Helminth ecological requirements shape the impact of climate change on the hazard of infection.

Outbreaks and spread of infectious diseases are often associated with seasonality and environmental changes, including global warming. Free-living stages of soil-transmitted helminths are highly susceptible to climatic drivers; however, how multiple climatic variables affect helminth species, and the long-term consequences of these interactions, is poorly understood. We used experiments on nine trichostrongylid species of herbivores to develop a temperature- and humidity-dependent model of infection hazard, which was then implemented at the European scale under climate change scenarios. Intestinal and stomach helminths exhibited contrasting climatic responses, with the former group strongly affected by temperature while the latter primarily impacted by humidity. Among the demographic traits, larval survival heavily modulated the infection hazard. According to the specific climatic responses of the two groups, climate change is expected to generate differences in the seasonal and spatial shifts of the infection hazard and group co-circulation. In the future, an intensification of these trends could create new opportunities for species range expansion and co-occurrence at European central-northern latitudes.

Temperature affects viral kinetics and vectorial capacity of Aedes aegypti mosquitoes co-infected with Mayaro and Dengue viruses.

BACKGROUND: Increasing global temperatures and unpredictable climatic extremes have contributed to the spread of vector-borne diseases. The mosquito Aedes aegypti is the main vector of multiple arboviruses that negatively impact human health, mostly in low socioeconomic areas of the world. Co-circulation and co-infection of these viruses in humans have been increasingly reported; however, how vectors contribute to this alarming trend remains unclear. METHODS: Here, we examine single and co-infection of Mayaro virus (D strain, Alphavirus) and dengue virus (serotype 2, Flavivirus) in Ae. aegypti adults and cell lines at two constant temperatures, moderate (27 °C) and hot (32 °C), to quantify vector competence and the effect of temperature on infection, dissemination and transmission, including on the degree of interaction between the two viruses. RESULTS: Both viruses were primarily affected by temperature but there was a partial interaction with co-infection. Dengue virus quickly replicates in adult mosquitoes with a tendency for higher titers in co-infected mosquitoes at both temperatures, and mosquito mortality was more severe at higher temperatures in all conditions. For dengue, and to a lesser extent Mayaro, vector competence and vectorial capacity were higher at hotter temperature in co- vs. single infections and was more evident at earlier time points (7 vs. 14 days post infection) for Mayaro. The temperature-dependent phenotype was confirmed in vitro by faster cellular infection and initial replication at higher temperatures for dengue but not for Mayaro virus. CONCLUSIONS: Our study suggests that contrasting kinetics of the two viruses could be related to their intrinsic thermal requirements, where alphaviruses thrive better at lower temperatures compared to flaviviruses. However, more studies are necessary to clarify the role of co-infection at different temperature regimes, including under more natural temperature settings.

Temperature affects viral kinetics and vectorial capacity of Aedes aegypti mosquitoes co-infected with Mayaro and Dengue viruses.

Increasing global temperatures and unpredictable climatic extremes have contributed to the spread of vector-borne diseases. The mosquito Aedes aegypti is the main vector of multiple arboviruses that negatively impact human health, mostly in low socioeconomic areas of the world. Co-circulation and co-infection of these viruses in humans have been increasingly reported; however, how vectors contribute to this alarming trend remains unclear. Here, we examine single and co-infection of Mayaro virus (-D strain, Alphavirus) and dengue virus (serotype 2, Flavivirus) in Ae. aegypti adults and cell lines at two constant temperatures, moderate (27°C) and hot (32°C), to quantify vector competence and the effect of temperature on infection, dissemination and transmission, including on the degree of interaction between the two viruses. Both viruses were primarily affected by temperature but there was a partial interaction with co-infection. Dengue virus quickly replicates in adult mosquitoes, with a tendency for higher titers in co-infected mosquitoes at both temperatures and mosquito mortality was more severe at higher temperatures in all conditions. For dengue, and to a lesser extent Mayaro, vector competence and vectorial capacity were higher at hotter temperature in co- vs single infections and was more evident at earlier timepoints (7 vs 14 days post infection). The temperature-dependent phenotype was confirmed in vitro by faster cellular infection and initial replication at higher temperatures for dengue but not for Mayaro virus. Our study suggests that contrasting kinetics of the two viruses could be related to their intrinsic thermal requirements, where alphaviruses thrive better at lower temperatures compared to flaviviruses, but further studies are necessary to clarify the role of co-infection at different and variable temperature regimes.

Modeling the contribution of antibody attack rates to single and dual helminth infections in a natural system.

Within-host models of infection can provide important insights into the processes that affect parasite spread and persistence in host populations. However, modeling can be limited by the availability of empirical data, a problem commonly encountered in natural systems. Here, we used six years of immune-infection observations of two gastrointestinal helminths (Trichostrongylus retortaeformis and Graphidium strigosum) from a population of European rabbits (Oryctolagus cuniculus) to develop an age-dependent, mathematical model that explicitly included species-specific and cross-reacting antibody (IgA and IgG) responses to each helminth in hosts with single or dual infections. Different models of single infection were formally compared to test alternative mechanisms of parasite regulation. The two models that best described single infections of each helminth species were then coupled through antibody cross-immunity to examine how the presence of one species could alter the host immune response to, and the within-host dynamics of, the other species. For both single infections, model selection suggested that either IgA or IgG responses could equally explain the observed parasite intensities by host age. However, the antibody attack rate and affinity level changed between the two helminths, it was stronger against T. retortaeformis than against G. strigosum and caused contrasting age-intensity profiles. When the two helminths coinfect the same host, we found variation of the species-specific antibody response to both species together with an asymmetric cross-immune response driven by IgG. Lower attack rate and affinity of antibodies in dual than single infections contributed to the significant increase of both helminth intensities. By combining mathematical modeling with immuno-infection data, our work provides a tractable model framework for disentangling some of the complexities generated by host-parasite and parasite-parasite interactions in natural systems.

The enemy of my enemy is my friend: Immune-mediated facilitation contributes to fitness of co-infecting helminths.

The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to long-term data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetric IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.

Within-host mechanisms of immune regulation explain the contrasting dynamics of two helminth species in both single and dual infections.

Variation in the intensity and duration of infections is often driven by variation in the network and strength of host immune responses. While many of the immune mechanisms and components are known for parasitic helminths, how these relationships change from single to multiple infections and impact helminth dynamics remains largely unclear. Here, we used laboratory data from a rabbit-helminth system and developed a within-host model of infection to investigate different scenarios of immune regulation in rabbits infected with one or two helminth species. Model selection suggests that the immunological pathways activated against Trichostrongylus retortaeformis and Graphidium strigosum are similar. However, differences in the strength of these immune signals lead to the contrasting dynamics of infections, where the first parasite is rapidly cleared and the latter persists with high intensities. In addition to the reactions identified in single infections, rabbits with both helminths also activate new pathways that asymmetrically affect the dynamics of the two species. These new signals alter the intensities but not the general trend of the infections. The type of interactions described can be expected in many other host-helminth systems. Our immune framework is flexible enough to capture different mechanisms and their complexity, and provides essential insights to the understanding of multi-helminth infections.