Understanding factors explaining both intra and interspecific variation in susceptibility to infection by parasites remains a key question in evolutionary biology. Within a species variation in susceptibility is often explained by differences in behaviour affecting exposure to infection and/or resistance affecting the degree by which parasite growth is controlled (Roy & Kirchner, 2000, Behringer et al., 2000). This can vary between the sexes (Kelly et al., 2018) and may be explained by the ability of a parasite to attack different organs or tissues (Brierley et al., 2019). However, what goes on within one species is not always relevant to another, making it unclear when patterns can be scaled up and generalised across species. This is also important to understand when parasites may jump hosts, or identify species that may be susceptible to a host jump (Longdon et al., 2015). Phylogenetic distance between hosts is often an important factor explaining susceptibility to a particular parasite in plant and animal hosts (Gilbert & Webb, 2007, Faria et al., 2013). 

In two separate experiments, Roberts and Longdon (Roberts & Longdon, 2022) investigated how sex and tissue tropism affected variation in the load of Drosophila C Virus (DCV) across multiple Drosophila species. DCV load has been shown to correlate positively with mortality (Longdon et al., 2015). Overall, they found that load did not vary between the sexes; within a species males and females had similar DCV loads for 31 different species. There was some variation in levels of DCV growth in different tissue types, but these too were consistent across males for 7 species of Drosophila. Instead, in both experiments, host phylogeny or interspecific variation, explained differences in DCV load with some species being more infected than others. 

This study is neat in that it incorporates and explores simultaneously both intra and interspecific variation in infection-related life-history traits which is not often done (but see (Longdon et al., 2015, Imrie et al., 2021, Longdon et al., 2011, Johnson et al., 2012). Indeed, most studies to date explore either inter-specific differences in susceptibility to a parasite (it can or can’t infect a given species) (Davies & Pedersen, 2008, Pfenning-Butterworth et al., 2021) or intra-specific variability in infection-related traits (infectivity, resistance etc.) due to factors such as sex, genotype and environment (Vale et al., 2008, Lambrechts et al., 2006). This work thus advances on previous studies, while at the same time showing that sex differences in parasite load are not necessarily pervasive. 

References

Behringer DC, Butler MJ, Shields JD (2006) Avoidance of disease by social lobsters. Nature, 441, 421–421. https://doi.org/10.1038/441421a

Brierley L, Pedersen AB, Woolhouse MEJ (2019) Tissue tropism and transmission ecology predict virulence of human RNA viruses. PLOS Biology, 17, e3000206. https://doi.org/10.1371/journal.pbio.3000206

Davies TJ, Pedersen AB (2008) Phylogeny and geography predict pathogen community similarity in wild primates and humans. Proceedings of the Royal Society B: Biological Sciences, 275, 1695–1701. https://doi.org/10.1098/rspb.2008.0284

Faria NR, Suchard MA, Rambaut A, Streicker DG, Lemey P (2013) Simultaneously reconstructing viral cross-species transmission history and identifying the underlying constraints. Philosophical Transactions of the Royal Society B: Biological Sciences, 368, 20120196. https://doi.org/10.1098/rstb.2012.0196

Gilbert GS, Webb CO (2007) Phylogenetic signal in plant pathogen–host range. Proceedings of the National Academy of Sciences, 104, 4979–4983. https://doi.org/10.1073/pnas.0607968104

Imrie RM, Roberts KE, Longdon B (2021) Between virus correlations in the outcome of infection across host species: Evidence of virus by host species interactions. Evolution Letters, 5, 472–483. https://doi.org/10.1002/evl3.247

Johnson PTJ, Rohr JR, Hoverman JT, Kellermanns E, Bowerman J, Lunde KB (2012) Living fast and dying of infection: host life history drives interspecific variation in infection and disease risk. Ecology Letters, 15, 235–242. https://doi.org/10.1111/j.1461-0248.2011.01730.x

Kelly CD, Stoehr AM, Nunn C, Smyth KN, Prokop ZM (2018) Sexual dimorphism in immunity across animals: a meta-analysis. Ecology Letters, 21, 1885–1894. https://doi.org/10.1111/ele.13164

