Host-Pathogen Interactions Influencing Zoonotic Spillover Potential and Transmission in Humans

Abstract

Emerging infectious diseases of zoonotic origin are an ever-increasing public health risk and economic burden. The factors that determine if and when an animal virus is able to spill over into the human population with sufficient success to achieve ongoing transmission in humans are complex and dynamic. We are currently unable to fully predict which pathogens may appear in humans, where and with what impact. In this review, we highlight current knowledge of the key host-pathogen interactions known to influence zoonotic spillover potential and transmission in humans, with a particular focus on two important human viruses of zoonotic origin, the Nipah virus and the Ebola virus. Namely, key factors determining spillover potential include cellular and tissue tropism, as well as the virulence and pathogenic characteristics of the pathogen and the capacity of the pathogen to adapt and evolve within a novel host environment. We also detail our emerging understanding of the importance of steric hindrance of host cell factors by viral proteins using a "flytrap"-type mechanism of protein amyloidogenesis that could be crucial in developing future antiviral therapies against emerging pathogens. Finally, we discuss strategies to prepare for and to reduce the frequency of zoonotic spillover occurrences in order to minimize the risk of new outbreaks.

Keywords: Ebola virus; Mobillivirus; Nipah virus; innate immune antagonism factors; interhuman transmission; species barriers; viral amyloidogenesis; viral spillover; zoonosis.

Figure 1

The three species barriers to zoonotic transmission and the factors that influence the ability of emerging or re-emerging zoonotic pathogens to cause epidemics/pandemics in humans. For a pathogen to be able to establish sustainable transmission chains in humans, all three barriers must be effectively surpassed. Boxes shown in red concern the pathogen and host factors and their interactions that are crucial in determining the relative success of a species jump for an animal virus to humans and which are developed further in this review. Further details are given in the text. Adapted with permission from [19]. Copyright 2022, Revue CONFLUENCE Sciences & Humanités.

Figure 2

Involvement of viral non-structural protein amyloidogenesis in immune response blockage and spillover potential. (A) As an example of fibrillation-prone viral proteins interfering with host cell functions, Henipavirus V and W are proposed to form fibrillar filaments with properties of amyloids, either in the cytosol (for V) or the nucleus (for W) of non-bat cells, as a virulence strategy to prevent and counteract the innate immune response by acting like a “flytrap”, sequestering key cell effectors. The filaments could also be useful for the virus to recruit cellular pro-viral factors and target them to intracellular viral factories for example. (B) These filaments may further evolve into large solid-like condensates resulting in steric hindrance in the host cell, thereby trapping innate immune interactors without the need for very specific and strong interactions. In this scenario, steric hindrance would hamper the downstream actions of the innate effectors. (C) Differential ability of amyloid fibrillation by V and W between the bat reservoir and humans could be at the origin of the absence or development of pathogenesis and may be a determinant of the spillover potential of the viruses. Further details and references are provided in the text.

Figure 3

The major biological factors affecting the zoonotic potential of an animal virus to infect, replicate and spread efficiently in humans. Key factors are shown in bold. Common receptor usage and the ability of an emerging virus to inhibit innate immune responses in humans are major factors linked to spillover potential from an animal reservoir. A pathogen’s replication dynamics and genetic fluidity will affect its ability to adapt to a new host environment and immune responses. For ongoing human-to-human transmission following spillover, tissue tropism and disease severity/symptomology are important, as well as the ability of the virus to survive in the external environmental conditions required for transmission. On a population level, pre-existing immunity to infection will impact the ability of an emerging virus to spread and to adapt its fitness to humans as a novel host species. Any factors negatively affecting the host immune system will favor viral replication, adaptation and transmission. On a population level, this includes factors impacting general health states such as obesity, malnutrition, pollution and age demographics. Further details are given in the text.