Parasites destabilize host populations by shifting stage-structured interactions.

Should parasites stabilize or destabilize consumer-resource dynamics? Recent theory suggests that parasite-enhanced mortality may confer underappreciated stability to their hosts. We tested this hypothesis using disease in zooplankton. Across both natural and experimental epidemics, bigger epidemics correlated with larger--not smaller--host fluctuations. Thus, we tested two mechanistic hypotheses to explain destabilization or apparent destabilization by parasites. First, enrichment could, in principle, simultaneously enhance both instability and disease prevalence. In natural epidemics, destabilization was correlated with enrichment (indexed by total phosphorous). However, an in situ (lake enclosure) experiment did not support these links. Instead, field and experimental results point to a novel destabilizing mechanism involving host stage structure. Epidemics pushed hosts from relatively more stable host dynamics with less-synchronized juveniles and adults to less stable dynamics with more-synchronized juveniles and adults. Our results demonstrate how links between host stage structure and disease can shape host/consumer-resource stability.

In North America, some ovarian cancers express the oncogenes of preventable human papillomavirus HPV-18.

Some researchers in other regions have recommended human papillomavirus (HPV) vaccination to reduce risk of ovarian cancer, but not in North America, where evidence has previously suggested no role for HPV in ovarian cancer. Here we use a large sample of ovarian cancer transcriptomes (RNA-Seq) from The Cancer Genome Atlas (TCGA) database to address whether HPV is involved with ovarian cancer in North America. We estimate that a known high-risk type of HPV (type 18) is present and active in 1.5% of cases of ovarian epithelial cancers in the US and Canada. Our detection methods were verified by negative and positive controls, and our sequence matches indicated high validity, leading to strong confidence in our conclusions. Our results indicate that previous reports of zero prevalence of HPV in North American cases of ovarian cancer should not be considered conclusive. This is important because currently used vaccines protect against the HPV-18 that is active in ovarian tumors and, therefore, may reduce risk in North America of cancers of the ovaries as well as of the cervix and several other organ sites.

The ecology of human papillomavirus-induced epithelial lesions and the role of somatic evolution in their progression.

BACKGROUND: Human papillomavirus (HPV) infection frequently induces hyperproliferation of epithelial cells, leading to both benign (warts) and malignant tumors (cervical cancer). We seek to understand how HPV may achieve these changes by modulating cellular population dynamics. Furthermore, HPV-induced lesion progression is generally understood as a series of molecular changes. As a complement to this approach, we investigate the role of phenotypic changes produced by natural selection during lesion progression. METHODS: We develop and numerically analyze spatially and evolutionarily explicit mathematical models of HPV-induced epithelial lesions. RESULTS: Infection of basal cells is a requirement for persistent infection. Increasing the maximum tissue density at which HPV-infected cells can divide and decreasing infected cell migration rate leads to large increases in the number of HPV-infected cells, and consequently, virions shed from the skin surface per day. Evolution by natural selection in an autonomous population of cells leads to tissue changes that are qualitatively similar to those observed during lesion progression. CONCLUSIONS: HPV modulates cell population dynamics, which can be characterized by specific ecological parameters. As an unintended consequence, this ecological strategy of the virus may be successfully co-opted by autonomous host cells and play a role in lesion progression.

Tumor evolution in space: the effects of competition colonization tradeoffs on tumor invasion dynamics.

We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations.

Cancer treatment as a game: integrating evolutionary game theory into the optimal control of chemotherapy.

Chemotherapy for metastatic cancer commonly fails due to evolution of drug resistance in tumor cells. Here, we view cancer treatment as a game in which the oncologists choose a therapy and tumors 'choose' an adaptive strategy. We propose the oncologist can gain an upper hand in the game by choosing treatment strategies that anticipate the adaptations of the tumor. In particular, we examine the potential benefit of exploiting evolutionary tradeoffs in tumor adaptations to therapy. We analyze a math model where cancer cells face tradeoffs in allocation of resistance to two drugs. The tumor 'chooses' its strategy by natural selection and the oncologist chooses her strategy by solving a control problem. We find that when tumor cells perform best by investing resources to maximize response to one drug the optimal therapy is a time-invariant delivery of both drugs simultaneously. However, if cancer cells perform better using a generalist strategy allowing resistance to both drugs simultaneously, then the optimal protocol is a time varying solution in which the two drug concentrations negatively covary. However, drug interactions can significantly alter these results. We conclude that knowledge of both evolutionary tradeoffs and drug interactions is crucial in planning optimal chemotherapy schedules for individual patients.

Coexistence and community structure in a consumer resource model with implicit stoichiometry.

We combine stoichiometry theory and optimal foraging theory into the MacArthur consumer-resource model. This generates predictions for diet choice, coexistence, and community structure of heterotroph communities. Tradeoffs in consumer resource-garnering traits influence community outcomes. With scarce resources, consumers forage opportunistically for complementary resources and may coexist via tradeoffs in resource encounter rates. In contrast to single currency models, stoichiometry permits multiple equilibria. These alternative stable states occur when tradeoffs in resource encounter rates are stronger than tradeoffs in elemental conversion efficiencies. With abundant resources consumers exhibit partially selective diets for essential resources and may coexist via tradeoffs in elemental conversion efficiencies. These results differ from single currency models, where adaptive diet selection is either opportunistic or selective. Interestingly, communities composed of efficient consumers share many of the same properties as communities based on substitutable resources. However, communities composed of relatively inefficient consumers behave similarly to plant communities as characterized by Tilman's consumer resource theory. The results of our model indicate that the effects of stoichiometry theory on community ecology are dependent upon both consumer foraging behavior and the nature of resource garnering tradeoffs.

Evolutionary ecology of human papillomavirus: trade-offs, coexistence, and origins of high-risk and low-risk types.

BACKGROUND: We address the ecological and evolutionary dynamics of human papillomavirus (HPV) that lead to the dichotomy between high-risk (HR) and low-risk (LR) types. We hypothesize that HPV faces an evolutionary tradeoff between persistence and per-contact transmission probability. High virion production enhances transmissibility but also provokes an immune response leading to clearance and limited persistence. Alternatively, low virion production increases persistence at the cost of diminished transmission probability per sexual contact. We propose that LR HPV types use the former strategy and that HR types use the latter. Sexual behaviors in a host population determine the success of each strategy. METHODS: We develop an evolutionary model of HPV epidemiology, which includes host sexual behavior, and we find evolutionarily stable strategies of HPV. RESULTS: A slow turnover of sexual partners favors HR HPV, whereas high frequency of partner turnover selects for LR. When both sexual behaviors exist as subcultures in a population, disruptive selection can result in the coevolution and ecological coexistence of both HR and LR HPV types. CONCLUSIONS: Our results indicate that the elimination of HR HPV through vaccines may alter the evolutionary trajectory of the remaining types and promote evolution of new HR HPV types.