Lambrechts L, Chavatte J-M, Snounou G, Koella JC (2006) Environmental influence on the genetic basis of mosquito resistance to malaria parasites. Proceedings of the Royal Society B: Biological Sciences, 273, 1501–1506. https://doi.org/10.1098/rspb.2006.3483

Longdon B, Hadfield JD, Day JP, Smith SCL, McGonigle JE, Cogni R, Cao C, Jiggins FM (2015) The Causes and Consequences of Changes in Virulence following Pathogen Host Shifts. PLOS Pathogens, 11, e1004728. https://doi.org/10.1371/journal.ppat.1004728

Longdon B, Hadfield JD, Webster CL, Obbard DJ, Jiggins FM (2011) Host Phylogeny Determines Viral Persistence and Replication in Novel Hosts. PLOS Pathogens, 7, e1002260. https://doi.org/10.1371/journal.ppat.1002260

Pfenning-Butterworth AC, Davies TJ, Cressler CE (2021) Identifying co-phylogenetic hotspots for zoonotic disease. Philosophical Transactions of the Royal Society B: Biological Sciences, 376, 20200363. https://doi.org/10.1098/rstb.2020.0363

Roberts KE, Longdon B (2023) Heterogeneities in infection outcomes across species: examining sex and tissue differences in virus susceptibility. bioRxiv 2022.11.01.514663, ver. 2 peer-reviewed and recommended by Peer Community in Evolutionary Biology. https://doi.org/10.1101/2022.11.01.514663 

Roy BA, Kirchner JW (2000) Evolutionary Dynamics of Pathogen Resistance and Tolerance. Evolution, 54, 51–63. https://doi.org/10.1111/j.0014-3820.2000.tb00007.x

Vale PF, Stjernman M, Little TJ (2008) Temperature-dependent costs of parasitism and maintenance of polymorphism under genotype-by-environment interactions. Journal of Evolutionary Biology, 21, 1418–1427. https://doi.org/10.1111/j.1420-9101.2008.01555.x

Within-host parasite density is tightly linked to parasite fitness often determining both transmission success and virulence (parasite-induced harm to the host) (Alizon et al., 2009, Anderson & May, 1982). Parasite density may thus be controlled by selection balancing these conflicting pressures. Actual within-host density regulation may be under host or parasite control, or due to other environmental factors (Wale et al., 2019, Vale et al., 2011, Chrostek et al., 2013). Vertically transmitted parasites may also be more vulnerable to drift associated with bottlenecks between generations, which may also determine within-host population size (Mathe-Hubert et al., 2019, Mira & Moran, 2002).

Bénard et al. (2021) use 3 experiments to disentangle the role of drift versus host factors in the control of within-host Wolbachia growth in Drosophila melanogaster. They use the wMelPop Wolbachia strain in which virulence (fly longevity) and within-host growth correlate positively with copy number in the genomic region Octomom (Chrostek et al., 2013, Chrostek & Teixeira, 2015). Octomom copy number can be used as a marker for different genetic lineages within the wMelPop strain.

In a first experiment, they introgressed and backcrossed this Wolbachia strain into 6 different host genetic backgrounds and show striking differences in within-host symbiont densities which correlate positively with Octomom copy number. This is consistent with host genotype selecting different Wolbachia strains, but also with bottlenecks and drift between generations. To distinguish between these possibilities, they perform 2 further experiments. 

A second experiment repeated experiment 1, but this time introgression was into 3 independent lines of the Bolivia and USA Drosophila populations; those that, respectively, exhibited the lowest and highest Wolbachia density and Octomom copy number. In this experiment, growth and Octomom copy number were measured across the 3 lines, for each population, after 1, 13 and 25 generations. Although there were little differences between replicates at generation 1, there were differences at generations 13 and 25 among the replicates of both the Bolivia and USA lines. These results are indicative of parasite control, or drift being responsible for within-host growth rather than host factors. 

