The spread and evolution of rabies virus: conquering new frontiers

Abstract

Rabies is a lethal zoonotic disease that is caused by lyssaviruses, most often rabies virus. Despite control efforts, sporadic outbreaks in wildlife populations are largely unpredictable, underscoring our incomplete knowledge of what governs viral transmission and spread in reservoir hosts. Furthermore, the evolutionary history of rabies virus and related lyssaviruses remains largely unclear. Robust surveillance efforts combined with diagnostics and disease modelling are now providing insights into the epidemiology and evolution of rabies virus. The immune status of the host, the nature of exposure and strain differences all clearly influence infection and transmission dynamics. In this Review, we focus on rabies virus infections in the wildlife and synthesize current knowledge in the rapidly advancing fields of rabies virus epidemiology and evolution, and advocate for multidisciplinary approaches to advance our understanding of this disease.

Figure 1a:. Cellular life cycle of rabies virus.

In the first phase of the rabies virus (RABV) life cycle, the virus binds to the cell surface receptors via its glycoprotein and enters by endocytosis (step 1). Subsequently, the viral membrane fuses with the endosomal membrane to release the viral genome (uncoating, step 2). In the second phase, the encapsidated negative-stranded RNA genome is transcribed by the polymerase complex, starting with a short uncapped leader RNA (leRNA), followed by the transcription of 5′ end-capped (cap) and polyadenylated (A) mRNAs, and their translation into the viral proteins nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L) (steps 3 and 4). Following replication, the full-length antigenomic RNA is encapsidated in the nucleoprotein protein along with the genomic RNA. The synthesized antigenome functions as a template for the synthesis of additional copies of genomic RNA (step 5). In the last phase, the viral components are assembled and the RABV virions bud and are released, starting a new round of infection (step 6).

Figure 1b:. RABV entry and transport in neurons.

The nicotinic acetylcholine receptor (nAchR) is located at the postsynaptic muscle membrane. It has been suggested that the nAchR receptor enriches RABV at the neuromuscular junction (NMJ, synaptic cleft), enabling more efficient infection of the connected motor neurons. Other research suggests that initial virus amplification occurs in muscle (indicated by the question mark), which indicates that nAchRs might be used to infect muscle cells. RABV can enter neurons by binding to NCAM or another, unknown receptor. Following uptake by clathrin-mediated endocytosis, RABV virions are then transported within the vesicle and are released in the cell body of the infected neurons, where replication and transcription occurs (not shown). Parts a and b modified from Ref

Figure 2:. Lyssavirus transmission dynamics in bats and terrestrial animals.

Lyssaviruses seem to circulate more successfully in bats than in terrestrial mammals. A variety of factors contribute to maintenance, such as general and reservoir-specific viral factors, habitat factors and levels of human interaction. Host-specific factors, especially immune status in bats, are less understood. Although bats die upon clinical manifestation of disease, high rates of seroprevalence seen in healthy bats suggests a high frequency of abortive infection, which occurs through a combination of low exposure dosages, functional innate immune, and presence or development of neutralizing antibodies. Experimental infection studies have shown that bats can develop sub-detectable immunological memory (protection in the absence of neutralizing antibodies). However, there has never been evidence to suggest that a healthy but virus-secreting “carrier” state contributes to maintenance within bat populations. Seroprevalence in non-bats arising from natural exposure (not vaccination) are lower by comparison. Maintenance of RABV in wild and domestic carnivore reservoirs of RABV depends more heavily on variation in life history traits, population density, habitat use and degree of associations with humans. Spillover infections (in humans, for example) almost exclusively result in death before transmission to another host. The biological factors underpinning whether hosts survive or succumb to rabies, if naturally acquired VNAs are protective, and what role this has in the long-term perpetuation of RABV remain unclear.

Figure 3A:. Current continental distribution of bat lyssaviruses.

Rabies disease-causing lyssaviruses circulate on all continents except Antarctica. In the Americas, all variants to date are strains of RABV. By contrast, RABV is largely absent from bats in the rest of the world, but 14 other lyssaviruses have been found in bats, including in Australia and Europe which are otherwise considered RABV-free. 3B: Current continental distribution of terrestrial mammal lyssavirus reservoirs. Most terrestrial lyssavirus reservoirs circulate strains of RABV, except in Africa, where IKOV and MOKV have been found. Europe is considered free of terrestrial RABV on account of vaccination efforts. Rabies in terrestrial mammals has never been reported in Australia. Common reservoirs are indicated.

Figure 4:. The influence of reservoir host ecology on the epidemiology of rabies.

a| The ‘SEI’ model for rabies epidemiology represents transitions of hosts between individuals that are classified as susceptible (S), infected and incubating RABV (‘exposed’ (E), infected and infectious (I) and temporarily immune (T). Both intraspecific transmission and spillover infections to non-reservoir hosts arise from infectious reservoirs in the I class. The force of infection (λ) depends on the frequency of susceptible and infected and infectious individuals in the population, total population size and transmission rate. Solid arrows indicate portions of the transmission cycle that are common to all RABV reservoirs. Dashed arrows may only occur for some reservoir hosts, depending on pathbiological relationships with rabies (see Fig. 2) or human interventions such as the presence of vaccination campaigns. b| Variation in reservoir host ecology influences different phases of the transmission cycle, causing reservoir host-specific transmission dynamics and maintenance mechanisms. Maps show the geographic range of four of the best-studied RABV reservoir hosts, although RABV may be absent from some parts of each species’ range, for example because of changing viral distributions or local eradication efforts. The drivers of transmission dynamics are mapped for each reservoir host to the compartmental model in panel a, to illustrate how ecology affects transmission dynamics. The epidemiological dynamics observed in each reservoir are summarized. Of note, spillover infections to a broad range of species occur from each reservoir; shown are the principle spillover hosts infected by each reservoir.