Seasonality and the persistence and invasion of measles

The critical community size (CCS) for measles, which separates persistent from extinction-prone populations, is arguably the best understood stochastic threshold in ecology. Using simple models, we explore a relatively neglected relationship of how the CCS scales with birth rate. A predominantly positive relationship of persistence with birth rate is complicated by the accompanying dynamical transitions of the underlying deterministic process. We show that these transitions imply a lower CCS for high birth rate less developed countries and contrary to the experience in lower birth rate, industrial countries, the CCS may increase after vaccination. We also consider the evolutionary implications of the CCS for the origin of measles; this analysis explores how the deterministic and stochastic thresholds for invasion and persistence set limits on the mechanism by which this highly infectious pathogen could have successfully colonized its human host.     

Seasonality and comparative dynamics of six childhood infections in pre-vaccination Copenhagen

Seasonal variation in infection transmission is a key determinant of epidemic dynamics of acute infections. For measles, the best-understood strongly immunizing directly transmitted childhood infection, the perception is that term-time forcing is the main driver of seasonality in developed countries. The degree to which this holds true across other acute immunizing childhood infections is not clear. Here, we identify seasonal transmission patterns using a unique long-term dataset with weekly incidence of six infections including measles. Data on age–incidence allow us to quantify the mean age of infection. Results indicate correspondence between dips in transmission and school holidays for some infections, but there are puzzling discrepancies, despite close correspondence between average age of infection and age of schooling. Theoretical predictions of the relationship between amplitude of seasonality and basic reproductive rate of infections that should result from term-time forcing are also not upheld. We conclude that where yearly trajectories of susceptible numbers are perturbed, e.g. via waning of immunity, seasonality is unlikely to be entirely driven by term-time forcing. For the three bacterial infections, pertussis, scarlet fever and diphtheria, there is additionally a strong increase in transmission during the late summer before the end of school vacations.     

Does multiple infection select for raised virulence?

Classical models of virulence evolution conclude that the increased competition favoured by multiple infection will select for increasing consumption and deterioration of the host resource, or 'virulence'. However, recent empirical and theoretical studies suggest that this view of virulence has some shortcomings. Here, we argue that the evolutionary consequences of multiple infection depend critically on whether the exploitation rate of an individual parasite is governed directly by the behaviour of the individual, or whether it is limited by the collective behaviour of the coinfecting group. We illustrate that, depending on the mechanistic details of exploitation, multiple infection can select for reduced virulence.     

Host densities as determinants of abundance in parasite communities

Several epidemiological models predict a positive relationship between host population density and abundance of directly transmitted macroparasites. Here, we generalize these, and test the prediction by a comparative study. We used data on communities of gastrointestinal strongylid nematodes from 19 mammalian species, representing examination of 6670 individual hosts. We studied both the average abundance of all strongylid nematodes within a host species, and the two components of abundance, prevalence and intensity. The effects of host body weight, diet, fecundity and age at maturity and parasite body size were controlled for directly, and the phylogenetically independent contrast method was used to control for confounding factors more generally. Host population density and average parasite abundance were strongly positively correlated within mammalian taxa, and across all species when the effects of host body weight were controlled for. Controlling for other variables did not change this. Even when looking at single parasite species occurring in several host species, abundance was highest in the host species with the highest population density. Prevalence and intensity showed similar patterns. These patterns provide the first macroecological evidence consistent with the prediction that transmission rates depend on host population density in natural parasite communities.     

HIV-1/parasite co-infection and the emergence of new parasite strains

HIV-1 and parasitic infections co-circulate in many populations, and in a few well-studied examples HIV-1 co-infection is known to amplify parasite transmission. There are indications that HIV-1 interacts significantly with many other parasitic infections within individual hosts, but the population-level impacts of co-infection are not well-characterized. Here we consider how alteration of host immune status due to HIV-1 infection may influence the emergence of novel parasite strains. We review clinical and epidemiological evidence from five parasitic diseases (malaria, leishmaniasis, schistosomiasis, trypanosomiasis and strongyloidiasis) with emphasis on how HIV-1 co-infection alters individual susceptibility and infectiousness for the parasites. We then introduce a simple modelling framework that allows us to project how these individual-level properties might influence population-level dynamics. We find that HIV-1 can facilitate invasion by parasite strains in many circumstances and we identify threshold values of HIV-1 prevalence that allow otherwise unsustainable parasite strains to invade successfully. Definitive evidence to test these predicted effects is largely lacking, and we conclude by discussing challenges in interpreting available data and priorities for future studies.     

