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.

The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in humans. CCHFV has a broad tropism and can infect a variety of species and tissues. Here, by using gene silencing, blocking antibodies or soluble receptor fragments, we identify the low-density lipoprotein receptor (LDL-R) as a CCHFV entry factor. The LDL-R facilitates binding of CCHFV particles but does not allow entry of Hazara virus (HAZV), another member of the genus. In addition, we show that apolipoprotein E (apoE), an exchangeable protein that mediates LDL/LDL-R interaction, is incorporated on CCHFV particles, though not on HAZV particles, and enhances their specific infectivity by promoting an LDL-R dependent entry. Finally, we show that molecules that decrease LDL-R from the surface of target cells could inhibit CCHFV infection. Our study highlights that CCHFV takes advantage of a lipoprotein receptor and recruits its natural ligand to promote entry into cells.

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients’ brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.

The Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne bunyavirus that causes high mortality in humans. This enveloped virus harbors two surface glycoproteins (GP), Gn and Gc, that are released by processing of a glycoprotein precursor complex whose maturation takes place in the ER and is completed through the secretion pathway. Here, we characterized the trafficking network exploited by CCHFV GPs during viral assembly, envelopment, and/or egress. We identified membrane trafficking motifs in the cytoplasmic domains (CD) of CCHFV GPs and addressed how they impact these late stages of the viral life cycle using infection and biochemical assays, and confocal microscopy in virus-producing cells. We found that several of the identified CD motifs modulate GP transport through the retrograde trafficking network, impacting envelopment and secretion of infectious particles. Finally, we identified PACS-2 as a crucial host factor contributing to CCHFV GPs trafficking required for assembly and release of viral particles.

Numerous pathogens, including viruses, enter the central nervous system and cause neurological disorders, such as encephalitis. Viruses are the main etiologic agents of such neurological diseases, and some of them cause a high death toll worldwide. Our knowledge about neuroinvasive and encephalitogenic virus infections is still limited due to the relative inaccessibility of the brain. To mitigate this shortcoming, neural ex vivo models have been developed and turned out to be of paramount importance for understanding neuroinvasive and neurotropic viruses. In this review, we describe the major ex vivo models for the central nervous system, including neural cultures, brain organoids, and organotypic brain cultures. We highlight the key findings from these models and illustrate how these models inform on viral processes, including neurotropism, neuroinvasion, and neurovirulence. We discuss the limitations of ex vivo models, highlight ongoing progress, and outline next-generation ex vivo models for virus research at the interface of neuroscience and infectious diseases.

The Hendra and Nipah viruses (HeV and NiV) are zoonotic biosafety level-4 pathogens belonging to the Paramyxoviridae family. We previously showed that their W protein, a key player in the evasion of the host antiviral response, forms highly flexible, curved fibrils in vitro . Here, we show that the cysteine oxidation state acts as a molecular switch controlling the formation of either amorphous aggregates or flexible fibrils, and that residues 2 to 29 are essential for fibrillation. We also uncover that the HeV W protein (W ^HeV ) can also self-assemble in cellula . W ^HeV forms distinct types of nuclear condensates that exhibit different dependencies on the cysteine redox-state. While deletion of residues 2-29 prevents formation of nuclear filaments, cysteine-to-serine substitution mainly impairs the formation of non-filamentous condensates. Both infection and W ^HeV ectopic expression trigger oxidative stress presumably favorable to W ^HeV condensation. Finally, we show that impaired ability to form redox-sensitive, non-filamentous condensates is associated with a reduced W ability to inhibit the NF-κB pathway, while it conversely enhances W ability to repress the interferon response pathway.