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Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats.

ABSTRACT: Bats are important reservoirs for emerging infectious diseases, yet the mechanisms that allow highly virulent pathogens to persist within bat populations remain obscure. In Latin America, vampire-bat-transmitted rabies virus represents a key example of how such uncertainty can impede efforts to prevent cross-species transmission. Despite decades of agricultural and human health losses, control efforts have had limited success. To establish persistence mechanisms of vampire-bat-transmitted rabies virus in Latin America, we use data from a spatially replicated, longitudinal field study of vampire bats in Peru to parameterize a series of mechanistic transmission models. We find that single-colony persistence cannot occur. Instead, dispersal of bats between colonies, combined with a high frequency of immunizing nonlethal infections, is necessary to maintain rabies virus at levels consistent with field observations. Simulations show that the strong spatial component to transmission dynamics could explain the failure of bat culls to eliminate rabies and suggests that geographic coordination of control efforts might reduce transmission to humans and domestic animals. These findings offer spatial dynamics as a mechanism for rabies persistence in bats that might be important for the understanding and control of other bat-borne pathogens.

SUBMITTER: Blackwood JC

PROVIDER: S-EPMC3870737 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats.

Blackwood Julie C JC Streicker Daniel G DG Altizer Sonia S Rohani Pejman P

Proceedings of the National Academy of Sciences of the United States of America 20131202 51

Bats are important reservoirs for emerging infectious diseases, yet the mechanisms that allow highly virulent pathogens to persist within bat populations remain obscure. In Latin America, vampire-bat-transmitted rabies virus represents a key example of how such uncertainty can impede efforts to prevent cross-species transmission. Despite decades of agricultural and human health losses, control efforts have had limited success. To establish persistence mechanisms of vampire-bat-transmitted rabies ...[more]

PMID: 24297874

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Project description:BACKGROUND:Animal control measures in Latin America have decreased the incidence of urban human rabies transmitted by dogs and cats; currently most cases of human rabies are transmitted by bats. In 2004-2005, rabies outbreaks in populations living in rural Brazil prompted widespread vaccination of exposed and at-risk populations. More than 3,500 inhabitants of Augusto Correa (Pará State) received either post-exposure (PEP) or pre-exposure (PrEP) prophylaxis. This study evaluated the persistence of rabies virus-neutralizing antibodies (RVNA) annually for 4 years post-vaccination. The aim was to evaluate the impact of rabies PrEP and PEP in a population at risk living in a rural setting to help improve management of vampire bat exposure and provide additional data on the need for booster vaccination against rabies. METHODOLOGY/PRINCIPAL FINDINGS:This prospective study was conducted in 2007 through 2009 in a population previously vaccinated in 2005; study participants were followed-up annually. An RVNA titer >0.5 International Units (IU)/mL was chosen as the threshold of seroconversion. Participants with titers ?0.5 IU/mL or Equivalent Units (EU)/mL at enrollment or at subsequent annual visits received booster doses of purified Vero cell rabies vaccine (PVRV). Adherence of the participants from this Amazonian community to the study protocol was excellent, with 428 of the 509 (84%) who attended the first interview in 2007 returning for the final visit in 2009. The long-term RVNA persistence was good, with 85-88.0% of the non-boosted participants evaluated at each yearly follow-up visit remaining seroconverted. Similar RVNA persistence profiles were observed in participants originally given PEP or PrEP in 2005, and the GMT of the study population remained >1 IU/mL 4 years after vaccination. At the end of the study, 51 subjects (11.9% of the interviewed population) had received at least one dose of booster since their vaccination in 2005. CONCLUSIONS/SIGNIFICANCE:This study and the events preceding it underscore the need for the health authorities in rabies enzootic countries to decide on the best strategies and timing for the introduction of routine rabies PrEP vaccination in affected areas.

Project description:Rabies virus (RABV) P gene mRNA encodes five in-frame start codons, resulting in expression of full-length P protein (P1) and N-terminally truncated P proteins (tPs), designated P2, P3, P4, and P5. Despite the fact that some tPs are known as interferon (IFN) antagonists, the importance of tPs in the pathogenesis of RABV is still unclear. In this study, to examine whether tPs contribute to pathogenesis, we exploited a reverse genetics approach to generate CE(NiP)?P2-5, a mutant of pathogenic CE(NiP) in which the P gene was mutated by replacing all of the start codons (AUG) for tPs with AUA. We confirmed that while CE(NiP) expresses detectable levels of P2 and P3, CE(NiP)?P2-5 has an impaired ability to express these tPs. After intramuscular inoculation, CE(NiP)?P2-5 caused significantly lower morbidity and mortality rates in mice than did CE(NiP), indicating that tPs play a critical role in RABV neuroinvasiveness. Further examinations revealed that this less neuroinvasive phenotype of CE(NiP)?P2-5 correlates with its impaired ability to replicate in muscle cells, indicative of the importance of tPs in viral replication in muscle cells. We also demonstrated that CE(NiP)?P2-5 infection induced a higher level of Ifn-? gene expression in muscle cells than did CE(NiP) infection, consistent with the results of an IFN-? promoter reporter assay suggesting that all tPs function to antagonize IFN induction in muscle cells. Taken together, our findings strongly suggest that tPs promote viral replication in muscle cells through their IFN antagonist activities and thereby support infection of peripheral nerves.Despite the fact that previous studies have demonstrated that P2 and P3 of RABV have IFN antagonist activities, the actual importance of tPs in pathogenesis has remained unclear. Here, we provide the first evidence that tPs contribute to the pathogenesis of RABV, especially its neuroinvasiveness. Our results also show the mechanism underlying the neuroinvasiveness driven by tPs, highlighting the importance of their IFN antagonist activities, which support viral replication in muscle cells.

Dataset Information

Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats.

Publications

Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats.

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