In June, I had the opportunity to spend two weeks in Princeton working with Andrea Graham and two postdocs, Sarah Budischak and Anieke van Leeuwen. The purpose of this visit was two-fold: (1) develop a mathematical model of within-host dynamics incorporating host immune responses, non-immune physiological processes (e.g., growth, storage), and parasite exploitation and growth; (2) use this model as a basis for identifying key experimental measurements to quantify the effect of diet on host and parasite fitness. This exchange stemmed from a theory paper I published last year showing that increased host resources could either increase or decrease parasite fitness, depending on the structure of the resource-immune-parasite interaction. Dr. Graham and Dr. Budischak initially contacted me to ask about extending the model to consider the role of host diet in driving within-host dynamics of macroparasites, focusing on understanding when host response should focus on tolerance over resistance. Out of this conversation, I developed an RCN proposal more broadly considering how diet links within-host and between-host scales to shape both host immune phenotype and parasite exploitation.
The research exchange was structured around daily meetings between the four of us. I would typically spend the day working in Dr. Graham’s lab alongside Dr. Budischak, who is primarily trained as an immunologist. This work environment allowed me to get instantaneous feedback as I was developing the model. During the first week of the exchange, the daily meetings were primarily spent defining, discussing, defending, and refining a biologically reasonable model structure. This was one of the most useful aspects of the process for me, as my knowledge of immunology is limited. As the model development proceeded, Dr. Budischak searched the biomedical literature for estimates of model parameters. This process helped identify key parameters that need to be quantified from subsequent Graham lab experiments. During the second week of the exchange, the focus shifted to model analysis (both analytical and numerical). This analysis helped further hone the search for parameter values and showed that the model is capable of producing both host tolerance and host resistance.
I am hopeful (and reasonably confident) that this research exchange has resulted in a profitable long-term collaboration. Already we have used results from this exchange in two grant proposals. The current plan is to use the data from mouse-helminth experiments to develop an empirically validated model of within-host dynamics and then use this model to study the ecological and evolutionary dynamics of both the host and parasite, focusing on questions like: (1) can diet shift parasites from being resource-limited to immune-limited, and does each type of limitation have a dynamical signature at the between-host scale? and (2) when do cross-scale interactions give rise to self-reinforcing feedbacks, such as the “negative spiral” of malnutrition and infection?