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Review
. 2017 Aug;15(8):502-510.
doi: 10.1038/nrmicro.2017.45. Epub 2017 May 30.

Pathways to zoonotic spillover

Affiliations
Review

Pathways to zoonotic spillover

Raina K Plowright et al. Nat Rev Microbiol. 2017 Aug.

Abstract

Zoonotic spillover, which is the transmission of a pathogen from a vertebrate animal to a human, presents a global public health burden but is a poorly understood phenomenon. Zoonotic spillover requires several factors to align, including the ecological, epidemiological and behavioural determinants of pathogen exposure, and the within-human factors that affect susceptibility to infection. In this Opinion article, we propose a synthetic framework for animal-to-human transmission that integrates the relevant mechanisms. This framework reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Understanding how these barriers are functionally and quantitatively linked, and how they interact in space and time, will substantially improve our ability to predict or prevent spillover events. This work provides a foundation for transdisciplinary investigation of spillover and synthetic theory on zoonotic transmission.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Pathways to spillover.
The risk of spillover is determined by a series of processes that link the ecological dynamics of infection in reservoir hosts, the microbiological and vector determinants of survival and dissemination outside of reservoir hosts, the epidemiological and behavioural determinants of exposure, and the within-host biological factors that shape the susceptibility of recipient hosts. The distribution and intensity of infection in reservoir hosts, followed by pathogen release, movement, survival and possible development to infectious stage, determine the pathogen pressure, which is defined as the amount of pathogen available to the recipient host at a given point in space and time. Pathogen pressure then interacts with the behaviour of the recipient host (and vector for vector-borne pathogens) to determine the likelihood, dose and route of exposure. A series of within-host barriers then determine host susceptibility, and, therefore, the probability and severity of infection for a given pathogen dose. PowerPoint slide
Figure 2
Figure 2. Barriers to spillover and dose–response relationships.
a | Determinants of spillover are being studied by researchers in many disciplines. b | A pathogen must overcome a series of barriers to transmit from one species to another. If any of these barriers is impenetrable, spillover cannot occur. Spillover of some pathogens requires that gaps (depicted as holes) in all of the barriers align within a narrow window in space and time (indicated by the blue arrow, see Supplementary information S2 (movie)). For other pathogens, protracted survival in the environment (for example, Bacillus anthracis spores), or wide dissemination (for example, the spread of aerosolized Coxiella burnetii by wind), may stagger the alignment of barriers to spillover. c | Top panel: hypothetical dose available over time for a given pathogen. In scenario 1 (dashed light blue line), the pathogen is excreted consistently from infected reservoir hosts. In scenario 2 (solid light blue line), the pathogen is excreted in regular but short high-intensity pulses over time. In both scenarios, the mean dose over the time interval is the same. Bottom panel: the likelihood that this dose will translate into infection depends on the functional form of the dose–response relationship. If the dose–response relationship is linear (green line), these two excretion scenarios generate the same total probability of spillover over the time interval shown. However, for nonlinear dose–response relationships, the total probability of spillover differs between scenarios. If the relationship is sigmoidal (red line), there is some probability of spillover whenever the dose exceeds zero (indicated by the intensity of the red shading in the top panel), but the total spillover probability in scenario 2 is markedly higher. In the extreme case in which the recipient host can be infected only by a dose that exceeds a sharp threshold, as suspected for Bacillus anthracis,,, the pathogen in scenario 2 will spill over when the dose peaks above the threshold (blue solid line near peak), but the pathogen in scenario 1 will never spill over. PowerPoint slide
Figure 3
Figure 3. Bottlenecks to spillover.
Different barriers permit or constrain the flow of pathogens from one species to another. The figure is illustrative, owing to the lack of sufficient data for more than one or two barriers for any given system. The width of the gaps in barriers represents the ease with which a pathogen can flow through the barriers and will vary depending on context. The question marks represent points at which the barriers are especially poorly understood and highlight gaps in our knowledge of some pathogens that are of global concern (for example, the lack of information on disease dynamics in reservoir hosts of Ebola virus). Many rabies virus reservoirs, such as domestic dogs, are widely distributed. The prevalence of rabies virus is generally low and the incidence of spillover closely tracks the prevalence of infection in the reservoir host. Rabies virus is almost always fatal to spillover hosts. Interventions are usually aimed at reducing the prevalence in reservoir hosts through vaccination. Leptospira interrogans survives in water and soil after being shed in the urine of a wide range of rodents and other reservoir hosts. Key bottlenecks to the zoonotic spillover of this pathogen are exposure and within-host barriers. For example, during floods in Brazil, many humans that are exposed do not become infected, probably because the initial within-host barrier, the skin, is not penetrated. However, once L. interrogans penetrates the skin (for example, through skin wounds), 1–10 leptospires may be sufficient to cause systemic infection. Therefore, wearing protective clothing and boots is an effective control measure. Important bottlenecks to Escherichia coli O157 spillover include heterogeneous shedding from cattle, (although it is still unknown whether super-shedding is a characteristic of particular individuals or is a transient phase that occurs in most cattle). In some contexts, exposure is an important bottleneck; for example, when the pathogen is eliminated from food through cooking. Widespread dispersal leads to uncertainties about the source of many outbreaks,, and weak within-human barriers enable low doses of E. coli to cause infection,. Humans are frequently exposed to Toxoplasma gondii carried by domestic cats and intermediate hosts, but the parasite rarely causes disease because most humans have strong within-host immunological barriers. Cats are widely and densely distributed, but the prevalence of T. gondii is low and cats shed oocysts only once in their lifetime. However, sporulated oocysts survive in the environment for long periods of time. Limiting exposure to oocysts may prevent spillover; however, this is challenging when it is unclear whether cats or the environment are the major sources of infection in humans,. Ebola virus has not been isolated from bats and the definitive reservoir bat species is unknown; therefore, characteristics of infection in bats are unknown,. The pathogen is released through excretion or slaughter, then survives for up to a week, depending on the environmental conditions. The most tractable bottlenecks for intervention may be the zoonotic exposure of humans through interaction with bats, bushmeat or the carcasses of other species,,, because once exposed, the within-host barriers to Ebola virus may be extremely low. PowerPoint slide

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