Bat Rabies Virus Variant Research Articles

Gene Expression Profile Induced by Two Different Variants of Street Rabies Virus in Mice.

Pathogenicity and pathology of rabies virus (RABV) varies according to the variant, but the mechanisms are not completely known. In this study, gene expression profile in brains of mice experimentally infected with RABV isolated from a human case of dog rabies (V2) or vampire bat-acquired rabies (V3) were analyzed. In total, 138 array probes associated with 120 genes were expressed differentially between mice inoculated with V2 and sham-inoculated control mice at day 10 post-inoculation. A single probe corresponding to an unannotated gene was identified in V3 versus control mice. Gene ontology (GO) analysis revealed that all of the genes upregulated in mice inoculated with V2 RABV were involved in the biological process of immune defense against pathogens. Although both variants are considered pathogenic, inoculation by the same conditions generated different gene expression results, which is likely due to differences in pathogenesis between the dog and bat RABV variants. This study demonstrated the global gene expression in experimental infection due to V3 wild-type RABV, from the vampire bat Desmodus rotundus, an important source of infection for humans, domestic animals and wildlife in Latin America.

Canine rabies in Rio Grande do Sul caused by an insectivorous bat rabies virus variant

Rabies is caused by rabies virus (RV), a RNA virus member of the Lyssavirus genus, family Rhabdoviridae . The aim of this study was to determine antigenic characteristics of a rabies virus isolate (RV183-07) recovered from a stray bitch that died of rabies and to infer the most likely source of contamination, since no urban rabies has been reported in the area in more than 20 years. The virus was identified by direct immunofluorescence and multiplied by one passage in mice. The antigenic profile of the isolate was determined with a panel of monoclonal antibodies to lyssavirus antigens on infected brain tissues. A fragment of the viral genome corresponding to the nucleoprotein (N) gene was submitted to reverse transcription/polymerase chain reaction and the amplicon obtained was subjected to restriction enzyme analysis. A 303 base pair fragment of the N gene was cloned, sequenced and compared to other RV sequences available at Genbank. The isolate RV183-07 displayed antigenic and genomic characteristics of rabies virus variants whose natural reservoir is the non-hematophagous bat Tadarida brasiliensis . Therefore, the most likely source of contamination of the bitch was an incidental contact with an infected bat of that species, common inhabitants of the area. In view of that, the status of “urban rabies-free” of the area was not compromised.

In Vivo Efficacy of a Cocktail of Human Monoclonal Antibodies (CL184) Against Diverse North American Bat Rabies Virus Variants.

Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally.

A Systematic Review of Human Bat Rabies Virus Variant Cases: Evaluating Unprotected Physical Contact with Claws and Teeth in Support of Accurate Risk Assessments.

In the United States and Canada, the most recent documented cases of rabies have been attributed to bat rabies viruses (RABV). We undertook this systematic review in an effort to summarize and enhance understanding of the risk of infection for individuals who have been potentially exposed to a suspect or confirmed rabid bat. United States rabies surveillance summaries documented a total of 41 human bat-rabies virus variant verified non-transplant cases between 1990 and 2015. All cases were fatal. Seven (17.1%) of 41 cases reported a bite from a bat. Ten (24.3%) cases had unprotected physical contact (UPC); these included seven cases that had a bat land or crawl on them (contact with claws) and one case that touched a bat’s teeth. Seven (17.1%) cases had probable UPC. Insectivorous bat teeth are extremely sharp and highly efficient for predation upon arthropod prey. Bats also have sharp claws on the end of their thumbs and feet. One of the most common bat RABV variants has an ability to replicate in non-neural cells. Questioning individuals about unprotected contact with bat teeth and claws (including a bat landing or crawling on a person) may help identify additional exposures.

Clinical Features of Dog- and Bat-Acquired Rabies in Humans

Clinical differences in rabies due to canine and bat rabies virus variants have been noted, but no detailed studies have been reported to support these observations. Using the Morbidity and Mortality Weekly Report and PubMed, we identified 142 case reports of rabies from North America, South America, Europe, Africa, and Asia. We systematically abstracted 126 selected data elements and compared clinical features and investigation results in dog- and bat-acquired cases of rabies. Survivors and cases acquired from aerosolized viral exposure or tissue/organ transplant were excluded (n = 20). Of 122 cases, 49 (40.2%) were dog-acquired and 54 (44.3%) were bat-acquired. Bat-acquired cases of rabies were more often misdiagnosed and lacked a bite history. Encephalopathy, hydrophobia, and aerophobia were more common in dog-acquired rabies. Abnormal cranial nerve, motor, and sensory examinations, tremor, myoclonus, local sensory symptoms, symptoms at the exposure site, and local symptoms in the absence of a bite or scratch were more common in patients with bat-acquired rabies, as was increased cerebrospinal fluid protein (P = .031). Patients with paralytic rabies had longer survival times than those with encephalitic rabies, and also had shorter incubation periods if they had received postexposure prophylaxis. Clinical differences in dog- and bat-acquired rabies may reflect differences in the route of viral spread of rabies virus variants in the nervous system, although certain variants could cause more severe dysfunction in neuronal subpopulations. Recognition that bat-acquired rabies may present with different clinical manifestations than dog-acquired rabies may help improve the early diagnosis of rabies.