Dynamics of Influenza Virus Infection and Pathology

A key question in pandemic influenza is the relative roles of innate immunity and target cell depletion in limiting primary infection and modulating pathology. Here, we model these interactions using detailed data from equine influenza virus infection, combining viral and immune (type I interferon) kinetics with estimates of cell depletion. The resulting dynamics indicate a powerful role for innate immunity in controlling the rapid peak in virus shedding. As a corollary, cells are much less depleted than suggested by a model of human influenza based only on virus-shedding data. We then explore how differences in the influence of viral proteins on interferon kinetics can account for the observed spectrum of virus shedding, immune response, and influenza pathology. In particular, induction of high levels of interferon (“cytokine storms”), coupled with evasion of its effects, could lead to severe pathology, as hypothesized for some fatal cases of influenza.Influenza A virus causes an acute respiratory disease in humans and other mammals; in humans, it is particularly important because of the rapidity with which epidemics develop, its widespread morbidity, and the seriousness of complications. Every year, an estimated 500,000 deaths worldwide, primarily of young children and the elderly, are attributed to seasonal influenza virus infections (49). Influenza pandemics may occur when an influenza virus with new surface proteins emerges, against which the majority of the population has no preexisting immunity. Both the emergence of H5N1 virus (34) and the current H1N1 virus pandemic (43) underline the importance of understanding the dynamics of infection and disease. A key question is, what regulates virus abundance in an individual host, causing the characteristic rapid decline in virus shedding following its initial peak? The main contenders in primary influenza virus infection are depletion of susceptible target cells and the impact of the host''s innate immune response (2, 20).On infection, the influenza virus elicits an immune response, including a rapid innate response that is correlated with the observed decline in the virus load after the first 2 days of infection (1). The slower adaptive response, including both humoral and cell-mediated components, takes several days to consolidate but is important for complete virus clearance and establishment of protective immunity. During infection of an immunologically naïve host, the innate immune response is particularly important as the first line of defense against infection. The innate immune response is regulated by chemokines and cytokines, chemical messengers produced by virus-infected epithelial cells and leukocytes (23), and natural interferon-producing cells, such as plasmacytoid dendritic cells (13). Among the key cytokines induced by epithelial cells infected with influenza A virus are type I interferons (IFNs) (IFN-α/β) (23), which directly contribute to the antiviral effect on infected and neighboring cells (38).Like other viruses, influenza A viruses have evolved strategies to limit the induction of innate immune responses (38). The NS1 protein plays a dominant role, and without it, the virus is unable to grow well or to cause pathology in an immunocompetent host (14). NS1 is multifunctional and counteracts both the induction of IFN expression and the function of IFN-activated antiviral effectors via multiple mechanisms (12, 17). Individual strains of influenza A virus possess these activities to various degrees (15, 21, 22, 26), and accordingly, NS1 has been implicated as a virulence factor (3, 17). A striking effect of the failure to control the innate response to virus infection is seen as a “cytokine storm,” which causes severe pathology (8).While there is an extensive literature on modeling influenza virus spread at the population level, the individual-host scale has received much less attention (2, 4, 5, 18, 19, 20, 27, 28). In a recent important paper, Baccam et al. modeled the kinetics of influenza A virus (2). The innate dynamics were included in the form of an IFN response that delayed and reduced virus production but did not prevent it; thus, the infection was resolved primarily through near-total depletion of epithelial cells. Their model was fitted to virus titers from human volunteers exposed to H1N1 influenza virus, but no data were available on the innate immune response or epithelial cell pathology. This has been a general difficulty in developing and validating more refined within-host models; there is a lack of detailed biological data from natural host systems, in particular, measures of immune kinetics and patterns of cellular depletion.The model presented here explicitly includes the ability of IFN to induce a fully antiviral state in order to explore the relative regulatory role of innate immunity and target cell depletion. Data from experimental infections of immunologically naïve horses with an equine influenza virus (36) allowed us to calibrate our model, not only to viral kinetics, but also to IFN dynamics and cell depletion in the context of infection of a naïve natural mammalian host. With our fitted model, we then investigate modulation of the immune response.