A third experiment tested whether Wolbachia density and copy number were under host or parasite control. This was done, again using the USA and Bolivia lines, but this time those from the first experiment, several generations following the initial introgression and backcrossing. The newly introgressed lines were again followed for 25 generations. At generation 1, Wolbachia phenotypes resembled those of the donor parasite population and not the recipient host population indicating a possible maternal effect, but a lack of host control over the parasite. Furthermore, Wolbachia densities and Octomom number differed among replicate lines through time for Bolivia populations and from the donor parasite lines for both populations. These differences among replicate lines that share both host and parasite origins suggest that drift and/or maternal effects are responsible for within-host Wolbachia density and Octomom number. 

These findings indicate that drift appears to play a role in shaping Wolbachia evolution in this system. Nevertheless, completely ruling out the role of the host or parasite in controlling densities will require further study. The findings of Bénard and coworkers (2021) should stimulate future work on the contribution of drift to the evolution of vertically transmitted parasites.

References

Alizon S, Hurford A, Mideo N, Baalen MV (2009) Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future. Journal of Evolutionary Biology, 22, 245–259. https://doi.org/10.1111/j.1420-9101.2008.01658.x

Anderson RM, May RM (1982) Coevolution of hosts and parasites. Parasitology, 85, 411–426. https://doi.org/10.1017/S0031182000055360

Bénard A, Henri H, Noûs C, Vavre F, Kremer N (2021) Wolbachia load variation in Drosophila is more likely caused by drift than by host genetic factors. bioRxiv, 2020.11.29.402545, ver. 4  recommended and peer-reviewed by Peer Community in Evolutionary Biology. https://doi.org/10.1101/2020.11.29.402545

Chrostek E, Marialva MSP, Esteves SS, Weinert LA, Martinez J, Jiggins FM, Teixeira L (2013) Wolbachia Variants Induce Differential Protection to Viruses in Drosophila melanogaster: A Phenotypic and Phylogenomic Analysis. PLOS Genetics, 9, e1003896. https://doi.org/10.1371/journal.pgen.1003896

Chrostek E, Teixeira L (2015) Mutualism Breakdown by Amplification of Wolbachia Genes. PLOS Biology, 13, e1002065. https://doi.org/10.1371/journal.pbio.1002065

Mathé‐Hubert H, Kaech H, Hertaeg C, Jaenike J, Vorburger C (2019) Nonrandom associations of maternally transmitted symbionts in insects: The roles of drift versus biased cotransmission and selection. Molecular Ecology, 28, 5330–5346. https://doi.org/10.1111/mec.15206

Mira A, Moran NA (2002) Estimating Population Size and Transmission Bottlenecks in Maternally Transmitted Endosymbiotic Bacteria. Microbial Ecology, 44, 137–143. https://doi.org/10.1007/s00248-002-0012-9

Vale PF, Wilson AJ, Best A, Boots M, Little TJ (2011) Epidemiological, Evolutionary, and Coevolutionary Implications of Context-Dependent Parasitism. The American Naturalist, 177, 510–521. https://doi.org/10.1086/659002

Wale N, Jones MJ, Sim DG, Read AF, King AA (2019) The contribution of host cell-directed vs. parasite-directed immunity to the disease and dynamics of malaria infections. Proceedings of the National Academy of Sciences, 116, 22386–22392. https://doi.org/10.1073/pnas.1908147116

