Phnom Penh, Cambodia
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Straimer J.,Columbia University | Gnadig N.F.,Columbia University | Witkowski B.,Institute Pasteur in Cambodia | Amaratunga C.,National Institute of Allergy and Infectious Diseases | And 16 more authors.
Science | Year: 2015

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. © 2015, American Association for the Advancement of Science. All rights reserved.


Wang K.,CAS Institut Pasteur of Shanghai | Deubel V.,CAS Institut Pasteur of Shanghai | Deubel V.,Institute Pasteur in Cambodia
PLoS ONE | Year: 2011

Background: Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes public health problems in Asian countries. Only a limited number of JEV-infected individuals show symptoms and develop severe encephalitis, indicating host-dependent susceptibilities. Methodology/Principal Findings: C3H/HeN and DBA/2 mice, which exhibit different mortalities when infected by intraperitoneal inoculation with JEV, were used as experimental models to compare viral pathogenesis and host responses. One hundred infectious virus particles killed 95% of C3H/HeN mice whereas only 40% of DBA/2 mice died. JEV RNA was detected with similar low levels in peripheral lymphoid organs and in the sera of both mouse strains. High levels of viral and cytokine RNA were observed simultaneously in the brains of C3H/HeN and DBA/2 mice starting on days 6 and 9 post-infection, respectively. The kinetics of the cytokines in sera correlated with the viral replication in the brain. Significantly earlier and higher titers of neutralizing antibodies were detected in the DBA/2 strain. Primary embryonic fibroblasts, bone marrow-derived dendritic cells and macrophages from the two mouse strains were cultured. Fibroblasts displayed similar JEV replication abilities, whereas DBA/2-derived myeloid antigen-presenting cells had lower viral infectivity and production compared to the C3H/HeN-derived cells. Conclusions/Significance: Mice with different susceptibilities to JEV neuroinvasion did not show changes in viral tropism and host innate immune responses prior to viral entry into the central nervous system. However, early and high neutralizing antibody responses may be crucial for preventing viral neuroinvasion and host fatality. In addition, low permissiveness of myeloid dendritic cells and macrophages to JEV infection in vitro may be elements associated with late and decreased mouse neuroinvasion. © 2011 Wang, Deubel.


Horm S.V.,Institute Pasteur in Cambodia | Gutierrez R.A.,Institute Pasteur in Cambodia | Sorn S.,National Veterinary Research Institute | Buchy P.,Institute Pasteur in Cambodia
Influenza and other Respiratory Viruses | Year: 2012

Background Very little is known regarding the persistence of highly pathogenic avian influenza H5N1 viruses in natural settings during outbreaks in tropical countries, although environmental factors may well play a role in the persistence and in the transmission of H5N1 virus. Objective To investigate various environmental compartments surrounding outbreak areas as potential sources for H5N1 virus transmission. Methods Environmental specimens were collected following outbreaks of avian influenza in Cambodia between April 2007 and February 2010. The methods used to concentrate H5N1 virus from water samples were based either on agglutination of the virus with chicken red blood cells or on adsorption on glass wool, followed by an elution-concentration step. An elution-concentration method was used for mud specimens. All samples that tested positive by real-time RT-PCRs (qRT-PCRs) targeting the HA5, M and NA1 genes were inoculated into embryonated hen eggs for virus isolation. Results Of a total of 246 samples, 46 (19%) tested positive for H5N1 by qRT-PCRs. Viral RNA was frequently detected in dust, mud and soil samples from the farms' environment (respectively, 46%, 31% and 15%). Samples collected from ponds gave a lower proportion of positive samples (6%) as compared to those collected from the farms (24%). In only one sample, infectious virus particles were successfully isolated. Conclusion During H5N1 virus outbreaks, numerous environmental samples surrounding outbreak areas are contaminated by the virus and may act as potential sources for human and/or animal contamination. © 2012 Blackwell Publishing Ltd.


Horm S.V.,Institute Pasteur in Cambodia | Sorn S.,Institute Pasteur in Cambodia | Allal L.,Food and Agriculture Organization | Buchy P.,Institute Pasteur in Cambodia
Emerging Infectious Diseases | Year: 2013

In Cambodia, influenza A(H5N1) virus surveillance at live poultry markets (LPMs) relies on virus isolation from poultry specimens; however, virus is rarely detected by this method. We tested 502 environmental LPM samples: 90 were positive by PCR, 10 by virus isolation. Virus circulation could be better monitored by environmental sampling of LPMs.


