (b) assortativity, (c) direct and indirect connections and (d) modularity. Left network in (d) was designed to have three modules and high modularity; right network in (d) is a random network with the same number of nodes, links and modules, but lower peak modularity.

Figure 2.

(a) Raw degree distribution for the mechanistic network. Solid line is the observed proportion of nodes with a degree greater than or equal to the value on the x-axis. Dashed line is the best-fitting statistical model (exponential model λ = 0.16, p < 0.001, R² = 0.87). (b) Assortativity: the degree of each node plotted against the degree of their linked nodes for all unique links for the mechanistic network (Pearson's correlation r = −0.12, p < 0.001). Plotting symbols are transparent such that 10 overlaid data points are black.

Figure 3.

The number of direct and indirect paths between parasites for (a) all link types, (b) mechanistic and correlative links and (c) mechanistic links only. Vertical black lines represent expected distributions (2 s.d., dot indicates mean) from 1000 simulations. All observed results deviated significantly from expected values (tested against normal distribution, p < 0.001). Vertical axis scales for (a–c) are identical.

Figure 4.

Number of within-module links between host immune components and parasite and between host resources and parasites in each of the 10 modules of the mechanistic network. Lines indicate 95% confidence intervals from the binomial test. Bars overlapping with lines (immune–parasite links for modules 1, 7 and 9) are within expectations (p > 0.05). There are more within-module links for all other modules and link types than expected (p < 0.001).