Posts Tagged ‘Africa’

Ebola virus glycoprotein and virulence – it’s complicated

Monday, August 13th, 2012

Ebola virus With Ebola virus in the news again, a new paper in PLoS Pathogens is highly topical.

Most Ebola virus species cause severe hemorrhagic fevers with high case fatality rates. However, Reston ebolavirus (REBOV) seems to be apathogenic for humans. While the reason for this is unknown, several lines of in vitro research have indicated that the viral glycoprotein (GP) may play a critical role in determining pathogenicity, although until now there was no data to support such a role in the context of an in vivo infection. In order to address this researchers built a novel reverse genetics system to facilitate rescue of REBOV entirely from cDNA, which together with a previously established full-length clone system for the highly pathogenic Zaire ebolavirus (ZEBOV) allowed them to generate chimeras in which the glycoprotein genes from these two viruses have been exchanged.

While exchange of the virus glycoprotein did not affect virus growth in cell culture, infection expressing Reston ebolavirus glycoprotein resulted in decreased virulence in a mouse model of infection. Recombinant Reston ebolavirus glycoprotein did not show any signs of virulence in this model, similar to wild-type recombinant REBOV, showing that while GP contributes significantly to filovirus virulence, it is clearly not the sole determinant of pathogenicity.

 

The Ebola Virus Glycoprotein Contributes to but Is Not Sufficient for Virulence In Vivo. (2012) PLoS Pathogens 8(8): e1002847. doi:10.1371/journal.ppat.1002847
Among the Ebola viruses most species cause severe hemorrhagic fever in humans; however, Reston ebolavirus (REBOV) has not been associated with human disease despite numerous documented infections. While the molecular basis for this difference remains unclear, in vitro evidence has suggested a role for the glycoprotein (GP) as a major filovirus pathogenicity factor, but direct evidence for such a role in the context of virus infection has been notably lacking. In order to assess the role of GP in EBOV virulence, we have developed a novel reverse genetics system for REBOV, which we report here. Together with a previously published full-length clone for Zaire ebolavirus (ZEBOV), this provides a unique possibility to directly investigate the role of an entire filovirus protein in pathogenesis. To this end we have generated recombinant ZEBOV (rZEBOV) and REBOV (rREBOV), as well as chimeric viruses in which the glycoproteins from these two virus species have been exchanged (rZEBOV-RGP and rREBOV-ZGP). All of these viruses could be rescued and the chimeras replicated with kinetics similar to their parent virus in tissue culture, indicating that the exchange of GP in these chimeric viruses is well tolerated. However, in a mouse model of infection rZEBOV-RGP demonstrated markedly decreased lethality and prolonged time to death when compared to rZEBOV, confirming that GP does indeed contribute to the full expression of virulence by ZEBOV. In contrast, rREBOV-ZGP did not show any signs of virulence, and was in fact slightly attenuated compared to rREBOV, demonstrating that GP alone is not sufficient to confer a lethal phenotype or exacerbate disease in this model. Thus, while these findings provide direct evidence that GP contributes to filovirus virulence in vivo, they also clearly indicate that other factors are needed for the acquisition of full virulence.

A single vaccine against both rabies and Ebola virus

Wednesday, August 31st, 2011

Gorilla Researchers have developed a single vaccine which protects against both rabies and Ebola virus. These two viruses are related to each other, but do not cross-react serologically. By inserting elements of the Ebola virus GP protein into an existing rabies virus vaccine, a single bivalent vaccine was produced. Although it works in the laboratory, the new vaccine – or something similar based on this first attempt – need to be tested in primates and eventually in humans.

Apart from people, Ebola virus is thought to have eradicated thousands of gorillas, prompting the World Conservation Union to raise their status to “critically endangered” in 2007, the first time a mammal has become critically endangered as a direct result of disease. Vaccination could help prevent future deaths.