Popovici J.,Institute Pasteur in Cambodia | Menard D.,Institute Pasteur in Cambodia
Trends in Molecular Medicine | Year: 2015

Plasmodium vivax is the most widespread human malaria parasite, but has received much less attention than Plasmodium falciparum during the past 50 years of research. Plasmodium vivax was historically seen as causing only benign disease, but this view has recently changed, with increased recognition of the burden of vivax malaria, as well as numerous case reports of severe malaria or death caused by this parasite. The complexity of P. vivax biology is characteristic of specific features of the parasite, and recent years have seen major progress in our understanding of this complexity. In this review, we analyze the latest advances in the field, describing the constraints that the unique features of P. vivax place on drug treatments aimed at controlling or eliminating it. © 2015 Published by Elsevier Ltd.


Blasdell K.,Institute Pasteur in Cambodia
EcoHealth | Year: 2011

In order to evaluate the circulation of hantaviruses present in southeast Asia, a large scale survey of small mammal species was carried out at seven main sites in the region (Cambodia, Lao People's Democratic Republic, and Thailand). Small scale opportunistic trapping was also performed at an eighth site (Cambodia). Using a standard IFA test, IgG antibodies reacting to Hantaan virus antigens were detected at six sites. Antibody prevalence at each site varied from 0 to 5.6% with antibodies detected in several rodent species (Bandicota indica, B. savilei, Maxomys surifer, Mus caroli, M. cookii, Rattus exulans, R. nitidius, R. norvegicus, and R. tanezumi). When site seroprevalence was compared with site species richness, seropositive animals were found more frequently at sites with lower species richness. In order to confirm which hantavirus species were present, a subset of samples was also subjected to RT-PCR. Hantaviral RNA was detected at a single site from each country. Sequencing confirmed the presence of two hantavirus species, Thailand and Seoul viruses, including one sample (from Lao PDR) representing a highly divergent strain of Seoul virus. This is the first molecular evidence of hantavirus in Lao PDR and the first reported L segment sequence data for Thailand virus.


Leang R.,National Center for Parasitology | Barrette A.,World Health Organization | Bouth D.M.,World Health Organization | Menard D.,World Health Organization | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

We describe here the results of antimalarial therapeutic efficacy studies conducted in Cambodia from 2008 to 2010. A total of 15 studies in four sentinel sites were conducted using dihydroartemisinin-piperaquine (DP) for the treatment of Plasmodium falciparum infection and chloroquine (CQ) and DP for the treatment of P. vivax infection. All studies were performed according to the standard World Health Organization protocol for the assessment of antimalarial treatment efficacy. Among the studies of DP for the treatment of P. falciparum, an increase in treatment failure was observed in the western provinces. In 2010, the PCRcorrected treatment failure rates for DP on day 42 were 25% (95% confidence interval [CI]=10 to 51%) in Pailin and 10.7% (95% CI4 to 23%) in Pursat, while the therapeutic efficacy of DP remained high (100%) in Ratanakiri and Preah Vihear provinces, located in northern and eastern Cambodia. For the studies of P. vivax, the day 28 uncorrected treatment failure rate among patients treated with CQ ranged from 4.4 to 17.4%; DP remained 100% effective in all sites. Further study is required to investigate suspected P. falciparum resistance to piperaquine in western Cambodia; the results of in vitro and molecular studies were not found to support the therapeutic efficacy findings. The emergence of artemisinin resistance in this region has likely put additional pressure on piperaquine. Although DP appears to be an appropriate new first-line treatment for P. vivax in Cambodia, alternative treatments are urgently needed for P. falciparum-infected patients in western Cambodia. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Beaute J.,Institute Pasteur in Cambodia
BMC public health | Year: 2010

