Lyssaviruses are responsible for rabies, which is arguably the deadliest encephalitic disease known. The prototype, rabies lyssavirus (RABV), is thought to be able to infect all terrestrial mammals. Transmission is through virus-laden saliva, typically through the bite of an infected animal, but sometimes through other means such as scratches and in rare occasions, organ transplants and other means (1, 2). The genus Lyssavirus (family Rhabdoviridae) is presently composed of 17 viral species and one putative (3). All lyssaviruses are bullet-shaped particles containing negative sense RNA genomes of approximately 11 000 nucleotides in length. The genome encodes 5 structural proteins, namely the nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and the polymerase (5’-N-P-M-G-L-3’) with a 5’ – 3’ transcriptional bias (4, 5). The N protein encapsidates the viral RNA, and together with the P and L proteins, forms the ribonucleoprotein (RNP) complex, which can initiate viral transcription and replication (6). The M protein condenses the RNP into the characteristic bullet-shape and recruits the RNP to the cellular membrane during replication. The M protein is also essential for the budding of the enveloped virus from the cell and specifically interacts with the G protein – also known as the transmembrane spike protein, which is the primary antigenic determinant (7, 8).

RABV is not only the type species of the genus, but by far poses the most significant public health threat among all the lyssaviruses. The domestic dog is the primary reservoir for RABV in dog-rabies endemic countries, but several other terrestrial mammalian species can maintain transmission – most notably carnivores such as raccoons, skunks, foxes, and jackals.

Globally, an estimated 59,000 people die from dog-mediated rabies every year, of which approximately 40% are children under the age of 15 years (9). Rabies affects the poorest and most underserved communities, with the burden being greatest in developing countries of Africa and Asia (10). However, the disease is seriously underreported for a variety of reasons and remains among the most significant diseases of neglect in the world (11).

By continent, Africa has the second highest burden of rabies, with an estimated 23,500 deaths annually, and has the highest per capita death rate (9). RABV is endemic throughout mainland Africa, with only a handful of island nations having never detected rabies in domestic or wildlife species (e.g., La Réunion, Mayotte, Mauritius) (12).

Of the seventeen recognized lyssavirus species, six confirmed and one putative species have been identified in Africa, namely, RABV, Duvenhage virus (DUVV), Lagos bat lyssavirus (LBV), Mokola lyssavirus (MOKV), Ikoma lyssavirus (IKOV), Shimoni Bat Lyssavirus (SHIBV) and the putative Matlo lyssavirus. Of these, only DUVV (n=3), MOKV (n=2) and RABV have been associated with human fatalities (13). While RABV is only associated with non-volant terrestrial mammals in Africa, DUVV and LBV are both associated with bat reservoirs, while IKOV and MOKV have yet unidentified reservoirs (14, 15).

Upon initial infection, the innate immune response is triggered in the periphery and evidence suggests that this response is partially effective against even the most pathogenic strains, with some viral particles being eliminated (57). However, further clearance is not achieved as pathogenic strains poorly stimulate and inhibit the activation and maturation of dendritic cells, resulting in a poorer antibody immune response (58–60). This prevention of the maturation of DCs is achieved through the inhibition of the interferon (IFN) autocrine feedback loop that is dependent on JAK-STAT signaling, which is specifically inhibited by the P protein (61).

The ability of lyssaviruses to evade the immune response is directly correlated to its pathogenicity, with pathogenic strains inducing a minimal response and successfully evading immune clearance (18). All the RABV proteins are multifunctional, with roles in viral entry, replication and spread, as well as in the sequestration of the immune system – either directly or indirectly (62). This ability is reliant solely on the immune-suppressive capabilities of viral proteins - primarily being the P, G and N proteins. The P protein is typically involved in sequestering the innate immune response by inhibiting the production of multiple antiviral products such as MxA, OAS1 and IFN-stimulated gene products (62). Furthermore, the P protein inhibits type I IFN responses and subsequent innate and adaptive immune responses through the inhibition of various IFN-related signaling pathways (63–67). The evasion of IFN responses in infected neurons is likely to be essential for the spread of RABV through the PNS, enabling the virus to reach the brainstem and eventually the salivary glands for spread to a new host (57). Similarly, the N is also predominantly involved in the sequestration of the innate response, primarily through the inhibition of RIG-I activation (68–70). Apoptosis in macrophages, T cells (including infiltrating T cells in the CNS) and microglia plays an important role in immune evasion and is stimulated by the G protein of pathogenic strains (71, 72), which appears to assist in the effective infiltration, replication and spread of the virus in the CNS (36, 73, 74).

While rabies has arguably been recognized for thousands of years, there remain many gaps in scientific knowledge of the disease and its causal agents. The rapid detection of 10 novel lyssaviruses in the past two decades raises multiple public health concerns, with their broader distribution and possible public health impact being yet unknown (13, 75). While information relating to many of the lyssavirus species remains poor, studies suggest that sustained spillover events from non-RABV lyssaviruses are likely to be rare, as almost all lyssaviruses – except for RABV and ABLV – are restricted to a single host species (76). However, many lyssavirus species have only a single, or few, isolates, including the novel GBLV which has a recent common ancestor with ABLV (56). In addition, host shifts in areas where RABV is endemic are likely to remain undetected due to poor surveillance (76). While host shift events remain rare, their impact can be devastating. North America alone is endemic for multiple terrestrial RABV variants, each being resultant of a host shift event (77). While host shift events may be geographically restricted, the potential for the translocation of the virus through human means remains a distinct possibility and risk (78–81). For example, the largest epizootic in recorded history resulted from the human-mediated translocation of a raccoon from the south-east of the United States to the north-eastern states (82). Further evidence suggests that raccoon rabies was enzootic at low levels for many years before its detection, natural spread, and subsequent human translocation (83). The raccoon RABV variant now accounts for nearly 75% of all terrestrial rabies cases in the USA and resulted in a significant increase in the number of human exposures in those areas where it is endemic (84). Thus, despite the rabies-related viruses not posing a significant health threat at present, continued efforts need to be made to ensure public health safety based on the limited knowledge and surveillance data available.

Despite the availability of an effective prophylactic treatment before the onset of symptoms, there remains no cure once rabies symptoms manifest. In addition, the majority of immunopathological knowledge available pertains to RABV, with limited studies being available for the rabies-related lyssaviruses. Therefore, there is a need for continued investigation into the mechanisms of infection, disease progression, host biology and a better understanding of bat immunology. Over and above, there is a dire need for improved global surveillance for all lyssaviruses. Given the significant public health threat posed by dog-mediated RABV, such surveillance data should play a critical role in the elimination of the disease from those dog populations where it is still rampant due to a failure to effectively break transmission through mass vaccination.

TS: Conception, preparation of first draft, editing and final review. LN: Conception, editing and final review. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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