 

Inactivated or Live-Attenuated Bivalent Vaccines that Confer Protection against Rabies and Ebola Viruses. J Virol. Aug 17 2011
The search for a safe and efficacious vaccine for Ebola virus continues as no current vaccine candidate is nearing licensure. We have developed (a) replication-competent, (b) replication-deficient, and (c) chemically inactivated rabies virus (RABV) vaccines expressing Zaire ebolavirus (ZEBOV) glycoprotein (GP) using a reverse genetics system based on the SAD B19 RABV wildlife vaccine. ZEBOV GP is efficiently expressed by these vaccine candidates and is incorporated into virions. The vaccine candidates were avirulent after inoculation of adult mice, and viruses with a deletion in the RABV glycoprotein have greatly reduced neurovirulence after intracerebral inoculation in suckling mice. Immunization with live or inactivated RABV vaccines expressing ZEBOV GP induced humoral immunity against each virus and conferred protection from both lethal RABV and EBOV challenge in mice. The bivalent RABV/ZEBOV vaccines described here have several distinct advantages that may speed the development of inactivated vaccines for use in humans and potentially live or inactivated vaccines for endemic nonhuman primates at risk of EBOV infection.

You are what you eat?

Wednesday, August 24th, 2011

Batwa Pygmies The Batwa Pygmies, also known as Twa, are believed to be the original inhabitants of the equatorial forests of the Great Lakes region of Central Africa. They live in southwestern Uganda, northern and southern Rwanda and in many areas of the Kivu province of the Democratic Republic of the Congo (DRC). An interersting feature of the Batwa is that they differ significantly from neighboring Bantu agriculturalists in having fewer caries lesions and reduced tooth loss. Differences in diet and lifestyle provide the most likely explanation for the greater prevalence of caries lesions and tooth loss among the Bantu than among the Batwa. The Batwa have less access to highly cariogenic, refined carbohydrates than do the Bantu. In addition, because of their hunter-gatherer lifestyle, the diet of the Batwa tends to be higher in animal protein than that of the Bantu, and this would also contribute to a lower caries rate.

It is also possible that the oral microbiome of the Batwa may either influence, or be influenced by, the lower prevalence of caries.To investigate this further, researchers analyzed the saliva microbiome diversity of the Batwa in comparison with agricultural groups from similar enviroments in Africa, in order to address the following questions:

  1. How different is the Batwa saliva microbiome from that of African agriculturalists
  2. Is the low level of dental caries in the Batwa associated with particular microbial taxa?

 

High Diversity of the Saliva Microbiome in Batwa Pygmies. 2011 PLoS ONE 6(8): e23352. doi:10.1371/journal.pone.0023352
We describe the saliva microbiome diversity in Batwa Pygmies, a former hunter-gatherer group from Uganda, using next-generation sequencing of partial 16S rRNA sequences. Microbial community diversity in the Batwa is significantly higher than in agricultural groups from Sierra Leone and the Democratic Republic of Congo. We found 40 microbial genera in the Batwa, which have previously not been described in the human oral cavity. The distinctive composition of the salvia microbiome of the Batwa may have been influenced by their recent different lifestyle and diet.

 

As if it wasn’t bad enough

Monday, August 22nd, 2011

Sudan Sudan is a large country with a diverse population and history of civil conflict. Poverty levels are high with a gross national income per capita of less than two thousand dollars. The country has a high burden of tuberculosis (TB) with an estimated 50,000 incident cases during 2009, when the estimated prevalence was 209 cases per 100,000 of the population. Few studies have been undertaken on TB in Sudan and the prevalence of drug resistant disease is not known.

In this study Mycobacterium tuberculosis isolates from 235 patients attending three treatment centers in Sudan were screened for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin by the proportion method on Lowenstein Jensen media. 232 isolates were also genotyped by spoligotyping. Demographic details of patients were recorded using a structured questionnaire. Statistical analyses were conducted to examine the associations between drug resistance with risk ratios computed for a set of risk factors (gender, age, case status – new or relapse, geographic origin of the patient, spoligotype, number of people per room, marital status and type of housing).

Multi drug-resistant tuberculosis (MDR-TB), being resistance to at least rifampicin and isoniazid, was found in 5% of new cases and 24% of previously treated patients. Drug resistance was associated with previous treatment with risk ratios of 3.51 for resistance to any drug and 5.23 for MDR-TB. Resistance was also associated with the geographic region of origin of the patient, being most frequently observed in patients from the Northern region and least in the Eastern region with risk ratios of 7.43 and 14.09 for resistance to any drug and MDR-TB.

“We conclude that emergence of drug resistant tuberculosis has the potential to be a serious public health problem in Sudan and that strengthened tuberculosis control and improved monitoring of therapy is needed. Further surveillance is required to fully ascertain the extent of the problem.”

