RE-EMERGING INFECTIOUS DISEASES: THE CHALLENGE AND OPPORTUNITY OF PERTUSSIS
Abstract: Complex systems paradigms, such as critical slowing down, regime shifts, systems theory, and computational forecasting, have taken center stage in the global effort to predict and mitigate emerging and re-emerging infectious diseases. Such approaches are predicated on models integrating information collected typically at microscopic scales and extrapolating macro-scale phenomena, such as bifurcation, percolation, and persistence. Complex systems perspectives and methodologies are essential as we come to grips with the ecology, immunology, and evolution of complicated infectious disease systems. Pertussis offers a prime example of this in the context of a scientific problem of great timeliness and importance.
The current re-emergence of pertussis, once seemingly on track to eradication, is enigmatic, due largely to its complexity as a host/pathogen system. In particular, the dynamics of pertussis are shaped by the interplay of pathogen transmission, host immunity, host contact-network structure, pathogen evolution, and public-health intervention across a wide range of spatio-temporal scales and levels of biological organization. Globally, trends and cycles in pertussis prevalence are idiosyncratic, due to variations in human behavior, geographic transmission bottlenecks, and dynamic variation in the nature and extent of public health intervention. The resulting scientific contention can only be resolved by theory capable of reconciling disparate, and seemingly contradictory, observations. Key elements of such a theory necessarily include: heterogeneities in immunity, age- and spatially-structured contact networks, dynamism in contact-network structure at behavioral time-scales, and large exogenous perturbations due to vaccination campaigns and behavior changes. Simplified versions of such theoretical systems display (1) prolonged transient dynamics which can contain signatures of the mode and efficacy of immunological protection, (2) sensitivity to contact-network structure, (3) prominent interactions between nonlinear and stochastic effects, and (4) manifold potential for counterintuitive emergent effects resulting from the above. The intellectual aim of the workshop will be to develop a complex-systems theory of pertussis within an inferential framework suitable for confronting models directly with extant data drawn from epidemiology, behavior, and immunology. This theory, and the techniques used to test it, will be readily generalizable to other disease systems because our efforts to resolve the causes and consequences of pertussis’ resurgence will necessarily be focused on the essential theoretical questions at issue in complex eco-epidemiological systems generally.
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?
The Odum School of Ecology at the University of Georgia is initiating a new track for doctoral training in Interdisciplinary Disease Ecology Across Scales. A postdoctoral associate is being sought to assist with curriculum development, student evaluation, and assessment.
Applicants must have a Ph.D. in either (1) ecology, evolution, or other field related to infectious disease biology (e.g., immunology, microbiology) or (2) education (with a strong emphasis and background in biology). Applicants are expected to have experience or a genuine interest in instruction, education research, or evaluation and assessment at the post-secondary level.
For more details about the position and how to apply please visit:
In April Nina Wale, an empiricist at Penn State University, collaborated with Aaron King, a theoretical evolutionary ecologist at the University of Michigan.
Experiments conducted by Wale have revealed that varying the availability of a micronutrient in the blood alters the infection dynamics in the mouse malaria model Plasmodium chabaudi. Importantly, her nutrient manipulations altered the dynamics during a period of the infection that has proven difficult to model and is associated with an augmentation of the host immune response. With these data in hand, Wale and King hoped to shed light on the determinants of parasite population dynamics and on how parasites interact with the host immune response. The research exchange gave Wale and King an opportunity to work intensely to build a model that could describe the data. Wale, an empiricist, learned how the models they made worked ‘under the hood’ and developed her programming skills. A number of hypotheses about the underlying causes of malaria infection dynamics have emerged from their modeling work and they are designing experiments to test them. They hope to continue using theory and data in combination to broaden our understanding of how parasite traits and the host immune response interact to create the characteristic dynamics of malaria infections.
The Inaugural meeting of The International Society for Evolution, Medicine, & Public Health will be held March 19-21, 2015 at Arizona State University in Tempe, Arizona (adjacent to Phoenix).
March 18, 2015 Pre-meeting for directors of evolutionary medicine programs
Thank you for applying to participate in our NSF-funded workshop on selection, to be held in conjunction with the 2015 Woods Hole Immunoparasitology (WHIP) Conference, 19-22 April in Woods Hole, Massachusetts, USA. We have received outstanding applications and have made our selection for this year’s workshop.
The 2015 workshop will be addressing the principle question: What are the functional forms for immunological killing of parasites, and in how much detail must we measure immunity to understand immune selection? We will explicitly compare immune selection pressures and immunity-transmission relationships across an array of protozoan and helminth taxa. We will benefit from being embedded in the great, long-standing WHIP meeting that combines top-notch science with many opportunities for informal discussions, and of course many sea views!
To understand the evolutionary biology of infectious diseases, we need to study both within-host (e.g., immunological) and between-host (e.g., transmission-related) processes. Why? We must study both scales because we know that parasites must succeed on both scales if they are going to spread and persist in host populations.
The logic is as follows. A parasite that outwits its host and escapes clearance by the immune system can only be successful evolutionarily — i.e., can only gain genetic representation in the next generation of parasites — if it is also transmitted from one host to the next. In other words, immune escape that leads to a transmission dead-end will get a parasite nowhere! And conversely, a parasite that excels at transmission (traveling from one host to the next, whether via a sneeze or an insect vector) yet fails to survive immune attack in the next host will also be an evolutionary dud.
So we as scientists must understand parasites across the whole life cycle if we are to understand and predict the evolution of parasites over time and in response to medical interventions.
There is growing recognition that the development of new, evolutionarily robust treatments and interventions against infectious disease requires a better understanding of the dynamics of parasites and pathogens inside their hosts. While progress in microbiology and immunology has continued to unravel complex molecular interactions between microbes and their hosts, population biologists have begun deploying new tools to understand the ecological causes and evolutionary consequences of the observed within-host dynamics. In particular, this work has formalised the dynamics of infection to enable quantification of the relative roles of target cell limitation and immune responses in controlling infection within a host. Such a framework, in turn, generates testable predictions about which parasite or pathogen genotypes will have a competitive advantage within hosts and thus will be transmitted across the host population. Theoreticians took the step from within-host dynamics to between-host transmission many years ago, but their models are only now beginning to be tested and improved, thanks to new developments in both experimental and statistical techniques.
To build upon and promote these developments, several RCN members (led by Olivier Restif and Andrea Graham) contributed to the current issue of Philosophical Transactions of the Royal Society, Within-host dynamics of infection: from ecological insights to evolutionary predictions.