Mechanisms of escape phenomenon of spinal cord and brainstem in human rabies

BACKGROUND: Rabies virus preferentially involves brainstem, thalamus and spinal cord in human furious and paralytic rabies beginning in the early stage of illness. Nevertheless, rabies patient remains alert until the pre-terminal phase. Weakness of extremities develops only when furious rabies patient becomes comatose; whereas peripheral nerve dysfunction is responsible for weakness in paralytic rabies. METHODS: Evidence of apoptosis and mitochondrial outer membrane permeabilization in brain and spinal cord of 10 rabies patients was examined and these findings were correlated with the presence of rabies virus antigen. RESULTS: Although apoptosis was evident in most of the regions, cytochrome c leakage was relatively absent in spinal cord of nearly all patients despite the abundant presence of rabies virus antigen. Such finding was also noted in brainstem of 5 patients. CONCLUSION: Cell death in human rabies may be delayed in spinal cord and the reticular activating system, such as brainstem, thus explaining absence of weakness due to spinal cord dysfunction and preservation of consciousness

Demyelination of the Peripheral Nervous System Causes Neurologic Signs in Myelin Basic Protein-Induced Experimental Allergic Encephalomyelitis - Implications for the Etiology of Multiple Sclerosis

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease induced by inoculation with whole central nervous system tissue, myelin basic protein or myelin proteolipid protein. It is widely studied as a model of multiple sclerosis, a human CNS demyelinating disease of unknown aetiology. Because of the reported absence of demyelination in some animals with neurologic signs of EAE, it has been suggested that the signs of EAE are due not to demyelination but to oedema. I report that, in myelin basic protein-induced experimental allergic encephalomyelitis in the Lewis rat, the ventral and dorsal spinal roots are principal sites of demyelination, whereas the spinal cord and brain are only slightly demyelinated, although considerably inflamed

Transmission dynamics of rabies virus in Thailand: Implications for disease control

BACKGROUND: In Thailand, rabies remains a neglected disease with authorities continuing to rely on human death statistics while ignoring the financial burden resulting from an enormous increase in post-exposure prophylaxis. Past attempts to conduct a mass dog vaccination and sterilization program have been limited to Bangkok city and have not been successful. We have used molecular epidemiology to define geographic localization of rabies virus phylogroups and their pattern of spread in Thailand. METHODS: We analyzed 239 nucleoprotein gene sequences from animal and human brain samples collected from all over Thailand between 1998 and 2002. We then reconstructed a phylogenetic tree correlating these data with geographical information. RESULTS: All sequences formed a monophyletic tree of 2 distinct phylogroups, TH1 and TH2. Three subgroups were identified in the TH1 subgroup and were distributed in the middle region of the country. Eight subgroups of TH2 viruses were identified widely distributed throughout the country overlapping the TH1 territory. There was a correlation between human-dependent transportation routes and the distribution of virus. CONCLUSION: Inter-regional migration paths of the viruses might be correlated with translocation of dogs associated with humans. Interconnecting factors between human socioeconomic and population density might determine the transmission dynamics of virus in a rural-to-urban polarity. The presence of 2 or more rabies virus groups in a location might be indicative of a gene flow, reflecting a translocation of dogs within such region and adjacent areas. Different approaches may be required for rabies control based on the homo- or heterogeneity of the virus. Areas containing homogeneous virus populations should be targeted first. Control of dog movement associated with humans is essential

Surveillance guidelines for disease elimination: a case study of canine rabies

Surveillance is a critical component of disease control programmes but is often poorly resourced, particularly in developing countries lacking good infrastructure and especially for zoonoses which require combined veterinary and medical capacity and collaboration. Here we examine how successful control, and ultimately disease elimination, depends on effective surveillance. We estimated that detection probabilities of <0.1 are broadly typical of rabies surveillance in endemic countries and areas without a history of rabies. Using outbreak simulation techniques we investigated how the probability of detection affects outbreak spread, and outcomes of response strategies such as time to control an outbreak, probability of elimination, and the certainty of declaring freedom from disease. Assuming realistically poor surveillance (probability of detection <0.1), we show that proactive mass dog vaccination is much more effective at controlling rabies and no more costly than campaigns that vaccinate in response to case detection. Control through proactive vaccination followed by 2 years of continuous monitoring and vaccination should be sufficient to guarantee elimination from an isolated area not subject to repeat introductions. We recommend that rabies control programmes ought to be able to maintain surveillance levels that detect at least 5% (and ideally 10%) of all cases to improve their prospects of eliminating rabies, and this can be achieved through greater intersectoral collaboration. Our approach illustrates how surveillance is critical for the control and elimination of diseases such as canine rabies and can provide minimum surveillance requirements and technical guidance for elimination programmes under a broad-range of circumstances

More Accurate Insight into the Incidence of Human Rabies in Developing Countries through Validated Laboratory Techniques

International audienceNo abstract availabl

Mechanism of Protection Induced by Group A Streptococcus Vaccine Candidate J8-DT: Contribution of B and T-Cells Towards Protection

Vaccination with J8-DT, a leading GAS vaccine candidate, results in protective immunity in mice. Analysis of immunologic correlates of protection indicated a role of J8-specific antibodies that were induced post-immunization. In the present study, several independent experimental approaches were employed to investigate the protective immunological mechanisms involved in J8-DT-mediated immunity. These approaches included the passive transfer of mouse or rabbit immune serum/antibodies in addition to selective depletion of T-cell subsets prior to bacterial challenge. Passive transfer of J8-DT antiserum/antibodies from mice and rabbits conferred significant resistance against challenge to mice. To exclude the possibility of involvement of other host immune factors, the studies were repeated in SCID mice, which highlighted the need for an ongoing immune response for long-lived protection. Depletion of CD4+ and CD8+ T-cell subsets confirmed that an active de novo immune response, involving CD4+ T-helper cells, is required for continued synthesis of antibodies resulting in protection against GAS infection. Taken together these results indicate an involvement of CD4+ T-cells in J8-DT-mediated protection possibly via an ability to maintain antibody levels. These results have considerable relevance to the development of a broad spectrum passive immunotherapy for GAS disease

Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection with RABV. Our results indicate that BMDC activation and type I IFN production following a RABV infection is independent of TLR signaling. However, IPS-1 is essential for both BMDC activation and IFN production. Interestingly, we see that the BMDC activation is primarily due to signaling through the IFNAR and only marginally induced by the initial infection. To further identify the receptor recognizing RABV infection, we next analyzed BMDC from Mda-5−/− and RIG-I−/− mice. In the absence of either receptor, there is a significant decrease in BMDC activation at 12h post infection. However, only RIG-I−/− cells exhibit a delay in type I IFN production. In order to determine the role that IPS-1 plays in vivo, we infected mice with pathogenic RABV. We see that IPS-1−/− mice are more susceptible to infection than IPS-1+/+ mice and have a significantly increased incident of limb paralysis