Responses of mice to inoculation with low doses of a bat rabies virus variant

Rabies is generally considered a fatal disease, yet neutralizing antibodies to rabies virus (RV) have frequently been found in sera from healthy, insectivorous bats, and mark-recapture studies have demonstrated bats that are still alive years after the first detection of anti-RV antibodies. To explore this phenomenon, we exposed mice to a big brown bat variant of RV, using three routes of inoculation, two doses of virus and two frequencies of exposure. We found the highest rate of seroconversion without mortality in mice that received repeated intramuscular inoculation of the higher dose of virus, and mice inoculated intranasally experienced the highest mortality.

Community survey after rabies outbreaks, Flagstaff, Arizona, USA.

Flagstaff, Arizona, USA, experienced notable outbreaks of rabies caused by a bat rabies virus variant in carnivore species in 2001, 2004, 2005, 2008, and 2009. The most recent epizootic involved transmission among skunk and fox populations and human exposures. Multiple, wide-ranging control efforts and health communications outreach were instituted in 2009, including a household survey given to community members. Although the Flagstaff community is knowledgeable about rabies and the ongoing outbreaks in general, gaps in knowledge about routes of exposure and potential hosts remain. Future educational efforts should include messages on the dangers of animal translocation and a focus on veterinarians and physicians as valuable sources for outreach. These results will be useful to communities experiencing rabies outbreaks as well as those at current risk.

Trends in National Surveillance Data for Bat Rabies in the United States: 2001–2009

Rabies remains an important public health concern in the United States, with most human cases associated with bat rabies virus variants. Cases of rabies virus (RV) infection in bats are widely distributed across the continental United States and elsewhere in the Americas. In this retrospective study, data on bats submitted to state laboratories for RV diagnosis between 2001 and 2009 were analyzed to investigate epidemiological trends in the United States. Season, region, and roosting habits were the primary risk factors of interest. During the study interval, more than 205,439 bats were submitted for RV diagnosis, and 6.7% of these bats were rabid. Increased odds of a submitted bat being rabid were associated with species that exhibit inconspicuous roosting habits, bats originating in the Southwest, and bats submitted for diagnosis during the fall. Periodic analysis of zoonotic disease surveillance is recommended to detect changes in trends regarding geographic distribution, seasonal fluctuations, and host associations; this is particularly necessary, as existing trends may be influenced by climate change or other emerging factors.

Rabies surveillance in the United States during 2010

During 2010, 48 states and Puerto Rico reported 6,154 rabid animals and 2 human rabies cases to the CDC, representing an 8% decrease from the 6,690 rabid animals and 4 human cases reported in 2009. Hawaii and Mississippi did not report any laboratory-confirmed rabid animals during 2010. Approximately 92% of reported rabid animals were wildlife. Relative contributions by the major animal groups were as follows: 2,246 raccoons (36.5%), 1,448 skunks (23.5%), 1,430 bats (23.2%), 429 foxes (6.9%), 303 cats (4.9%), 71 cattle (1.1 %), and 69 dogs (1.1 %). Compared with 2009, number of reported rabid animals decreased across all animal types with the exception of a 1 % increase in the number of reported rabid cats. Two cases of rabies involving humans were reported from Louisiana and Wisconsin in 2010. Louisiana reported an imported human rabies case involving a 19-year-old male migrant farm worker who had a history of a vampire bat (Desmodus rotundus) bite received while in Mexico. This represents the first human rabies case reported in the United States confirmed to have been caused by a vampire bat rabies virus variant. Wisconsin reported a human rabies case involving a 70-year-old male that was confirmed to have been caused by a rabies virus variant associated with tri-colored bats (Perimyotis subflavus).

Rabies surveillance in the United States during 2009

During 2009, 49 states and Puerto Rico reported 6,690 rabid animals and 4 human rabies cases to the CDC, representing a 2.2% decrease from the 6,841 rabid animals and 2 human cases reported in 2008. Approximately 92% of reported rabid animals were wildlife. Relative contributions by the major animal groups were as follows: 2,327 (34.8%) raccoons, 1,625 (24.3%) bats, 1,603 (24.0%) skunks, 504 (75%) foxes, 300 (4.5%) cats, 81 (1.2%) dogs, and 74 (1.1%) cattle. Compared with 2008, numbers of rabid raccoons and bats that were reported decreased, whereas numbers of rabid skunks, foxes, cats, cattle, dogs, and horses that were reported increased. Fewer rabid raccoons, compared with 2008, were reported by 12 of the 20 eastern states where raccoon rabies is enzootic, and number of rabid raccoons decreased by 2.6% overall nationally. Despite a 10% decrease in the number of rabid bats that were reported and a decrease in the total number of bats submitted for testing, bats were the second most commonly submitted animal, behind cats, during 2009. The number of rabid skunks that were reported increased by 0.9% overall. The proportion of rabid skunks in which infection was attributed to the raccoon rabies virus variant decreased from 473% in 2008 to 40.9% in 2009, resulting in a 12.7% increase in the number of rabid skunks infected with a skunk rabies virus variant. The number of rabid foxes increased 11.0% overall from the previous year. Four cases of rabies involving humans were reported from Texas, Indiana, Virginia, and Michigan. The Texas case represented the first presumptive abortive human rabies case, with the patient recovering after the onset of symptoms without intensive care. The Indiana and Michigan cases were associated with bat rabies virus variants. The human rabies case in Virginia was associated with a canine rabies virus variant acquired during the patient's travel to India.