Parasites can manipulate their host’s behaviour to ensure their own transmission. These manipulated behaviours may be outside the range of ordinary host activities [1], or alter the crucial timing and/or location of a host’s regular activity. Vantaux et al show that the latter is true for the human malaria parasite, Plasmodium falciparum [2]. They demonstrate that three species of Anopheles mosquito were 24% more likely to choose human hosts, rather than other vertebrates, for their blood feed when they harboured transmissible stages (sporozoites) compared to when they were uninfected, or infected with non-transmissible malaria parasites [2]. Host choice is crucial for the malaria parasite Plasmodium falciparum to complete its life-cycle, as their host range is much narrower than the mosquito’s for feeding; P. falciparum can only develop in hominids, or closely related apes [3].
The study only shows this stage-dependent parasite manipulation retrospectively (by identifying host type and parasite stage in mosquitoes after their blood feed [2]). There was no difference in the preferences of infectious (with sporozoites) or un-infectious (infected without sporozoites, or uninfected) mosquitoes between human versus cow hosts in a choice test [2]. This suggests that the final decision about whether to feed occurs when the mosquito is in close range of the host.
This, coupled with previous findings, shows that vector manipulation is a fine-tuned business, that can act at multiple stages of the parasite life-cycle and on many behaviours [4]. Indeed, mosquitoes with non-transmissible Plasmodium stages (oocysts) are more reluctant to feed than sporozoite-infected mosquitoes [5] as vectors can be killed by their host whilst feeding, doing so before they are ready to transmit is risky for the malaria parasite. Thus, it seems that Plasmodium is, to some extent, master of its vector; commanding it not to feed when it cannot be transmitted, to feed when it is ready to be transmitted and to feed on the right type of host. What does this mean for our understanding of malaria transmission and epidemics?
Vantaux et al use a mathematical model, parameterised using data from this experiment, to highlight the consequences of this 24% increase in feeding on humans for P. falciparum transmission. They show that this increase raises the number of infectious bites humans receive from 4 (if sporozoite-infected mosquitoes had the same probability as uninfected mosquitoes) to 14 (an increase in 250%), for mosquitoes with a 15-day life-span, at ratios of 1:1 mosquitoes to humans. Longer mosquito life-spans and higher ratios of mosquitoes to humans further increases the number of infectious bites.
These results [2] have important implications for epidemiological forecasting and disease management. Public health strategies could focus on possible ways to trap sporozoite-infected mosquitoes, mimicking cues they use to locate their human hosts, or identify the behaviour of mosquitoes harbouring non-yet infectious Plasmodium, and trap them before they bite. Moreover, the results of the model show that failing to take into account the preference for humans of sporozoite-infected mosquitoes could underestimate the size of pending epidemics.
An important question previously raised is whether Plasmodium-induced alteration in host behaviour really is manipulation, or just a side-effect of being infected [4,5]. The fact that Vantaux et al show that these altered feeding behaviours increases the likelihood of transmission, in that a sporozoite-infected mosquito is more likely to feed on a human, strongly suggests that it is adaptive for the parasite [2]. Ultimately, to show that it is manipulation would require the identification of molecular factors released by Plasmodium that are responsible for physiological changes in the mosquito [6].

References

[1] Thomas, F., Schmidt-Rhaesa, A., Martin, G., Manu, C., Durand, P., & Renaud, F. (2002). Do hairworms (Nematomorpha) manipulate the water seeking behaviour of their terrestrial hosts? Journal of Evolutionary Biology, 15(3), 356–361. doi: 10.1046/j.1420-9101.2002.00410.x
[2] Vantaux, A., Yao, F., Hien, D. F., Guissou, E., Yameogo, B. K., Gouagna, L.-C., … Lefevre, T. (2018). Field evidence for manipulation of mosquito host selection by the human malaria parasite, Plasmodium falciparum. BioRxiv, 207183 ver 6. doi: 10.1101/207183
[3] Prugnolle, F., Durand, P., Ollomo, B., Duval, L., Ariey, F., Arnathau, C., … Renaud, F. (2011). A Fresh Look at the Origin of Plasmodium falciparum, the Most Malignant Malaria Agent. PLOS Pathogens, 7(2), e1001283. doi: 10.1371/journal.ppat.1001283
[4] Cator, L. J., Lynch, P. A., Read, A. F., & Thomas, M. B. (2012). Do malaria parasites manipulate mosquitoes? Trends in Parasitology, 28(11), 466–470. doi: 10.1016/j.pt.2012.08.004
[5] Cator, L. J., George, J., Blanford, S., Murdock, C. C., Baker, T. C., Read, A. F., & Thomas, M. B. (2013). “Manipulation” without the parasite: altered feeding behaviour of mosquitoes is not dependent on infection with malaria parasites. Proceedings. Biological Sciences, 280(1763), 20130711. doi: 10.1098/rspb.2013.0711
[6] Herbison, R., Lagrue, C., & Poulin, R. (2018). The missing link in parasite manipulation of host behaviour. Parasites & Vectors, 11. doi: 10.1186/s13071-018-2805-9