 

Tuberculosis in Sudan: a study of Mycobacterium tuberculosis strain genotype and susceptibility to anti-tuberculosis drugs. BMC Infectious Diseases 11:219 2011

The Pathogenesis of Rift Valley Fever

Wednesday, May 11th, 2011

Rift Valley fever (RVF), a mosquito-borne zoonotic disease among humans and ruminants, is caused by Rift Valley fever virus (RVFV) belonging to the family Bunyaviridae, genus Phlebovirus. RVF is endemic to sub-Saharan African countries and has caused major outbreaks in several countries including Kenya, Tanzania, Somalia, South Africa, Madagascar, Egypt, Sudan, Mauritania, Senegal, Saudi Arabia, and Yemen. Pregnant ruminants infected with RVFV typically are subject to high- rate abortions, fetal malformation, and subclinical-to-fatal febrile illness, while newborn lambs usually die by acute hepatitis. RVFV infection in humans primarily causes a self-limiting febrile illness; however, some patients develop hemorrhagic fever, neurological disorders, or blindness after the febrile period. In endemic area, floodwater Aedes mosquitoes serve as vectors, and the virus could be transmitted into offspring transovarially. Heavy rainfall or flooding of river banks due to construction of dams increases the number of permanent fresh water species of mosquitoes such as Culex pipens, which play a role in amplifying RVFV among mosquitoes, ruminants and humans. An outbreak of RVF in developed countries, e.g., the U.S. or Europe, could force a curtailing of livestock movement to prevent RVFV spread, causing massive economic loss, and a substantial degree of panic in our society, because the body fluids of infected animals contain infectious RVFV, and mosquitoes such as Culex spp. Aedes spp. or Anopheles spp. might further spread RVFV into other mosquitoes, humans and animals. Effective vaccines and antiviral drugs are necessary for the containment of outbreaks and treatment of RVF patients, respectively. However, neither safe and effective vaccines nor efficient treatment is available. A correct understanding of RVF pathogenesis is essential for the development of effective vaccines and antiviral drugs against RVF. This review describes clinical and pathological findings of RVF in humans and animals and discuss viral and host factors that affect RVF pathogenesis.

Rift Valley Fever

The Pathogenesis of Rift Valley Fever. Viruses 2011, 3(5), 493-519; doi:10.3390/v3050493
Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub-Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted by mosquitoes, and virus replication in domestic ruminant results in high rates of mortality and abortion. RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis.

Human metapneumovirus in wild mountain gorillas

Monday, April 11th, 2011

Mountain gorilla The world’s remaining 786 mountain gorillas (Gorilla beringei beringei) live in 2 parks in Rwanda, Uganda, and the Democratic Republic of the Congo. An ecotourism industry for viewing human-habituated mountain gorillas in the wild is thriving in all 3 countries. Mountain gorilla tourism helps ensure the sustainability of the species by generating much-needed revenue and increasing global awareness of the precarious status of this species in the wild. Tourism, however, also poses a risk for disease transmission from humans to the gorillas.

Habitat encroachment and poaching are threats to wildlife survival, particularly in the developing world. Mountain gorillas face an additional threat from infectious diseases. Second only to trauma, infectious diseases, primarily respiratory, account for 20% of sudden deaths. The close genetic relatedness of mountain gorillas and humans has led to concerns about the potential interspecies transmission of infectious agents. Although most surveillance efforts focus on risk for humans, mountain gorillas are immunologically naive and susceptible to infection with human pathogens. The parks in which mountain gorillas live are surrounded by the densest human populations in continental Africa. In addition, research and gorilla ecotourism brings thousands of persons from the local communities and from around the world into direct and indirect contact with the gorillas. The frequency and closeness of contact is particularly pronounced in Virunga National Park, where 75% of mountain gorillas are habituated to the presence of humans.

To minimize the threat of disease transmission, the Rwandan, Ugandan, and Congolese governments restrict tourist numbers and proximity, and the Congolese wildlife authority mandates that masks be worn by persons visiting gorillas. Nonetheless, the frequency and severity of respiratory disease outbreaks among mountain gorillas in the Virunga Massif have recently increased. From May through August 2008, sequential respiratory outbreaks occurred in 4 groups of mountain gorillas accustomed to tourism in Rwanda. Between June 28 and August 6, 2009, a fifth outbreak occurred in 1 of these groups, Hirwa. This paper describes the Hirwa outbreak. Respiratory outbreaks were defined as more than one third of animals in a group exhibiting signs of respiratory disease (coughing, oculonasal discharge, and/or lethargy).