Rabies surveillance in the United States during 2006

During 2006, 49 states and Puerto Rico reported 6,940 cases of rabies in animals and 3 cases in humans to the CDC, representing an 8.2% increase from the 6,417 cases in animals and 1 case in a human reported in 2005. Approximately 92% of the cases were in wildlife, and 8% were in domestic animals. Relative contributions by the major animal groups were as follows: 2,615 raccoons (37.7%), 1,692 bats (24.4%), 1,494 skunks (21.5%), 427 foxes (6.2%), 318 cats (4.6%), 82 cattle (1.2%), and 79 dogs (1.1%). Compared with numbers of reported cases in 2005, cases in 2006 increased among all groups except cattle. Increases in numbers of rabid raccoons during 2006 were reported by 11 of the 20 eastern states where raccoon rabies was enzootic, and reported cases increased by 3.2% overall, compared with 2005. On a national level, the number of rabies cases in skunks during 2006 increased by 6.1% from the number reported in 2005. Once again, Texas reported the greatest number (n = 351) of rabid skunks and the greatest overall state total of animal rabies cases (889). No cases of rabies associated with the dog/coyote rabies virus variant were reported. The last identified case of this canine rabies virus variant was identified in March 2004, along the US/Mexico border. With 2006 marking the second year of no apparent transmission of the dog/coyote variant, these findings from surveillance data support the contention that the canine rabies virus variant is no longer in circulation in the United States. Total number of cases of rabies reported nationally in foxes increased 13.6%, compared with 2005. Increases in the number of reported rabid foxes were attributable to greater numbers of foxes reported with the Arctic fox rabies virus variant in Alaska, the Texas gray fox rabies virus variant in Texas, and the raccoon rabies virus variant in Virginia. The 1,692 cases of rabies reported in bats represented a 14.5% increase, compared with numbers reported in 2005, making bats the second most reported rabid animal behind raccoons. Cases of rabies in cats, dogs, horses and mules, and sheep and goats increased 18.2%, 3.9%, 12.8%, and 22.2%, respectively, whereas cases reported in cattle decreased 11.8%. In Puerto Rico, reported cases of rabies in mongooses increased 9.2%, and rabies in domestic animals, presumably attributable to spillover infection from mongooses, increased 20%. Three cases of human rabies were reported from Texas, Indiana, and California during 2006. The cases in Indiana and Texas were attributed to bat rabies virus variants, whereas the case in California was attributed to an exposure to a dog in the Philippines.

Update on rabies.

Rabies remains an important public health problem worldwide due to endemic dog rabies in developing countries. Rabies was a re-emerging disease in the United States during the 1990s due to bat rabies virus variants. Australian bat lyssavirus also emerged in Australian bat populations and caused two human deaths. There have been important recent advances in our knowledge of the pathogenesis of rabies and in our ability to diagnose and prevent it.

Silver-haired bat rabies virus variant does not induce apoptosis in the brain of experimentally infected mice.

To examine whether induction of apoptosis plays a role in the pathogenesis of street rabies, we compared the distribution of viral antigens, histopathology, and the induction of apoptosis in the brain of mice infected with a street rabies virus (silver-haired bat rabies virus, SHBRV) and with a mouse-adapted laboratory rabies virus strain (challenge virus standard, CVS-24). Inflammation was identified in the meninges, but not in the parenchyma of the brain of mice infected with either CVS-24 or SHBRV. Necrosis was present in numerous cortical, hippocampal, and Purkinje neurons in CVS-24-infected mice, but only minimal necrosis was identified in mice infected with SHBRV. Likewise, extensive terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining was observed in the brain of mice infected with CVS-24 but little or none in the brain of mice infected with SHBRV. Rabies virus antigens were distributed similarly in the CNS infected with either virus. However, the expression of the glycoprotein (G) is more widespread and the staining of G is generally stronger in CVS- than SHBRV-infected mice, whereas the expression of rabies virus nucleoprotein (N) is similar in mice infected with either CVS or SHBRV. The positive TUNEL staining thus correlates with the high level of G expression in CVS-infected mouse brain. Northern blot hybridization revealed that the ratio between the N and G transcripts is similar in brains infected with either virus, indicating that the reduced expression of G protein is not caused by reduced transcription in SHBRV-infected animals. Taken together, these observations suggest that apoptosis is not an essential pathogenic mechanism for the outcome of a street rabies virus infection and that other pathologic processes may contribute to the profound neuronal dysfunction characteristic of street rabies.