As plants cannot run from their enemies, natural selection has favoured the evolution of diverse chemical compounds (phytochemicals) to protect them against herbivores and pathogens. This provides an opportunity for plant feeders to exploit these compounds to combat their own enemies. Indeed, it is widely known that herbivores use such compounds as protection against predators [1]. Recently, this reasoning has been extended to pathogens, and elegant studies have shown that some herbivores feed on phytochemical-containing plants reducing both parasite abundance within hosts [2] and their virulence [3].
Suffering less from parasites is clearly beneficial for infected herbivores. Why then, is this behaviour not fixed in nature? There are, at least, two possible explanations. First, feeding on ‘medicinal’, often toxic, plants may impose costs upon uninfected individuals. Second, parasites may evolve resistance to such chemicals. Whereas the first possibility has been explored, and is taken as evidence for ‘self-medication’ [3], the second hypothesis requires investigation. A recent study by Palmer-Young et al. [4] fills this gap. This article reports evolution of resistance to two different phytochemicals, alone and in combination, in the trypanosome Crithidia bombi, a bumble bee (Bombus impatiens) parasite. To show this, the authors experimentally evolved a strain of C. bombi in the presence of thymol, eugenol or both simultaneously. These phytochemicals are commonly found in the nectar of several plant species, in particular those of the Lamiaceae, a family containing several aromatic herbs. Prior to selection both phytochemicals reduced C. bombi growth by about 50%. However, C. bombi rapidly evolved resistance in both single and the double phytochemical treatments. Moreover, no cost of resistance was detected when evolved parasites were placed in the ancestral, phytochemical-free environment. Therefore, resistance to phytochemicals would be expected to spread rapidly in natural populations of C. bombi. Clearly, thus, the herbivore strategy of sequestering plant secondary chemical compounds as a defence against their pathogens should fail. The question then is ‘why do they still do it’? Can self-medication work in the longer-term for bumblebees?
Well, yes. The very fact that resistance evolved shows that resistance is not fixed in natural C. bombi populations. This is surprising considering that resistance is not costly. This might be due to a number of reasons. Firstly, there may be costs of resistance that were not detected in this experiment. Second, it may not be possible to evolve universal resistance to the heterogeneity present in the phytochemical environment. Indeed, phytochemical environments are highly varied in time and space and bumblebees will visit different plants presenting different phytochemical cocktails throughout the season. Furthermore, migration of bees from populations exposed to different phytochemicals may prevent the fixation of one resistance type.
Or, it may be self-medication behaviour itself that prevents the evolution of resistance? Indeed, in the same way that infected bees seek cooler temperatures to slow growth of a parasitoid fly [5], they may also seek a more varied diet with diverse phytochemicals to which the parasite cannot evolve, but which reduces parasite growth. Further understanding of arthropod self-medication may thus be instrumental to prevent the observed worldwide decline of pollinators [6]. Furthermore, it may inform on mechanisms that prevent rapid evolution of drug resistance in other systems.

References

[1] Duffey SS. 1980. Sequestration of plant natural products by insects. Annual Review of Entomology 25: 447-477. doi: 10.1146/annurev.en.25.010180.002311

[2] Richardson LL et al. 2015. Secondary metabolites in floral nectar reduce parasite infections in bumblebees. Proceedings of the Royal Society of London B 282: 20142471. doi: 10.1098/rspb.2014.2471

[3] Lefèvre T et al. 2010. Evidence for trans-generational medication in nature. Ecology Letters 13: 1485-93. doi: 10.1111/j.1461-0248.2010.01537.x

[4] Palmer-Young EC, Sadd BM, Adler LS. 2017. Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite. Journal of Evolutionary Biology 30: 300-312. doi: 10.1111/jeb.13002

[5] Müller CB, Schmid-Hempel P. 1993. Exploitation of cold temperature as defence against parasitoids in bumblebees. Nature 363: 65-67. doi: 10.1038/363065a0

[6] Potts SG et al. 2010. Global pollinator declines: trends, impacts and drivers. Trends in Ecology and Evolution 25: 345-353. doi: 10.1016/j.tree.2010.01.007