Human metapneumovirus infection in wild mountain gorillas, Rwanda. Emerg Infect Dis. Apr 2011 doi: 10.3201/eid1704.100883
The genetic relatedness of mountain gorillas and humans has led to concerns about interspecies transmission of infectious agents. Human-to-gorilla transmission may explain human metapneumovirus in two wild mountain gorillas that died during a respiratory disease outbreak in Rwanda in 2009. Surveillance is needed to ensure survival of these critically endangered animals.

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PLoS Pathogens: Measles Outbreak in Africa – Is There a Link to the HIV-1 Epidemic?

Friday, February 11th, 2011

To reduce the risk of contracting measles in areas with high HIV-1 prevalence, WHO recommended that infants receive two doses of measles vaccine, at 6 and 9 months. This regimen was evaluated in Zambia and results published in 2008 showed that 59% of children with HIV-1 were measles antibody positive after the first vaccine dose; this number increased to 64% after the second dose. Among HIV-1-exposed non-infected children, 68% and 94% were seropositive after the first and second immunisation, respectively, and similar figures were shown for control children (62% and 92%). To further pinpoint the B cell impairments leading to low antibody levels after measles vaccination in children with HIV-1, Nair characterised early antibody responses to measles following vaccination at 9 months of age. Interestingly, HIV-1 infection impaired IgG responses after vaccination as well as the development of high avidity measles antibodies. In a study from Kenya, antibody titres to measles were evaluated 2 to 5 years after measles immunisation received during the first year of life. Several years after immunisation, only 33% of the children with HIV-1 maintained measles IgG antibodies, indicating impairment in the establishment and the maintenance of serological memory responses.

PLoS Pathogens: Measles Outbreak in Africa—Is There a Link to the HIV-1 Epidemic?

Understanding the spread of rabies

Friday, November 12th, 2010

Understanding the spread of rabies At least 15 million doses of anti-rabies post-exposure prophylaxis are administered annually worldwide, and an estimated 55,000 people die of rabies every year. Over 99% of these deaths occur in developing countries, predominantly in Asia and in Africa where rabies is endemic in domestic dogs. Despite the global health burden due to rabies, little is known about the patterns of the spread of dog rabies in these endemic regions. A recent paper examines the dynamics and determinants of the spatial diffusion of dog rabies viruses in North Africa based on virus genetic data. This analysis reveals a combination of restricted spread across administrative borders, the occasional long-distance movement of rabies viruses, and a strong fit between spatial spread of the virus and road distances between localities. Together, these data indicate that by transporting dogs, humans have played a key role in the dispersal of a major animal pathogen. This study provides essential new information on the transmission dynamics of rabies in Africa and will greatly assist in future intervention strategies.

Phylodynamics and Human-Mediated Dispersal of a Zoonotic Virus. (2010) PLoS Pathog 6(10): e1001166. doi:10.1371/journal.ppat.1001166
Understanding the role of humans in the dispersal of predominately animal pathogens is essential for their control. We used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. Each of the countries studied exhibited largely disconnected spatial dynamics with major geo-political boundaries acting as barriers to gene flow. Road distances proved to be better predictors of the movement of dog RABV than accessibility or raw geographical distance, with occasional long distance and rapid spread within each of these countries. Using simulations that bridge phylodynamics and spatial epidemiology, we demonstrate that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens.

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World Rabies Day, 28 September

Tuesday, September 28th, 2010

World Rabies Day According to official estimates, rabies kills 55,000 people each year, primarily in India, Southeast Asia and Africa. However, the death toll is probably much higher; one report estimates that the number of deaths in some areas is possibly 100 times that reported. As rabies cases do not need to be reported to the authorities in many countries, and many people do not seek treatment or are misdiagnosed, obtaining an accurate estimate of the overall prevalence is difficult. Even the official death toll is higher than that for diseases such as human African trypanosomiasis, leishmaniasis and Chagas disease.

As with other diseases that are preventable and treatable, such as pneumonia, it seems unthinkable that rabies still claims so many lives. Successful control of rabies in the United Kingdom and the Americas shows that rabies can be controlled and possibly eliminated. Further research will bring us closer to this goal, but it will require funding agencies and governments to better understand the scope of the problem. Until then, important events like World Rabies Day will remain vital to shed light on this neglected problem.

Biting back against rabies. Nature Reviews Microbiology 8: 676 (October 2010) doi:10.1038/nrmicro2451

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