Lloviu: a possible new pandemic threat


Researchers from the Medway School of Pharmacy (a partnership between the universities of Kent and Greenwich) have helped isolate the Lloviu virus (LLOV) – a close relative of Ebola virus – for the first time, highlighting the need for future research to ensure pandemic preparedness.

LLOV is part of the filovirus family – which includes the Ebola virus. While Ebola (and other filoviruses including the similarly pathogenic Marburg virus) have only occurred naturally in Africa, Lloviu has been discovered in Europe.

The filovirus LLOV, was identified via its genetic material (RNA) in 2002 in Schreiber’s bats in Spain and was subsequently detected in bats in Hungary.

As a zoonotic virus – one which passes between animals and humans – LLOV is of interest to public health around the world due to our close relationship with animals in agriculture, as companions and in the natural environment. This is even more the case in recent years with the continued destruction and encroachment of natural habitats of many wild creatures.

The World Health Organization states that “Zoonoses comprise a large percentage of all newly identified infectious diseases, as well as many existing ones.”

Dr. Simon Scott and Dr. Nigel Temperton from the Viral Pseudotye Unit (VPU) at Medway School of Pharmacy were part of a team led by Dr. Gábor Kemenesi from Pécs University/National Laboratory of Virology in Hungary. The VPU, including former Ph.D. student Dr. Martin Mayora-Neto, were involved in conducting all the antibody detection experiments using bat sera as part of the study, even before the virus itself was isolated. This isolation occurred in the Hungarian lab from the very last bat which tested LLOV positive.

Significantly the team have now discovered that Lloviu has the potential to both infect human cells and also to replicate. This raises concerns about potential widespread transmission in Europe and urges immediate pathogenicity and antiviral studies.

The VPU work also revealed no antibody cross-reactivity between LLOV and Ebola, suggesting that existing Ebola vaccines may not protect against Lloviu, should it be transmitted to man.

Dr. Scott says that their “research is a smoking gun. It’s vital that we know both more about the distribution of this virus and that research is done in this area to assess the risks and to ensure we are prepared for potential epidemics and pandemics.”

From this research, it is clear that there is a considerable knowledge gap regarding the pathogenicity, animal hosts, and transmissibility of these newly discovered viruses. Funding from the British Academy has enabled Dr. Scott to create a consortium of European bat virologists, harnessing expertise in the field, from ecology to virology.

The group are aiming to carry out essential further research across Europe into the risks of the Lloviu virus to humans, in addition to other families of viruses including coronavirus and lyssavirus (rabies) which have bats as hosts.

The research paper, “Isolation of infectious Lloviu virus from Schreiber’s bats in Hungary,” is published by Nature Communications.

Zoonotic viruses are a major public health threat. A single spillover event from an animal host into the human population can initiate deadly epidemics or even pandemics. Bats play an important role as natural reservoirs of RNA viruses with the potential to cause significant harm to humans.

Examples of bat-borne viruses that have been transmitted to humans, either directly or via intermediate hosts, causing multiple epidemics include Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Hendra virus, Nipah virus, and Marburg virus (MARV).

For other viruses, such as Middle East Respiratory Syndrome coronavirus (MERS-CoV), pandemic SARS-CoV-2, and Ebola virus (EBOV), there is strong evidence that bats might be the natural reservoir, although these viruses have not yet been isolated from bats [1]. While some of these represent reemerging viruses that were already known to cause severe disease in humans, this list also includes a number of bat-borne viruses that were either unknown or understudied prior to spillover into the human population.

To better prepare for potential future zoonotic epidemics and pandemics, it is necessary to study newly discovered viruses that are closely related to highly pathogenic viruses to both determine their pathogenic potential and to develop and assess potential antiviral therapies.

Since 2000, multiple new filoviruses have been discovered via next generation sequencing of samples from wild bats across the globe, including Lloviu virus (LLOV), Bombali virus, and Mengla virus [2–4], but the ability to study these viruses has been limited because none of these new viruses have been cultured to date.

One particular virus of concern is LLOV, a filovirus whose viral RNA was initially isolated from carcasses of Schreiber’s bats (Miniopterus schreibersii) in Spain and France using deep sequencing and PCR techniques and later found in the same species of bats in Hungary, although no infectious virus has been cultured to date [2,5,6]. Recently, LLOV re-emerged in bat populations in Northeast Hungary, and again its emergence correlated with unexplained increased mortality among Schreiber’s bats [5].

Interestingly, many of the bats in which LLOV RNA was found showed symptoms of respiratory infection, but it remains to be determined if LLOV is the causative agent of the disease [2,5]. One worrying factor regarding the spillover potential for LLOV is the geographic range of the host species, Miniopterus schreibersii, which can be found across most of southern Europe, parts of northern Africa, and much of the Middle East, in which over 100 million people live.

At the sequence level, LLOV is distinct enough from the ebola- and marburgviruses to be classified within its own genus Cuevavirus [7]. Although the pathogenic potential of LLOV remains unknown, similarities to EBOV and MARV raise concerns that it could be pathogenic for humans. However, the pathogenicity of filoviruses varies considerably, highlighting the need to study LLOV in more detail.

Like many of the genomic sequences of these other uncultured RNA viruses, the LLOV genome is incomplete [2]. The lack of the terminal genomic sequences that orchestrate viral transcription and replication makes development of a fully wild-type reverse genetic system to rescue the virus impossible.

Here we describe the complementation of the LLOV sequence with terminal genomic sequences from other filoviruses in mono- and bicistronic minigenome systems to determine the ability of these sequences to facilitate different aspects of the LLOV replication cycle. Leveraging the data from these complementation assays, we were able to develop a reverse genetic system that facilitated the rescue of infectious recombinant Lloviu virus complemented with sequences from EBOV or MARV (rLLOVcomp).

We analyzed rLLOVcomp in various assays, ranging from ultrastructural analysis of infected cells to infection studies with primary human cells, antiviral testing, and host response analysis. Our data suggest that LLOV has the potential to infect humans but does not induce an inflammatory response in human macrophages, a hallmark of severe Ebola virus disease [8]. The success of this approach provides a roadmap for the rescue and characterization of other uncultured RNA viruses of pathogenic concern for which we currently only have incomplete genomic sequences.

reference link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010268#sec001

More information: Gábor Kemenesi et al, Isolation of infectious Lloviu virus from Schreiber’s bats in Hungary, Nature Communications (2022). DOI: 10.1038/s41467-022-29298-1


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