Dengue is endemic in Cambodia (pop. estimates 14.4 million), a country with poor health and economic indicators. Disease burden estimates help decision makers in setting priorities. Using recent estimates of dengue incidence in Cambodia, we estimated the cost of dengue and its burden using disability adjusted life years (DALYs). Recent population-based cohort data were used to calculate direct and productive costs, and DALYs. Health seeking behaviors were taken into account in cost estimates. Specific age group incidence estimates were used in DALYs calculation. The mean cost per dengue case varied from US$36 - $75 over 2006-2008 respectively, resulting in an overall annual cost from US$3,327,284 in 2008 to US$14,429,513 during a large epidemic in 2007. Patients sustain the highest share of costs by paying an average of 78% of total costs and 63% of direct medical costs. DALY rates per 100,000 individuals ranged from 24.3 to 100.6 in 2007-2008 with 80% on average due to premature mortality. Our analysis confirmed the high societal and individual family burden of dengue. Total costs represented between 0.03 and 0.17% of Gross Domestic Product. Health seeking behavior has a major impact on costs. The more accurate estimate used in this study will better allow decision makers to account for dengue costs particularly among the poor when balancing the benefits of introducing a potentially effective dengue vaccine.


Kruy S.L.,Institute Pasteur in Cambodia | Van Cuyck H.,Biology Clinic Laboratory | Koeck J.L.,Biology Clinic Laboratory
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2011

Genomic analysis of Salmonella enterica revealed the existence of a variable number of tandem repeats (VNTR) at multiple loci. Some S. enterica strains are considered as references (Typhi Ty2, Typhi CT18, Typhimurium LT2, Enteritidis LK5, PT4, and Enteritidis 07-2642, and Newport). These allowed the selection of markers to develop the genotyping technique, multiple-locus VNTR analysis (MLVA). These markers were used to discriminate S. enterica isolated from humans, food, or the environment. In this report, the characteristics and specifications of 58 salmonella markers described from 2003 to 2009 are analyzed. Some VNTR loci were used as markers. The markers were used to discriminate S. enterica isolates from different sources and geographical localizations. Among the VNTR loci described in the published reports, eight presented with a high diversity index (DI) of polymorphism of more than 0.80. The selection of several markers within a single locus validated their polymorphism characteristic. Despite unequal DI values, the use of a panel of markers is a powerful discriminatory tool for the surveillance and identification of the source of salmonella outbreak. Depending on the markers selected, MLVA should be used either for macro- or microepidemiological purposes. The main challenge in the future for this technique is standardization. © Springer-Verlag 2010.


Baron S.,Institute Pasteur in Cambodia | Goutard F.,Institute Pasteur in Cambodia | Goutard F.,AGIRs unit | Nguon K.,Institute Pasteur in Cambodia | Tarantola A.,Institute Pasteur in Cambodia
Journal of Medical Internet Research | Year: 2013

Background: There is no functional pharmacovigilance system in Cambodia to our knowledge. Mobile phone-based tools, such as short message service (SMS) text messages, are increasingly used for surveillance purposes. Objective: To pilot-test the FrontlineSMS mobile phone-based tool for notification of adverse events, using Cambodia's only International Vaccination Center at the Institut Pasteur du Cambodge as a field site. Methods: People receiving vaccinations, aged over 18 years, and who owned a cell phone were recruited in the study following informed consent. The names and mobile phone numbers of the participants interviewed were entered each day into the FrontlineSMS software. Two days after being vaccinated, participants received an automatically generated SMS text message asking whether any adverse events had occurred. Their SMS reply was number-coded and exported from the software daily to an Excel spreadsheet and examined before being saved. If the participant replied with a code for a severe adverse event (8 or 9), they were automatically advised to consult the nearest doctor. Results: The active surveillance study was conducted over 72 days in the spring of 2012. Patients agreed to be asked by SMS text message whether unwanted events had occurred after vaccination. Of 1331 persons aged over 18 years referred to the vaccination unit, 184 (13.8%) were asked and agreed to participate. When texted for clinical status 48 hours after vaccination, 52 (28.3%) participants did not reply, 101 (54.9%) sent an immediate SMS reply, and 31 (16.8%) sent an SMS reply after additional prompting. Of the initial 184 participants, 132 (71.7%) replied. These 132 participants received 135 vaccine doses and 109 (82.6%) reported no adverse events, whereas 23 (17.4%) reported adverse events, all benign. Conclusions: Notification using an SMS-based text message system is already used in Cambodia for syndromic surveillance in health centers and reporting by health care workers. Our results show that such tools can also be useful for notification by patients or health users in Cambodia, especially in an urban setting.

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